Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.2 %

Procedure:
A stirred mixture of methyl 2-methyl-3-nitrobenzoate (17.6 g, 87.1 mmol) and N-bromosuccinimide (18.9 g, 105 mmol) in carbon tetrachloride (243 mL) was heated under gentle reflux with a 100 W light bulb situated 2 cm away shining on the reaction mixture overnight. After 18 hours, the reaction mixture was cooled to room temperature and filtered. The filtrate was washed with water (2×120 mL), brine (120 mL), and dried (MgSO4). The solvent was removed in vacuo to give a yellow solid. The product was purified by flash chromatography (hexane:ethyl acetate 8:2) to give 22 g (93%) of methyl 2-bromomethyl-3-nitrobenzoate as a yellow solid: mp 69-72° C.; 1H NMR (CDCl3) δ 8.13-8.09 (dd, J=1.36 and 7.86 Hz, 1H), 7.98-7.93 (dd, J=1.32 and 8.13 Hz, 1H), 7.57-7.51 (t, J=7.97 Hz, 1H), 5.16 (s, 2H), 4.0 (s, 3H); 13C NMR (CDCl3) δ 65.84, 150.56, 134.68, 132.64, 132.36, 129.09, 53.05, 22.70; HPLC: Waters Nova-Pak C18 column, 4 micron, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4(aq), 8.2 min 99%. Anal. Calcd for C9H8NO4Br: C, 39.44; H, 2.94; N, 5.11, Br, 29.15. Found: C, 39.51; H, 2.79; N, 5.02; Br, 29.32.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][CH:66]([CH2:80][C:81]([F:84])([F:83])[F:82])[C:67](=[O:79])[C:68]([NH:70][C:71]1[CH:76]=[CH:75][C:74]([CH3:77])=[CH:73][C:72]=1[CH3:78])=[O:69])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29]C(C)(C)C)=[O:23])[CH2:14][C:15](=[O:21])[O:16]C(C)(C)C)=[O:11])=[O:7])(C)(C)C>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][CH:66]([CH2:80][C:81]([F:82])([F:83])[F:84])[C:67](=[O:79])[C:68]([NH:70][C:71]1[CH:76]=[CH:75][C:74]([CH3:77])=[CH:73][C:72]=1[CH3:78])=[O:69])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:29])[OH:34])=[O:23])[CH2:14][C:15](=[O:16])[OH:21])=[O:11])([OH:7])=[O:5]
Reactant: Cc1ccc(NC(=O)C(=O)C(CC(F)(F)F)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc2ccccc2C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(C)(C)C)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)C(=O)C(CC(F)(F)F)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc2ccccc2C)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CCC(=O)O)C(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
50 mg (0.042 mmol) of 3(RS)-[[N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-5,5,5-trifluoro-2′,4′-dimethyl-2-oxovaleranilide were dissolved in 3 ml of trifluoroacetic acid and the solution was stirred at room temperature for 30 minutes. The solution was then diluted with 10 ml of toluene and the solvent was removed by evaporation. The solid was triturated with diethyl ether to give 29 mg of 3(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-α-aspartyl]-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-5,5,5-trifluoro-2′,4′-dimethyl-2-oxovaleranilide as a white solid, MS: m/e 1020.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].Cl[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]([NH:33][CH3:34])=[O:32])[CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=2)[O:18][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]([NH:33][CH3:34])=[O:32])[CH:26]=2)=[CH:4][C:3]=1[C:20]([F:21])([F:22])[F:23]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: O=C(CCc1cccc(O)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2cccc(CCC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c2)ccn1
Temperature: 100 °C

