Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][N:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH:13]([CH3:21])[C:14](=O)[C:15]([O:17][CH2:18]C)=[O:16]>C1COCC1>[CH3:21][C:13]1[N:7]2[C:6]([C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:10]=3[CH:9]=[CH:8]2)=[N:11][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: CCOC(=O)C(=O)C(C)Br
Reactant: Nc1nccc2ncccc12
Solvent: C1CCOC1
Product: COC(=O)c1nc2c3cccnc3ccn2c1C
Yield: 63.5 %

Procedure:
A solution of 1,6-naphthyridin-5-amine (700 mg, 4.83 mmol) in THF (25 mL) was added ethyl 3-bromo-2-oxobutanoate (1.51 g, 7.24 mmol). The mixture was stirred at reflux for 36 h. Then the mixture was concentrated under reduced pressure, and purified by column chromatography to give the product as a yellow solid (740 mg, 60% yield). ESI MS: m/z 256.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[N:15]=[N:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].CCN(C(C)C)C(C)C.Cl[CH2:30][O:31][CH3:32]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:30][O:31][CH3:32])[C:14]2[N:15]=[N:16][CH:17]=[CH:18][CH:19]=2)(=[O:11])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N#Cc1cc(S(=O)(=O)Nc2cccnn2)ccc1F
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCN(c1cccnn1)S(=O)(=O)c1ccc(F)c(C#N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-cyano-4-fluoro-N-(pyridazin-3-yl)benzenesulfonamide (Preparation 6, 6.70 g, 24.1 mmol) in DCM (150 mL) at 0° C. was added DIPEA (6.48 mL, 35.18 mmol) followed by chloromethoxymethane (1.46 mL, 25.54 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by the addition of 1N NaOH (aq) solution, the organic layer was collected, washed with water, brine, and dried over Na2SO4 before concentrating in vacuo. The residue was purified using silica gel column chromatography eluting with EtOAc:Heptane 1:1 to afford the title compound as a mixture of isomers (3.85 g, 49%) that was used without further purification.
Reaction SMILES: [C:1](=[O:21])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C@@H:3]1[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1.[C:22]1([C@H:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH2:30][NH:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[N:5]12[CH2:6][CH2:7][CH:8]([CH2:9][CH2:10]1)[C@@H:3]([O:2][C:1]([N:29]1[CH2:30][CH2:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:28]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:21])[CH2:4]2
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@H]1CN2CCC1CC2
Product: O=C(O[C@H]1CN2CCC1CC2)N1CCc2ccccc2[C@@H]1c1ccccc1

Procedure:
The above mentioned step (b) comprises treating the reaction mixture comprising (3R)-1-azabicyclo[2.2.2]oct-3-yl 4-nitrophenyl carbonate of formula (IV) of step (a) with (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline of formula (V) in an organic solvent and in an inert atmosphere at temperature of −20 to 50° C. to obtain (1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl-3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylate (Solifenacin) of formula (I).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([NH:15][C:16](=[O:32])[CH2:17][C@H:18]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:19]O)=[N:11][N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(P(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([N:15]2[C:16](=[O:32])[CH2:17][C@H:18]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19]2)=[N:11][N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(NC(=O)OC(C)(C)C)c(NC(=O)C[C@@H](CO)NC(=O)OCc2ccccc2)n1
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cn1cc(NC(=O)OC(C)(C)C)c(N2C[C@@H](NC(=O)OCc3ccccc3)CC2=O)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a mixture of benzyl ((2S)-4-((4-((tert-butoxycarbonyl)amino)-1-methyl-1H-pyrazol-3-yl)amino)-1-hydroxy-4-oxobutan-2-yl)carbamate (1.6 g), tri-n-butylphosphine (1.3 mL), toluene (18 mL) and THF (6.0 mL) was added 40% diethyl azodicarboxylate toluene solution (1.8 mL) under ice-cooling, and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.3 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[NH2:16][C:17]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][NH:19][N:18]=1>CC(O)=O>[C:7]1([CH:5]2[CH2:4][CH:3]([C:2]([F:15])([F:14])[F:1])[N:18]3[N:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]3[NH:16]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c1NC(c1ccccc1)CC2C(F)(F)F
Temperature: 25 °C
Yield: 78.9 %

