Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]=[C:9]=[S:10].[Cl:11][C:12]1[C:13]([O:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.Cl>CN(C=O)C>[CH3:7][NH:8][C:9]([N:25]1[C:26]([CH3:28])=[CH:27][C:23]([O:22][C:13]2[C:12]([Cl:11])=[CH:17][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:15][N:14]=2)=[N:24]1)=[S:10]
Reactant: Cc1cc(Oc2ncc(C(F)(F)F)cc2Cl)n[nH]1
Reactant: CN=C=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=S)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
Potassium carbonate (0.75 g, 5.4 mmol) and methyl isothiocyanate (0.39 g, 5.4 mmol) were added to a solution of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole (1.00 g, 3.6 mmol) in DMF (10 ml), and the mixture was stirred at room temperature for 8 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-methyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carbothioamide (0.35 g, yield: 37.7%) mp: 63-65° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.87 (d, J=0.6 Hz, 3H), 3.21 (d, J=4.9 Hz, 3H), 6.14 (q, J=0.6 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H), 8.36 (m, 1H), 8.80-9.05 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:6]([CH3:9])=[CH:7][CH:8]=1.[Br:15]N1C(=O)CCC1=O>>[Br:15][CH2:9][C:6]1[C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(OC)ccc1C
Product: CCOC(=O)c1cc(OC)ccc1CBr

Procedure:
Reaction of ethyl 4-methoxy-o-toluate with N-bromosuccinimide as described in Example 1a provides ethyl α-bromo-4-methoxy-o-toluate as a colorless liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([F:22])[CH:24]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccccc2)ccn1Cc1cccc(F)c1
Temperature: 110 °C
Yield: 67.2 %

Procedure:
To a solution of 4-benzyloxy-1H-pyridin-2-one (1.0 g, 5 mmol) and K2CO3 (2.0 g, 9.9 mmol) in DMF (30 mL) was added 3-fluorobenzyl bromide (1.4 g, 7.5 mmol), and the reaction mixture was heated to 110° C. for 3 h. The reaction mixture was cooled to room temperature, and partitioned between EtOAc and water. The organic solution was washed with water and then brine, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent 97:3 to 93:7 methylene chloride/methanol) afforded 4-benzyloxy-1-(3-fluorobenzyl)-1H-pyridin-2-one (1.04 g, 67%): 1H NMR (300 MHz, CDCl3) δ 7.45-7.25 (m, 5H), 7.13 (d, J=8 Hz, 1H), 7.10-6.90 (m, 3H), 6.10-5.95 (m, 2H), 5.07 (s, 2H), 5.00 (s, 2H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][CH2:9][CH:8]2[CH:3]1[NH:4][C:5](=[O:20])[C:6](=[O:19])[N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+].I[CH2:27][CH2:28][CH2:29][CH2:30]I>CC#N>[CH2:12]([N:7]1[CH:8]2[CH:3]([CH:2]([N:1]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:11][CH2:10][CH2:9]2)[NH:4][C:5](=[O:20])[C:6]1=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC1CCCC2C1NC(=O)C(=O)N2Cc1ccccc1
Reactant: ICCCCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C1NC2C(N3CCCC3)CCCC2N(Cc2ccccc2)C1=O

Procedure:
(4aRS,5SR,8aRS)-5-Amino-1-benzylperhydroquinoxaline-2,3-dione (3.06 g, 11.2 mmol) was dissolved in CH3CN (300 ml). NaHCO3 (6.4 g, 76.2 mmol) and 1,4-diiodobutane (13.9 g, 44.8 mmol, 5.9 ml) were added and the mixture was heated under reflux for 18 hours. NaHCO3 was separated off with a blue-band filter (Schleicher&Schuell) and the yellow solution was concentrated in vacuo. The solid was taken up in CH2Cl2 and the mixture was extracted by shaking three times with HCl (1 N). The aqueous phase was then brought to pH 8 with NaOH (2 N) and extracted by shaking three times with CH2Cl2. The organic phases were dried over Na2SO4 and evaporated in vacuo. A pale yellow solid was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22]/[CH:23]=[CH:24]/[C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[F:32]>C(O)C>[F:32][C:26]1[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:25]=1/[CH:24]=[CH:23]/[CH2:22][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Fc1ccc(F)c(/C=C/CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(C/C=C/c2cc(F)ccc2F)CC1
Temperature: 80 °C
Yield: 70.9 %

