Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=O)[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>CCCCO>[CH3:9][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:13][N:12]=1
Reactant: CC(=O)c1cccnc1Cl
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: Cc1n[nH]c2ncccc12
Temperature: 120 °C
Reaction time: 0.83 h

Procedure:
To a solution of the above crude 1-(2-chloropyridin-3-yl)ethanone (XIII) in n-BuOH (512 L) was added 85% hydrazine hydrate (78 L, 1360 mol). The reaction was heated at refluxed (˜120° C.) for 48 hours. The reaction was cooled and evaporated under vacuum. The crude material was taken up in DCM (834 L) and washed with 2× aqueous 25% NaCl (214 L) by adding aqueous 25% NaCl, stirring for 50 min, allowing to stand for 50 min, separating the layers and then repeating. The organic layer was evaporated to produce 3-methyl-1H-pyrazolo[3,4-b]pyridine (XIV) as a solid (13.2 Kg, 99 mol, 94.1% purity, 36.3% assay yield for 3 steps). 1H NMR (DMSO-d6, 400 MHz) δ ppm 2.50 (s, 3H), 7.13 (dd, J=4.4 Hz, J=8 Hz, 1H), 8.19 (dd, J=1.2 Hz, J=8 Hz, 1H), 8.47 (dd, J=1.6 Hz, J=4.8 Hz, 1H), 13.18 (brs, 1H); ESIMS found C7H7N3 m/z 133.8 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:14]=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=[C:11]2[C:10]([CH3:30])=[C:9]1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].I[CH3:35].O>CN(C)C=O>[CH3:35][O:18][C:17]([C:15]1[CH:16]=[C:11]2[C:10]([CH3:30])=[C:9]([CH3:31])[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12]2=[C:13]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)[N:14]=1)=[O:19]
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)nc(C(=O)O)cc12
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(C)c(C)n(Cc3ccccc3)c2c(N2CCc3ccccc3C2)n1
Yield: 35 %

Procedure:
A solution of 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid (20 mg, 0.05 mmol) prepared in Example 733, potassium hydroxide (10.1 mg, 0.07 mmol) and iodomethane (4.3 μl, 0.07 mmol) in anhydrous N,N-dimethylformamide (1 ml) was stirred for 10 hours at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/10, v/v) to give the titled compound as a white solid. (Yield: 35%)
Reaction SMILES: [F:1][CH:2]([F:16])[C:3]1[N:8]2[N:9]=[C:10]([C:12]([OH:14])=O)[N:11]=[C:7]2[N:6]=[C:5]([CH3:15])[CH:4]=1.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]([C:26]2[C:34]3[CH:33]=[N:32][CH:31]=[N:30][C:29]=3[N:28]([CH:35]([CH3:37])[CH3:36])[CH:27]=2)=[O:25])[CH:21]=[N:22][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:35]([N:28]1[C:29]2[N:30]=[CH:31][N:32]=[CH:33][C:34]=2[C:26]([C:24]([C:20]2[CH:19]=[C:18]([NH:17][C:12]([C:10]3[N:11]=[C:7]4[N:6]=[C:5]([CH3:15])[CH:4]=[C:3]([CH:2]([F:1])[F:16])[N:8]4[N:9]=3)=[O:14])[CH:23]=[N:22][CH:21]=2)=[O:25])=[CH:27]1)([CH3:37])[CH3:36]
Reactant: Cc1cc(C(F)F)n2nc(C(=O)O)nc2n1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(F)F)n2nc(C(=O)Nc3cncc(C(=O)c4cn(C(C)C)c5ncncc45)c3)nc2n1
Temperature: 50 °C
Reaction time: 16 h
Yield: 12 %

Procedure:
7-Difluoromethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylic acid (29.64 mg, 0.130 mmol) was added to (5-amino-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (28.1 mg, 0.1 mmol), HATU (49.42 mg, 0.130 mmol) and DIPEA (22.4 uL, 0.13 mmol) in anhydrous DMF (1 mL). The mixture was stirred at 50° C. for 16 hours and then evaporated in vacuo and purified by prep-HPLC (method 5) to afford the title compound in 12% yield, 6.1 mg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[CH:6][CH:5]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(OCC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.2 %