Procedure:
A mixture of 4,4,4-trifluoro-1-phenyl-1,3-butanedione 1 (6.97 g, 32.24 mmol) and ethyl 3-aminopyrazole-4-carboxylate 2 (5.0 g, 32.22 mmol) in AcOH (100 mL) was refluxed for 4 h. The mixture was cooled to room temperature and concentrated and precipitated crystals were collected by filtration to give 8.63 g (79%) of the title compound as yellow crystals. 1H NMR (CDCl3, 200 MHz): 1.47 (3H, t, J=7.0 Hz), 4.47 (2H, q, J=7.0 Hz), 7.54-7.61 (3H, m), 7.80 (1H, s), 8.23-8.28 (2H, m), 8.68 (1H, s).
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C@@H:15]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[C:16]2=[O:28])[CH2:3]1.[C:29]([O:33][C:34](=[O:48])[C@@H:35]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36][C:37](O)=[O:38])([CH3:32])([CH3:31])[CH3:30].C1CCC(N=C=NC2CCCCC2)CC1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:44]([O:43][C:41]([NH:40][C@@H:35]([CH2:36][C:37]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C@@H:7]2[CH2:6][CH2:5][N:4]([C@@H:15]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=4)[C:16]3=[O:28])[CH2:3][C@H:2]2[F:1])=[CH:9][CH:10]=1)=[O:38])[C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:48])=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(O)cc4)[C@H](F)C3)C2=O)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(OC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc4)[C@H](F)C3)C2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
To a solution of (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (0.03 g, 0.078 mmol) in DCM (5 mL) was added (S)-4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid (0.118 g, 0.408 mmol) followed by DCC (0.049 g, 0.235 mmol) and DMAP (9.58 mg, 0.078 mmol). The reaction was stirred at rt for 18 hours. Water (15 mL) was then added, and the layers were separated. The aqueous layer was extracted with DCM (3×15 mL) and the organic layers were combined, dried over Na2SO4, and concentrated to a crude product. The crude product was purified by preparative TLC eluting with 25% ethyl acetate in petroleum ether to provide the purified product (37 mg, 68%) as an off-white semi solid. LC-MS (Method A) RT=2.55 min, (M+H)+=654.4. 1H NMR (400 MHz, DMSO-d6) δ 7.46-7.34 (m, 2H), 7.20-6.98 (m, 6H), 4.82-4.53 (m, 1H), 4.43-4.24 (m, 2H), 4.11 (d, J=14.1 Hz, 1H), 3.58 (t, J=8.8 Hz, 1H), 3.48-3.39 (m, 1H), 3.22-3.07 (m, 3H), 3.02 (dd, J=16.1, 6.5 Hz, 1H), 2.87 (dd, J=15.8, 7.8 Hz, 1H), 2.78-2.63 (m, 2H), 2.38-2.31 (m, 1H), 2.29 (s, 3H), 2.17-2.03 (m, 1H), 1.98-1.86 (m, 1H), 1.78 (br. s., 1H), 1.74-1.58 (m, 1H), 1.42 (s, 9H), 1.39 (s, 9H). 19F NMR (376 MHz, DMSO-d6) δ −180.707.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][N:44]=2)=[CH:38][C:37]=1[CH3:51].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:51])=[CH:38][C:39]([C:43]6[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][N:44]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COc1ccc(-c2cc(C)c(Br)c(C)c2)nc1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ccc(OC)cn6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-bromo-3,5-dimethyl-phenyl)-5-methoxy-pyridine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.98 min; Mass spectrum (ESI+): m/z=554 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([C:8]([OH:10])=[O:9])[C:4]([C:11]([F:14])([F:13])[F:12])=[CH:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CO>[CH3:26][O:25][C:23](=[O:24])[CH2:22][N:7]1[C:2](=[O:1])[CH:3]=[C:4]([C:11]([F:14])([F:12])[F:13])[C:5]([C:8]([OH:10])=[O:9])=[CH:6]1
Reactant: COC(=O)CBr
Reactant: O=C(O)c1c[nH]c(=O)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)Cn1cc(C(=O)O)c(C(F)(F)F)cc1=O
Reaction time: 16 h

Procedure:
To a stirred suspension of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxylic acid (0.207 g) and potassium carbonate (0.553 g) in methanol (5 mL) was added methyl bromoacetate (0.104 mL) at room temperature. After 16 h, the reaction was not complete, so further methyl bromoacetate (0.15 mL) was added. After a further 16 h, the mixture was concentrated in vacuo before the addition of 1 N aqueous hydrochloric acid (30 mL) and extracted into ethyl acetate (3×25 mL), dried over Na2SO4, filtered, and concentrated in vacuo to leave a white solid (300 mg).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.O>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([CH2:26][C:25]2[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cnc2[nH]nc(I)c2c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(I)c3cc([N+](=O)[O-])cnc32)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 70.7 %