Procedure:
A mixture of tert-butyl piperidin-4-ylcarbamate (248 mg, 1.2 mmol), potassium carbonate (188 mg, 1.4 mmol) and 2-[(1E)-3-chloroprop-1-en-1-yl]-1,4-difluorobenzene (Intermediate 124, 257 mg, 1.4 mmol) in ethanol (7 mL) was heated to 80° C. for 18 hours. The mixture was concentrated under reduced pressure, the residue taken up in dichloromethane (20 mL) and water (20 mL), the aqueous phase was back extracted with dichloromethane (2×20 mL) and the combined organic phases were dried over sodium sulfate. Chromatography on silica gel with dichloromethane/methanol (95:5) gave 300 mg (69%) of product as a brown foam.
Reaction SMILES: Cl[C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1.[Na][S:17][C:18](=[C:21]([C:24]#[N:25])[C:22]#[N:23])[S:19][Na].O>CN(C)C=O>[N+:13]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]1[S:17][C:18](=[C:21]([C:24]#[N:25])[C:22]#[N:23])[S:19][C:11]1=[N:10]2)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc2nc(Cl)c(Cl)nc2c1
Reactant: N#CC(C#N)=C(S[Na])S[Na]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)=C1Sc2nc3ccc([N+](=O)[O-])cc3nc2S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of 2,3-dichloro-6-nitro-quinoxaline (0.5 g, 0.002 mol) in dimethylformamide (15 mL) is added, in several portions, di(sodiomercapto)methylenemalononitrile (0.53 g, 0.0029 mol). The resulting solution is stirred overnight at room temperature. Water (50 mL) is slowly added to the reaction mixture, dropwise, with stirring. The resulting solid is isolated by filtration, washed with water and dried, giving 0.48 g (78 percent yield) of a dark brown powder.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:31]([O:33][C:34](=[O:39])[CH2:35][CH2:36][CH2:37]Br)[CH3:32]>CN(C)C=O.C(OCC)(=O)C>[CH2:31]([O:33][C:34](=[O:39])[CH2:35][CH2:36][CH2:37][N:3]1[C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[N:5]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:4]1)[CH3:32]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN1CN(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 60 °C
Reaction time: 60 h

Procedure:
To a solution of tert-butyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.15 g, 0.45 mmol) and potassium carbonate (0.124 g, 0.9 mmol) in N,N-dimethylformamide (4 mL), was added ethyl-4-bromobutyrate (0.072 mL, 0.5 mmol, d=1.35). After stirring at 60° C. for 60 hours, the reaction mixture was diluted with ethyl acetate (25 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to obtain tert-butyl 3-(4-ethoxy-4-oxobutyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10](=[O:18])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20].[NH4+].[OH-]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:26](=[O:27])[C:25]4[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:30][CH:29]=4)[CH:16]=3)[NH:11][C:10](=[O:18])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(c2cccc(Cl)c2)c2ccccc2N1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: [NH4+]
Agent: [OH-]
Product: O=C1CC(c2cccc(Cl)c2)c2cc(C(=O)c3ccc([N+](=O)[O-])cc3)ccc2N1
Temperature: 140 °C
Reaction time: 72 h
Yield: 26.9 %