Procedure:
A mixture of N-[4-chloro-3-(trifluoromethyl)phenyl]-3-(3-hydroxyphenyl)propanamide (585 mg, 1.70 mmol), 4-chloro-N-methylpyridine-2-carboxamide (318 mg, 1.87 mmol), and Cs2CO3 (7.76 g, 8.5 mmol) in DMF (3.4 mL) was heated at 100° C. overnight. The reaction mixture was concentrated and diluted with EtOAc. The organic solution was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, 0-30% EtOAc in hexanes) to give the product as a white solid. 1H NMR (400 MHz, CD3OD) δ: 8.62 (d, 1H), 8.26 (m, 1H), 7.89-7.96 (m, 1H), 7.71-7.74 (m, 1H), 7.63 (t, 1H), 7.41-7.47 (m, 1H), 7.28 (br s, 1H), 7.17-7.24 (m, 2H), 2.58 (t, 2H), 3.15 (s, 3H), and 2.93 (t, 2H). LCMS, AA: Rt=2.05 min, [MH+ 478.3].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:12]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH3:13])[CH2:11][O:10]1.[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1.[Na].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH:12]([C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH3:13])[CH2:11][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: CC(c1ncccn1)C1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(c1ncccn1)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
Treatment of the product of part (iii) (0.80 g) with 1H-1,2,4-triazole, sodium salt (0.82 g) in N,N-dimethylformamide according to the method of Example 12(iv), followed by chromatography of the crude product on silica gel using ethyl acetate as eluant, first gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair A, (0.26 g), m.p. 193°-195° (from dichloromethane/ether).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:15]3[C:14](=[O:25])[N:13]([CH2:26][CH2:27][CH3:28])[CH:12]=[N:11][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:36][C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=1)=[O:38]>CC(C)=O>[C:46]([C:43]1[CH:42]=[CH:41][C:40]([NH:39][C:37](=[O:38])[CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[C:15]4[C:14](=[O:25])[N:13]([CH2:26][CH2:27][CH3:28])[CH:12]=[N:11][C:10]=4[N:9]=3)=[CH:6][CH:7]=2)=[CH:45][CH:44]=1)#[N:47]
Reactant: CCCn1cnc2nc(-c3ccc(O)cc3)n(COCC[Si](C)(C)C)c2c1=O
Reactant: N#Cc1ccc(NC(=O)CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCn1cnc2nc(-c3ccc(OCC(=O)Nc4ccc(C#N)cc4)cc3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 80 °C
Yield: 78.8 %

Procedure:
A mixture of 8-(4-hydroxy-phenyl)-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.100 g, 0.25 mmol), potassium carbonate (0.052 g, 0.38 mmol), and 2-chloro-N-(4-cyano-phenyl)-acetamide (0.053 g, 0.28 mmol) in acetone (10 ml) was heated at 80° C. for 2 hours. The mixture was cooled to room temperature and filtered through sintered funnel, washed with acetone. The solvent was evaporated and the residue was purified by preparative TLC to obtain pure pale yellow solid of N-(4-cyano-phenyl)-2-{4-[6-oxo-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-6,7-dihydro-1H-purin-8-yl]-phenoxy}-acetamide (0.110 g, 79%) as a off white solid.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:18]([C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24])([O-:20])=[O:19]>>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:24][C:23]([C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[N+:18]([O-:20])=[O:19])=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(C)cc1
Reactant: NCc1ccccc1[N+](=O)[O-]
Product: CCOC(=O)c1nc(-c2ccccc2[N+](=O)[O-])[nH]c1-c1ccc(C)cc1
Yield: 18.3 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-methylphenyl)-3-oxopropionate (12.8 g) and 2-nitrobenzylamine (8.6 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-methylphenyl)-2-(2-nitrophenyl)imidazole-4-carboxylate(3.5g). 3.0 g therefrom was dissolved in ethyl alcohol (100 ml) and 1 M sodium hydroxide solution (20 ml) was added. The mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-methylphenyl)-2-(2-nitrophenyl)imidazole-4-carboxyic acid (2.4 g), melting point 144° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16]>CN(C)C=O>[CH3:1][C:2]1[CH:11]=[C:10]([O:12][C:15]([N:14]([CH3:18])[CH3:13])=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(O)c2ccccc2n1
Reactant: CN(C)C(=O)Cl
Solvent: CN(C)C=O
Product: Cc1cc(OC(=O)N(C)C)c2ccccc2n1

Procedure:
24 g (0,15 mole) of 2-methyl-4-hydroxyquinoline were dissolved in 200 ml of dimethylformamide (anhydrous and free from amine), 23 g (0,22 mole) of triethylmine were added and, subsequently, 24 g (0,22 mole) of dimethylcarbamic acid chloride added dropwise.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH2:29])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:37][C:38]([F:45])([F:44])[CH2:39][S:40](Cl)(=[O:42])=[O:41]>O1CCCC1.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH:29][S:40]([CH2:39][C:38]([F:45])([F:44])[F:37])(=[O:42])=[O:41])[C:25]([F:26])([F:27])[F:28])=[CH:4][CH:3]=1
Reactant: NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Reactant: O=S(=O)(Cl)CC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(CC(F)(F)F)NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Yield: 96.4 %