Procedure:
3-Iodo-5-nitro-1H-pyrazolo[3,4-b]pyridine (1.00 g, 3.45 mmol) and cesium carbonate (1.69 g, 5.17 mmol) were combined in dry DMF (35 mL). p-Methoxybenzyl chloride (0.702 mL, 5.17 mmol) was added to this mixture, and the mixture was stirred at room temperature for 22 hours. Water (200 mL) was then added to the reaction mixture, resulting in a precipitate, which was collected by filtration. The solids were triturated with 3:1 EtOAc/Et2O (50 mL) to give 3-iodo-1-(4-methoxybenzyl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (1 g, 71%) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[C:15]([O:20]CC4C=CC=CC=4)=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:28](=[O:36])[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:7]=1)=[O:5])[CH3:2].C1CC=CCC=1>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[C:15]([OH:20])=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:28](=[O:36])[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1c(OCc3ccccc3)cccc21
Agent: [Pd]
Solvent: C1=CCC=CC1
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1c(O)cccc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
A mixture of 7-benzyloxy-3-(4-fluorobenzoyl)-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (82 mg, 0.17 mmol) and 10% Pd/C (82 mg) and 1,4-cyclohexadiene (0.15 mL, 1.58 mmol) was stirred at 50° C. for 2 hours. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with hexane-EtOAc (85:15) to give the title compound as a yellow solid (42 mg, 62%); 1H-NMR (CDCl3): δ 10.56 (1H, s), 8.0 (1H, s), 7.64-7.59 (2H, m), 7.20-7.11 (3H, m), 6.97-6.93 (1H, m), 6.61-6.55 (1H, m), 5.33 (1H, brs), 4.27-4.20 (4H, m), 3.26-3.23 (2H, m), 1.25 (3H, t); MS (ES): 395 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:20]([N:21]([CH2:36]C(OCC)=O)[C:22](=[O:35])[CH2:23][N:24]2C(=O)C3=CC=CC=C3[C:25]2=[O:34])=[CH:19][CH:18]=[C:17]([Cl:42])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.CN>ClCCl.CO>[Cl:1][C:2]1[C:20]([N:21]2[CH2:36][C:25](=[O:34])[NH:24][CH2:23][C:22]2=[O:35])=[CH:19][CH:18]=[C:17]([Cl:42])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: CCOC(=O)CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Agent: CN
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N4CC(=O)NCC4=O)c3Cl)c2n1
Reaction time: 24 h
Yield: 50 %

Procedure:
To the solution of 8-[2,6-dichloro-3-[N-ethoxycarbonylmethyl-N-(phthalimidoacetyl)amino]benzyloxy]-2-methylquinoline (527 mg) in dichloromethane (5.3 ml) was added 30% solution of methylamine in methanol (2 ml) at ambient temperature. After stirring for 24 hours, the reaction mixture was evaporated in vacuo. The residue was purified by flash column chromatography (silica gel 50 ml) eluting with dichloromethane/methanol (20/1, V/V) and by crystallizing from isopropyl ether to give 8-[2,6-dichloro-3-(2,5-dioxopiperazin-1-yl)benzyloxy]-2-methylquinoline (187 mg) as colorless crystals. mp: 211-213° C.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=1.C1OCCOCCOCCOCCOCCOC1.[CH2:34]([N:38]1[C:42]2=[C:43](Cl)[N:44]=[N:45][CH:46]=[C:41]2[C:40]([CH3:48])=[C:39]1[CH3:49])[CH:35]=[CH:36][CH3:37]>O1CCCC1>[CH2:34]([N:38]1[C:42]2=[C:43]([O:13][CH2:12][C:11]3[CH:14]=[CH:15][C:8]([F:7])=[CH:9][CH:10]=3)[N:44]=[N:45][CH:46]=[C:41]2[C:40]([CH3:48])=[C:39]1[CH3:49])[CH:35]=[CH:36][CH3:37]
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: OCc1ccc(F)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3ccc(F)cc3)c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.1 %