Procedure:
(±)-4-(3-chlorophenyl)-3,4-dihydro-2(1H)-quinolinone (described in WO 97/21701) (0.0776 mol), then 4-nitro-benzoic acid (0.233 mol) were added at 100° C. to polyphosphoric acid (200 g). The mixture was stirred at 140° C. for 72 hours, cooled at 80° C., poured out into ice water, basified with NH4OH (concentrated) and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (19.4 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2; 15–35 μm). One fraction was collected and the solvent was evaporated. The residue (9.1 g) was crystallized from 2-propanone. The precipitate was filtered off and dried, yielding 8.5 g (27%) of (±)-4-(3-chlorophenyl)-3,4-dihydro-6-(4-nitrobenzoyl)-2(1H)-quinolinone, mp. 147° C. (intermediate 15).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][CH:8]([CH3:10])[CH3:9])=[N:4][N:3]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH3:9][CH:8]([N:7]([C:5]1[S:6][C:2]([CH3:1])=[N:3][N:4]=1)[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:10]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nnc(NC(C)C)s1
Solvent: c1ccncc1
Product: Cc1nnc(N(C(=O)c2ccccc2)C(C)C)s1

Procedure:
N-(5-methyl-1,3,4-thiadiazol-2-yl)-1-methylethylamine (5 g, 0.032 mole) in pyridine (100 ml) was treated with benzoyl chloride (4.1 ml). The reaction mixture was stirred and heated to reflux for 51/2 hours. The pyridine was removed under reduced pressure and the residue treated with water and extracted with ether (× 3). The ethereal solution was dried, filtered and evaporated to dryness and the residue recrystallised from ether/petrol ether (40°-60° C.) to give the title compound as a pale yellow crystalline solid m.p. 82.5°-83.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](C=O)[C:3]=1[O:10][CH3:11].[Na].FC(F)(F)C(OO)=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.C(OCC)C>[Br:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([OH:16])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(Br)cccc1C=O
Reactant: O=C(OO)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CCOCC
Product: COc1c(O)cccc1Br
Reaction time: 8 h

Procedure:
A solution of 0.037 g 2-bromo-6-formyl-anisole in 1 ml methylene chloride is treated with 0.54 sodium dibasic phosphate and 1.3 ml trifluoroperacetic acid, stirred overnight, treated with 10% aqueous sodium carbonate (5 ml) and 5 ml diethyl ether, stirred for 1.5 hours, and partitioned between water and ether. The ether portion is extracted with 1 N aqueous sodium hydroxide, the hydroxide extracts acidified and then extracted with ether. Concentration of the ether extracts affords 3-bromo-2-methoxyphenol.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]=2[CH:8]=[O:9])=[CH:23][CH:22]=1
Reactant: O=Cc1cccnc1Cl
Reactant: Cn1c(Nc2ccc(O)cc2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cn1c(Nc2ccc(Oc3ncccc3C=O)cc2)nc2ccccc21

Procedure:
A solution of 2-chloropyridine-3-carboxaldehyde (3 g, 21 mmol), 4-(1-methyl-1H-benzo[d]imidazol-2-ylamino)phenol (5 g, 21 mmol), CESIUM CARBONATE (10 g, 32 mmol) in DMSO (60 mL) was heated to 80° C. overnight. Purification by aqueous workup (water, brine) and DCM extraction then Biotage (0-10% DCM/MeOH) produced product which partially solidified.
Reaction SMILES: Br[CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][CH:6]=1)[OH:4].[I-].[Na+].[N-:18]=[N+:19]=[N-:20].[Na+].CS(C)=O>O>[N:18]([CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][CH:6]=1)[OH:4])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)Nc1ccc([C@H](O)CBr)cc1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)Nc1ccc([C@@H](O)CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 37 %

Procedure:
A mixture of N-{4-[(1S)-2-bromo-1-hydroxyethyl]phenyl}methanesulfonamide (which was obtained in Example 112) (1.73 g, 5.9 mmol), sodium iodide (0.88g, 5.9 mmol), sodium azide (1.53 g, 23.6 mmol), and methyl sulfoxide (15 mL) was stirred at ambient temperature for 7 days, poured into water and extracted with ethyl acetate. The organic extracts were washed with water, and dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/chloroform/isopropylalcohol 5/4.5/0.5) gave an off-white solid (0.56 g, 70% yield); MS (ES) m/z: 256 (M)+; 1H NMR (400 MHz, DMSO-d6) δ 2.94 (s, 3H), 3.30 (m, 2H), 4.74 (m, 1H), 5.75 (d, 1H), 7.17 (d, 2H), 7.32 (d, 2H), 9.67 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[C:9]([OH:13])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][CH2:19][O:20][CH3:21].[H-].[Na+]>CN(C=O)C.CC(=O)OCC>[C:1]([C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[C:9]([O:13][CH2:18][CH2:19][O:20][CH3:21])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(O)cc(C(C)=O)cc1C(C)(C)C
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1cc(C(C)=O)cc(C(C)(C)C)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.4 %