Procedure:
To a mixture of 1-[9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanamine (80.0 mg, 0.165 mmol) and triethylamine (0.0460 mL, 0.330 mmol) in tetrahydrofuran (2 mL) was added 2,2,2-trifluoroethanesulfonyl chloride (0.0219 mL, 0.198 mmol) at 0° C. The resultant mixture was stirred at room temperature for 30 min and diluted with aqueous sodium bicarbonate. The resultant mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (100 mg, 0.159 mmol, 96%).
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([O:17][CH3:18])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1.C(N(CC)C(C)C)(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([O:17][CH3:18])[CH2:15][N:14]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1
Reactant: CO[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: CS(=O)(=O)Cl
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CO[C@H]1CN(S(C)(=O)=O)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
A solution of 6-bromo-4-(((3R,4S)-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide (from Step 2 of Example 202, 210 mg, 0.436 mmol) in dichloromethane (2 mL), was added N,N-diisopropylethylamine (0.23 mL, 1.31 mmol) and methanesulfonyl chloride (0.043 mL, 0.52 mmol) at rt. The mixture was stirred at rt for 2 h. The reaction was then quenched with water, diluted with dichloromethane, washed with aq. sodium bicarbonate and brine. The organic layer was dried and concentrated. The crude was tritrated in ether and filtered to give 6-bromo-4-(((3R,4S)-4-methoxy-1-(methylsulfonyl)pyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (136 mg, 72% yield) as a yellow solid. MS (ES+) m/z: 432.3, 463.1 (M+H); LC retention time: 2.31 min (analytical HPLC Method H).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]([N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH2:39][CH2:40][OH:41])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O[C:43]1[C:44]([I:53])=[N:45][CH:46]=[C:47]([CH:52]=1)[C:48]([O:50][CH3:51])=[O:49].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>O>[I:53][C:44]1[C:43]([O:41][CH2:40][CH2:39][C:35]2[N:34]([C:15]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:38]=[CH:37][N:36]=2)=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:46][N:45]=1
Reactant: OCCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cnc(I)c(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cnc(I)c(OCCc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reaction time: 3 h
Yield: 43.6 %

Procedure:
Diisopropyl azodicarboxylate (1160 uL, 5.90 mmol) was added dropwise to a mixture of 2-(1-trityl-1H-imidazol-2-yl)ethanol (1900 mg, 5.4 mmol), methyl 5-hydroxy-6-iodonicotinate (1570 mg, 5.63 mmol) and Triphenylphosphine (1550 mg, 5.90 mmol) in Tetrahydrofuran (45.0 mL, 555 mmol) at 00 C. After stirring for 3 hours the mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over MgSO4 and concentrated in vacuum. The residue was purified on 40 g silica column eluting with 50% ethyl acetate in DCM to give 1.45 g (44%) of methyl 6-iodo-5-(2-(1-trityl-1H-imidazol-2-yl)ethoxy)nicotinate. MS (ESI+): 616.0. 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J=1.9, 1H), 7.40-7.28 (m, 10H), 7.20-7.16 (m, 6H), 6.99 (d, J=1.5, 1H), 6.81 (d, J=1.5, 1H), 3.98-3.91 (m, 5H), 2.46 (t, J=7.3, 2H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=1)(=O)=O.[CH3:19][S:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][C:25]=1[CH3:36])(=[O:22])=[O:21]>C(O)C>[CH3:19][S:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH2:6][CH2:7][C:8]3[CH:9]=[CH:10][C:11]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])=[CH:12][CH:13]=3)[CH2:32][CH2:31]2)=[CH:26][C:25]=1[CH3:36])(=[O:21])=[O:22]
Reactant: CS(=O)(=O)Nc1ccc(CCOS(C)(=O)=O)cc1
Reactant: Cc1cc(N2CCNCC2)ccc1NS(C)(=O)=O
Solvent: CCO
Product: Cc1cc(N2CCN(CCc3ccc(NS(C)(=O)=O)cc3)CC2)ccc1NS(C)(=O)=O