Procedure:
0.85 g (0.0076 mole) of potassium tert-butoxide was added to a solution of 0.48 g-(0.0038 mole) of 4-fluorobenzyl alcohol and 0.08 g (0.0003 mole) of 18-crown-6 in 30 ml of tetrahydrofuran and the mixture was stirred at room temperature for 10 minutes. 0.45 g (0.0019 mole) of 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine was then added to the mixture and stirred at room temperature for 8 hours. After completion of the reaction, the reaction mixture was poured into ice-water and the aqueous mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel using a 4:1 mixture of toluene and ethyl acetate as an eluent. An oily material thus obtained was crystallized in hexane to give 0.39 g of 1-(2-butenyl)-7-(4-fluorobenzyloxy)-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=13/87) as a pale brown powder.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[C-:9]#[N:10].[Na+]>CS(C)=O>[N:4]1[CH:5]=[CH:6][CH:7]=[N:8][C:3]=1[CH2:2][C:9]#[N:10]
Reactant: [C-]#N
Reactant: ClCc1ncccn1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ncccn1
Temperature: 50 °C

Procedure:
A solution of 6.8 g. of 2-(chloromethyl)pyrimidine is added dropwise to a solution of 5.2 g. of sodium cyanide in 100 ml. of dimethylsulfoxide. The mixture is heated at 50°C. for 2 hours, then diluted with 150 ml. of 5% aqueous sodium carbonate solution and extracted with ether. The extract is dried and concentrated to give 2-(2-pyrimidyl)acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:27][CH2:26][C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]3[O:12][C:13](=[O:15])[CH3:14])[C:6]=2[CH:28]=1.[Br:29]N1C(=O)CCC1=O>O1CCCC1>[Br:29][C:8]1[N:7]([C@@H:10]2[O:27][CH2:26][C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]2[O:12][C:13](=[O:15])[CH3:14])[C:6]2[CH:28]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1cnc2ccc(Cl)cc21
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1c(Br)nc2ccc(Cl)cc21
Yield: 129.4 %

Procedure:
The title compound was prepared according to General Procedure IV using 6-chloro-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.20 g, 0.41 mmol), 30 ml tetrahydrofuran (Aldrich Sure Seal, Milwaukee), and a total of 0.30 g (0.17 mmol) of N-bromosuccinimide that was added over 0.5 h. The product from work-up by General Procedure IV was purified on a silica gel column (2.5×20 cm, 230-400 mesh) with dichloromethane containing 1.0% methanol to give 2-Bromo-6-chloro-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.11 g, 0.22 mmol, 54%); MS (AP+): m/z (rel. intensity) 511 (0.10, M+23 (Na)) 1H NMR (DMSO-d6) δ8.16 (s,1H), 7.60-7.58 (d, 1H, J=8.7 Hz), 7.28-7.26 (dd, 1H, J=1.9 Hz, J=8.6 Hz), 5.95-5.92 (d, 1H, J=9.7 Hz), 5.67-5.60 (m, 3H), 4.13-4.09 (dd, 1H, J=5.3 Hz, J=9.2 Hz), 4.00-3.90 (overlapping dd, 1H) 2.20 (s, 3H), 1.98 (s, 3H), 1.74 (s, 3H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][C:13]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[N:16]=[CH:15][CH:14]=1>ClCCl>[CH3:12][C:13]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[N+:16]([O-:6])=[CH:15][CH:14]=1
Reactant: Cc1ccnc2c1CCCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc[n+]([O-])c2c1CCCC2
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A stirred suspension of 3-chloroperoxybenzoic acid (34 g, 197 mmol) in dichloromethane (170 ml) at 0° was treated dropwise with 5,6,7,8-tetrahydro-4-methylquinoline (23.7 g, 161 mmol) in dichloromethane (30 ml), warmed to room temperature, washed with lN-NaOH (3×200 ml), and extracted with dichloromethane (5×150 ml). The extracts were dried (MgSO4) and evaporated in vacuo to give the product (21 g) as an oil.
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]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11].F[C:20]1[C:21]([CH:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]2)=[N:22][CH:23]=[CH:24][N:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:20]2[C:21]([CH:26]3[CH2:27][CH2:28][N:29]([C:32](=[O:34])[CH3:33])[CH2:30][CH2:31]3)=[N:22][CH:23]=[CH:24][N:25]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: CC(=O)N1CCC(c2nccnc2F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(=O)N1CCC(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 80 °C