Procedure:
1-(3-tert-Butyl-5-hydroxy-4-methoxyphenyl)ethanone (03.070; 2.00 g) and 1-bromo-2-methoxyethane (1.5 g) were dissolved in DMF (20 ml), and sodium hydride (259 mg) was added. After stirring at RT for 3 h, the mixture was left to stand overnight. Then the DMF was drawn off and the residue was taken up in EA. The EA phase was washed with water, dried, filtered and concentrated. The residue was purified using silica gel (80 g cartridge, n-heptane/EA 0-40% within 60 min). 1.17 g of the title compound were obtained.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:18]1([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:28][CH:25]4[CH2:27][CH2:26]4)=[O:24])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COC(=O)c1ccc(OCc2c(C3CCCCC3)noc2C)nc1
Reactant: NC1CC1
Product: Cc1onc(C2CCCCC2)c1COc1ccc(C(=O)NC2CC2)cn1
Yield: 41 %

Procedure:
As described for example 31e, 6-(3-cyclohexyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (708 mg, 1.5 mmol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (219 mg, 41%) which was obtained as a white solid after purification by chromatography (silica, 0 to 60% ethyl acetate in heptane). MS: m/e=356.3 [M+H]+.
Reaction SMILES: [Na].[NH2:2][C:3]1[C:12]2[N:11]=[CH:10][C:9](=[O:13])[N:8]([C@@H:14]3[O:28][C@H:27]([CH2:29][O:30]C(=O)C4C=CC(Cl)=CC=4)[C@@H:16]([O:17]C(=O)C4C=CC(Cl)=CC=4)[CH2:15]3)[C:7]=2[N:6]=[C:5]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:4]=1.CC(O)=O>CO>[NH2:2][C:3]1[C:12]2[N:11]=[CH:10][C:9](=[O:13])[N:8]([C@@H:14]3[O:28][C@H:27]([CH2:29][OH:30])[C@@H:16]([OH:17])[CH2:15]3)[C:7]=2[N:6]=[C:5]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:4]=1
Reactant: Nc1nc(-c2ccccc2)nc2c1ncc(=O)n2[C@H]1C[C@H](OC(=O)c2ccc(Cl)cc2)[C@@H](COC(=O)c2ccc(Cl)cc2)O1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1nc(-c2ccccc2)nc2c1ncc(=O)n2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of 10 mg of sodium in 50 mL of anhydrous methanol was added 0.632 g (1 mmol) of 4-amino-2-phenyl-8-[2-deoxy-3,5-di-O-(4-chlorophenyl)-βD-ribofuranosyl]pteridine-7-one (4). The solution was stirred at room temperature for 1 hour. The solution was then neutralized by the addition of AcOH and then evaporated. The residue was re, crystallized from methanol/H2O to give 5 as 0.323 g (91% yield) of colorless crystals (m.p. 169°-172° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.B(O)(O)[C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2ccccc2C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1
Yield: 70.1 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), p-tolylboronic acid (0.025 g; 0.176 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) furnished 0.048 g (70%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-2-carboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11](I)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)#[CH:25]>>[Cl:1][C:2]1[C:3]2[C:11]([C:25]#[C:24][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(N)nc32)c1C
Reactant: C#Cc1ccccn1
Product: COc1c(C)cnc(Cn2cc(C#Cc3ccccn3)c3c(Cl)nc(N)nc32)c1C