Procedure:
4-Methanesulphonamidophenethyl methanesulphonate (1.47 g) and 1-(4-methanesulphonamido-3-methylphenyl)piperazine 1/4 hydrate (1.37 g) in ethanol (15 ml) were refluxed overnight, evaporated to dryness, and partitioned between ethyl acetate and water. The title compound (0.2 g) was filtered from the 2-phase mixture and recrystallised from methanol/acetone, yield 0.128 g, m.p. 235°-7°.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=O.[NH2:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][C:31]=1[NH2:32])[C:16]([NH:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1)=[O:17]>CS(C)=O>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[NH:18][C:16]([C:15]1[CH:29]=[CH:30][C:31]2[N:32]=[C:4]([C:3]3[C:2]([Cl:1])=[CH:9][C:8]([Cl:10])=[CH:7][C:6]=3[Cl:11])[NH:12][C:13]=2[CH:14]=1)=[O:17]
Reactant: Nc1ccc(C(=O)Nc2ccc3ccccc3n2)cc1N
Reactant: O=Cc1c(Cl)cc(Cl)cc1Cl
Solvent: CS(C)=O
Product: O=C(Nc1ccc2ccccc2n1)c1ccc2nc(-c3c(Cl)cc(Cl)cc3Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 2,4,6-trichlorobenzaldehyde (150 mg, 0.72 mmol) and 3,4-diamino-N-quinolin-2-yl-benzamide (200 mg, 0.72 mmol) in DMSO (10 mL) was added FeCl3 (23 mg, 0.14 mmol). The solution was stirred at ambient temperature for 2 days. The reaction was quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried with MgSO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (1/3) as eluent to give the title compound as a white solid. 1H NMR (Methanol-d4, 400 MHz): δ 8.45 (m, 3H), 8.08 (d, 1H), 7.93 (m, 2H), 7.85 (s, 1H), 7.76 (s, 2H), 7.75 (m, 1H), 7.55 (m, 1H). MS (m/z) 467.0 (M+1); Retention time: 1.48 min (Method 10).
Reaction SMILES: N1CCOCC1.[OH:7][CH2:8][C:9](=O)[C:10]([CH3:13])([CH3:12])[CH3:11].[CH2:15]([C:18]#[N:19])[C:16]#[N:17]>CN(C)C=O>[NH2:19][C:18]1[O:7][CH:8]=[C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:15]=1[C:16]#[N:17]
Reactant: N#CCC#N
Reactant: CC(C)(C)C(=O)CO
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: CC(C)(C)c1coc(N)c1C#N
Temperature: 0 °C
Yield: 51.8 %

Procedure:
174 g (2 moles) of morpholine were added dropwise to a solution of 232 g (2 moles) of hydroxy-pinacolone and 132 g (2 moles) of malonic acid dinitrile in 500 ml of dimethylformamide, while cooling, in a manner such that the internal temperature did not rise above 40° C. After the reaction had ended, the reaction mixture was stirred into 5 liters of ice-water. The solid product which thereby precipitated was filtered off, washed with water and dried. 170 g of 2-amino-3-cyano-4-tert.-butyl-furan of melting point 86° C. were obtained in this manner.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[CH3:20][CH:21]1[CH2:26][NH:25][CH2:24][CH2:23][N:22]1[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(N(CC)CC)C.[I-].[K+]>CN(C)C=O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([CH:6]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:5][CH2:4][CH2:3][CH2:2][N:25]2[CH2:24][CH2:23][N:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:21]([CH3:20])[CH2:26]2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)N1CCNCC1C
Reactant: Fc1ccc(C(CCCCCl)c2cccnc2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(CCCCC(c2ccc(F)cc2)c2cccnc2)CC1C
Temperature: 70 °C
Reaction time: 40 h
Yield: 96.7 %

Procedure:
A mixture of 14 parts of 3-[5-chloro-1-(4-fluorophenyl)pentyl]-pyridine, 7.75 parts of ethyl 2-methyl-1-piperazinecarboxylate, 8.7 parts of N,N-diethylethanamine, 0.1 parts of potassium iodide and 198 parts of N,N-dimethylformamide was stirred for 40 hours at 70° C. The reaction mixture was evaporated and the residue was taken up in a mixture of water and sodium carbonate. The aqueous layer was extracted with trichloromethane. The extract was washed with a sodium carbonate solution in water and water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 18 parts (96.7%) of ethyl 4-[5-(4-fluorophenyl)-5-(3-pyridinyl)pentyl]-2-methyl-1-piperazinecarboxylate as a residue (int. 38).
Reaction SMILES: [NH2:1][C:2]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:3]=1[NH:4][S:5]([C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1)(=[O:7])=[O:6].S([O-])(O[CH3:26])(=O)=O>[OH-].[Na+]>[NH2:1][C:2]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:3]=1[N:4]([CH3:26])[S:5]([C:8]1[CH:9]=[CH:10][C:11]([CH3:12])=[CH:13][CH:14]=1)(=[O:7])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)Nc2cccc([N+](=O)[O-])c2N)cc1
Reactant: COS(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)N(C)c2cccc([N+](=O)[O-])c2N)cc1