Procedure:
The mixture of (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.16 g, 0.67 mmol), 1-(4-(3-fluoropyrazin-2-yl)piperidin-1-yl)ethanone (0.1 g, 0.45 mmol), and cesium carbonate (0.22 g, 0.67 mmol) in DMSO (1.5 mL) was heated at 80° C. for 20 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and brine. The aqueous layer was back extracted with EtOAc (2×) and the combined organic layer was dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in hexane, then 5% MeOH in EtOAc, to provide 1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone as off-white solid. MS (ESI, pos. ion) m/z: 442.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][S:6]([OH:9])(=O)=[O:7].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17].FC(F)(F)S(O)(=O)=O>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:6]([CH3:5])(=[O:9])=[O:7])=[CH:13][C:12]=1[F:17]
Reactant: CS(=O)(=O)O
Reactant: Fc1ccccc1F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=S(Cl)Cl
Product: CS(=O)(=O)c1ccc(F)c(F)c1
Temperature: 80 °C
Yield: 59 %

Procedure:
A mixture of thionyl chloride (12.73 mL, 0.175 mol) and methanesulfonic acid (28.4 mL, 0.438 mol) was heated at reflux overnight and then cooled to 80° C. 1,2-Difluorobenzene (8.64 mL, 88 mmol) was and trifluoromethanesulfonic acid (0.675 mL, 8.8 mmol) were added dropwise. The reaction mixture was then heated at 120° C. for 3 h, cooled to room temperature and poured into ice-water (200 mL). The mixture was extracted three times with ethyl acetate and the combined organic extracts were dried (sodium sulfate), filtered, evaporated, and purified by flash chromatography, eluting with 15% ethyl acetate/hexanes, to give 1,2-difluoro-4-methanesulfonyl-benzene (9.98 g, 59%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 3.27 (s, 3H), 7.70-7.84 (m, 2H), 8.02-8.09 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13](OC)=[O:14])=[CH:4][C:3]1=[O:17].[BH4-].[Na+].CO.Cl>O1CCCC1>[OH:14][CH2:13][CH2:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:2]([CH3:1])[C:3](=[O:17])[CH:4]=1
Reactant: COC(=O)Cc1cc(=O)n(C)c2ccccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(=O)cc(CCO)c2ccccc21
Yield: 87.2 %

Procedure:
Methyl 1,2-dihydro-l-methyl-2-oxo-4-quinoline acetate (2.35 g, 10.16 mmol) was dissolved in dry tetrahydrofuran (50 ml) and sodium borohydride (1.92 g, 50.8 mmol) was added thereto. The mixture was refluxed. Under the same conditions, methanol (19 ml) was slowly added dropwise thereto (over 1 hour) and the mixture was refluxed for 1 hour. To the reaction mixture was acidified (pH about 2) with 2N-hydrochloric acid. The solvent was distilled off and water (300 ml) was poured to the residue. The mixture was extracted with chloroform (300 ml×3). The organic layer was separated, dried (over magnesium sulfate) and the solvent was distilled off. The residue was crystallized with ether to give the entitled compound (1.80 g) as white crystals (yield 87.2%, mp 149°-150 ° C. (chloroform--hexane)).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[NH:22][N:21]=[N:20][N:19]=3)=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1CCCCC=1.[N+:29]([O-:34])([N+]([O-])=O)=[O:30]>C(O)(=O)C>[N+:29]([C:2]1[O:3][C:4]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[NH:22][N:21]=[N:20][N:19]=3)=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O-:34])=[O:30]
Reactant: Brc1oc2ccc(Cc3nnn[nH]3)cc2c1-c1ccccc1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Solvent: C1=CCCCC1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1oc2ccc(Cc3nnn[nH]3)cc2c1-c1ccccc1

Procedure:
To a stirred solution of 1.9 g. (0.005 mole) of 2-bromo-3-phenyl-5-tetrazolylmethylbenzofuran in 50 ml. of warm acetic acid and 1 ml. of cyclohexene is added 1 g. of dinitrogen tetraoxide. The mixture is heated on a steam bath for 30 minutes, then cooled to ice bath temperature. The product is separated by filtration, washed with acetic acid and diethyl ether and recrystallized from ethanol to provide yellow needles of 2-nitro-3-phenyl-5(1H-tetrazol-5-ylmethyl)benzofuran, m.p. 245°-247° C. having the structure ##STR38##