Procedure:
The title compound was prepared by Sonogashira coupling of 4-chloro-5-iodo-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (see, Example 1) with 2-ethynylpyridine according to the General Procedure A. tR: 4.65 min. 1H-NMR (DMSO-d6) δ 8.59 (s, 1H), 8.07 (s, 1H), 7.82 (td, 1H), 7.62 (s, 1H), 7.56 (d, 1H), 7.36 (td, 1H), 6.84 (br. S, 2H), 5.36 (s, 2H), 3.74 (s, 3H), 2.28 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][C:12]2[CH:21]=[CH:20][C:15]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1.Cl>N1C=CC=CC=1>[S:2]([O:19][CH2:18][CH2:17][O:16][C:15]1[CH:20]=[CH:21][C:12]([O:11][C:10]2[CH:22]=[CH:23][C:7]([Cl:6])=[CH:8][CH:9]=2)=[CH:13][CH:14]=1)(=[O:4])(=[O:3])[CH3:1]
Reactant: OCCOc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCOc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
2.6 g (0.0227 mol) of methanesulphonyl chloride are run over the course of 5 minutes, at about +10° C., into a solution of 6 g (0.0227 mol) of 2-[4-(4-chlorophenoxy)-phenoxy]-1-ethanol (CRL 40,293) in 11 ml of pyridine and the mixture is then stirred for 1 hour at ambient temperature. Thereafter the reaction mixture is poured onto ice and acidified to Congo Red with concentrated hydrochloric acid. After extracting the insoluble matter with ethyl acetate, washing the organic phase obtained with water and drying it over dry sodium sulphate, evaporation of the solvent gives 7.8 g of a white powder.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH2:18][C:19]([O:21]CC)=[O:20])[CH:17]=3)[CH:12]=[C:6]2[C:5]=1[NH:24][C@H:25]1[C@@H:29]([CH3:30])[CH2:28][N:27]([C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][N:32]=2)[CH2:26]1)(=[O:3])[NH2:2].[OH-].[Na+].CO>O1CCCC1>[C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH2:18][C:19]([OH:21])=[O:20])[CH:17]=3)[CH:12]=[C:6]2[C:5]=1[NH:24][C@H:25]1[C@@H:29]([CH3:30])[CH2:28][N:27]([C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][N:32]=2)[CH2:26]1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)Cn1cc(-c2cc3c(N[C@@H]4CN(c5ccc(C#N)cn5)C[C@@H]4C)c(C(N)=O)cnn3c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H]1CN(c2ccc(C#N)cn2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(CC(=O)O)c3)cc12

Procedure:
A mixture of the crude ethyl 2-(4-(3-carbamoyl-4-(((3S,4S)-1-(5-cyanopyridin-2-yl)-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazin-6-yl)-1H-pyrazol-1-yl)acetate from Step 1, a 2 N aqueous solution of NaOH (0.5 mL), methanol (0.5 mL) and tetrahydrofuran (0.5 mL) was stirred at room temperature for 1 h. The organic solvents were evaporated in vacuo. The aqueous residue was treated with 1 N HCl (1 mL) and water (1 mL) and filtered. The filter cake was washed with water and dried under vacuum to give crude 2-(4-(3-carbamoyl-4-(((3S,4S)-1-(5-cyanopyridin-2-yl)-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazin-6-yl)-1H-pyrazol-1-yl)acetic acid as dark brown solid (66.3 mg). This material was used in the next step without further purification. MS (ES+) m/z: 486.1 (M+H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.S(=O)(=O)(O)[OH:26].[OH-].[NH4+]>>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH2:22])=[O:26])=[CH:23][CH:24]=3)=[O:16])[CH2:6][C:5]=12
Reactant: N#Cc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(5H,11H-Pyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-benzonitrile (0.5 g) from Example 44 was added to concentrated sulfuric acid (5 ml) and the mixture was stirred for 18 hours at room temperature to yield a bright yellow solution. The solution was poured onto ice and made basic with the addition of concentrated ammonium hydroxide. The resultant solid was filtered, dissolved in dichloromethane, and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (5.05 g), m.p. 226-228° C.