Procedure:
0.093 mol (28.5 g) of 2-amino-3-nitro-N-tosylaniline is dissolved in 112 ml of normal sodium hydroxide solution at 30° C. 0.122 mol (15.45 g) of methyl sulphate is added gradually, in the course of 1 hour 30 minutes, whilst stirring. The temperature remains between 35° and 40° C. Towards the end of the addition of the methyl sulphate, 3 ml of 10N sodium hydroxide solution are gradually added simultaneously in order to keep the pH alkaline.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@H:4]([OH:5])[C@@H:2]1[OH:3]>O.[Rh]>[C@@H:1]1([N:10]2[CH2:17][CH2:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@H](O)[C@@H]2O)c(=O)[nH]1
Agent: [Rh]
Solvent: O
Product: O=C1CCN([C@@H]2O[C@H](CO)[C@H](O)[C@@H]2O)C(=O)N1

Procedure:
In the manner given in Example 2A, 1-β-D-lyxofuranosyl-uracil [Fletcher et al., J. Am. Chem. Soc. 83, 1889 (1961)] was catalytically hydrogenated in water in the presence of rhodium on alumina catalyst to give 1-β-D-lyxofuranosyl-dihydrouracil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](N)[S:8][C:4]=2[CH:3]=1.C([CH2:14][O:15][C:16]1[C:17]([F:26])=[C:18]([C:23]([NH2:25])=[O:24])[C:19]([F:22])=[CH:20][CH:21]=1)#N>>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH2:14][O:15][C:16]3[C:17]([F:26])=[C:18]([C:23]([NH2:25])=[O:24])[C:19]([F:22])=[CH:20][CH:21]=3)[S:8][C:4]=2[CH:3]=1
Reactant: N#CCOc1ccc(F)c(C(N)=O)c1F
Reactant: Nc1nc2ccc(Cl)cc2s1
Product: NC(=O)c1c(F)ccc(OCc2nc3ccc(Cl)cc3s2)c1F
Yield: 38 %

Procedure:
Synthesised from 6-chloro-1,3-benzothiazol-2-amine and 3-(cyanomethoxy)-2,6-difluorobenzene carboxamide, according to Method K, scheme 26. Yield 38% (second step), mp 190-191° C., HPLC-MS (method 1): m/z 355 [M+H]+, Rt=3.85 min.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[S:10]([C:13]1[CH:18]=[CH:17][C:16](F)=[CH:15][C:14]=1F)(=[O:12])=[O:11])(C)C.[OH:30][C:31]1[CH:32]=[C:33]([CH:43]=[C:44]([O:46][C@@H:47]([CH3:60])[CH2:48][O:49][Si](C(C)C)(C(C)C)C(C)C)[CH:45]=1)[C:34]([NH:36][C:37]1[CH:41]=[CH:40][N:39]([CH3:42])[N:38]=1)=[O:35].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[O:12]=[S:10]1(=[O:11])[C:13]2[CH:14]=[CH:15][C:16]([O:30][C:31]3[CH:32]=[C:33]([CH:43]=[C:44]([O:46][C@@H:47]([CH3:60])[CH2:48][OH:49])[CH:45]=3)[C:34]([NH:36][C:37]3[CH:41]=[CH:40][N:39]([CH3:42])[N:38]=3)=[O:35])=[CH:17][C:18]=2[O:6][CH2:7][CH2:8][N:9]1[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN(Cc1ccccc1)S(=O)(=O)c1ccc(F)cc1F
Reactant: CC(C)[Si](OC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1)(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: C[C@@H](CO)Oc1cc(Oc2ccc3c(c2)OCCN(Cc2ccccc2)S3(=O)=O)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 150 °C
Yield: 117.8 %

Procedure:
N-(2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}ethyl)-2,4-difluoro-N-(phenylmethyl)benzenesulfonamide (291 mg, 0.66 mmol) was added to 3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-{(s)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzamide (296 mg, 0.66 mmol) and potassium carbonate (183 mg, 1.31 mmol) in dry DMA (4 mL). The mixture was heated in a Smith Creator microwave at 150° C. for 45 mins. Water (25 mL) was added to the reaction mixture and extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried (MgSO4), filtered and evaporated. Purification by column chromatography on silica, eluting with 80-90% ethyl acetate in isohexane, afforded the title compound as a colourless oil (450 mg). 1H NMR δ (CDCl3): 1.25 (d, 3H), 2.16-2.19 (m, 1H), 3.53 (t, 2H), 3.68-3.71 (m, 2H), 3.74 (s, 3H), 4.14 (t, 2H), 4.18 (s, 2H), 4.50 (ddd, 1H), 6.70 (d, 1H), 6.72 (d, 1H), 6.75 (t, 1H), 6.78 (dd, 1H), 7.09 (t, 1H), 7.22 (ddd, 1H), 7.24-7.26 (m, 1H), 7.28-7.29 (m, 5H), 7.78 (d, 1H), 8.45 (s, 1H). m/z 579 (M+H)+