Procedure:
To a solution of 4-tert-butoxycarbonylmethoxy-benzoic acid methyl ester (5 g, 18.8 mmol) in dry DCM (40 ml) is added trifluoro-acetic acid (40 ml) at 0° C. The solution is stirred for 5 h at rt and evaporated in vacuo to give 4-carboxymethoxy-benzoic acid methyl ester 4 g as a white solid. LC-MS2: tR=3.24 min, [M+1]+=211.04, [M−1]−=208.96.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][C:24]([CH3:29])([CH3:28])[O:25]3)=[CH:20][CH:19]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][C:24]([CH3:29])([CH3:28])[O:25]3)=[CH:20][CH:19]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(COc2ccc3c(c2)OC(C)(C)CC3)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCc2ccc(OCc3cc(F)c(C(=O)O)cc3Cl)cc2O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.8 %

Procedure:
A mixture of tert-butyl 5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-2-fluorobenzoate (290 mg, 0.689 mmol) and trifluoroacetic acid (10 mL) in DCM (10 mL) was stirred at room temperature for 16 hrs. The solvents were removed and the residue was extracted with EtOAc (150×3 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase combiflash (15%-19% MeCN in 0.5% NH4HCO3) to give target product of 5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-2-fluorobenzoic acid (100 mg, 49%) as a white solid. LCMS (ESI) m/z: 364.9 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:11](=[S:13])[NH2:12])=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.N1C=CC=CC=1>>[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:10][C:11](=[S:13])[NH2:12])=[O:21])=[CH:18][CH:17]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(NNC(N)=S)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N(NC(N)=S)c2ccc(OC)cc2)cc1
Yield: 33 %

Procedure:
A mixture of 2-(4-methoxyphenyl)hydrazinecarbothioamide (0.5 g, 2.53 mmol), 4-methoxybenzoyl chloride (541 mg, 3.17 mmol), and pyridine (0.256 mL, 3.17 mmol) intoluene (10 mL) was refluxed for 1 hour. After cooling, the solvent was removed under reduced pressure. diisopropyl ether and small amount of methanol was added to the residue and a generated precipitate was isolated by filtration, washed with methanol-diisopropyl ether, and dried in vacuo to give 2-(4-methoxybenzoyl)-2-(4-methoxyphenyl)hydrazinecarbothioamide (277 mg, 33% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([OH:34])[CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.O[CH2:39][CH2:40][CH2:41][N:42]([CH2:45][CH3:46])[CH2:43][CH3:44].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH2:43]([N:42]([CH2:45][CH3:46])[CH2:41][CH2:40][CH2:39][O:34][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[O:35][CH3:36])[N:27]=[CH:26][CH:25]=[C:24]2[O:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:11]2([C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:10])[CH2:12][CH2:13]2)=[O:15])=[CH:18][C:19]=1[F:37])[CH3:44]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1O
Reactant: CCN(CC)CCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCN(CC)CCCOc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccnc2cc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a slurry of cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(6-hydroxy-7-methoxy-quinolin-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (0.12 g, 0.23 mmol), hydroxypropyldiethylamine (0.090 mL, 0.61 mmol), triphenylphosphine (0.20 g, 0.76 mmol) in DCM (10 mL) was added DIAD (0.17 mL, 0.86 mmol). The resulting mixture was stirred at room temperature for 12 hours, after which time, the solvent was removed under reduced pressure. The residue was extracted with EtOAc and 1N HCl (6×) and brine (1×) followed by drying with Na2SO4. Concentration of the organic fraction in vacuo afforded ‘N-(4-{[6-{[3-(diethylamino)propyl]oxy}-7-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide as a yellow oil (0.18 g, wet, ca 95% purity by analytical HPLC). Further purification by preparatory HPLC using ammonium acetate afforded the product in 99% purity by analytical HPLC. LCMS: m/z 619 (M+H)+. 1H NMR (DMSO-d6) δ 10.37 (br s, 1H), 10.00 (s, 1H), 8.44 (d, 1H), 7.87 (d, 1H), 7.62 (m, 2H), 7.49 (m, 2H), 7.41 (m, 2H), 7.13 (t, 2H), 6.40 (d, 1H), 4.17 (t, 2H), 3.93 (s, 3H), 2.59 (t, 2H), 2.49 (m, 6H), 1.91 (m, 4H), 0.94 (t, 6H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=4)[CH2:12][NH:11][CH2:10]3)[O:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(C2CNCC(c3nc(C4CC4)no3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.23 g (7.38 mmol) of the compound from Example 182A were initially charged in 60 ml of dichloromethane and, at RT, reacted with 5.7 ml (8.42 g, 73.8 mmol) of trifluoroacetic acid. The reaction mixture was stirred at RT for 16 h and then concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 2.48 g (92% of theory)
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16](=O)C)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([N:31]3[CH2:35][CH2:34][CH2:33][C:32]3=[O:36])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O.C([O-])(O)=O.[Na+]>ClCCCl>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:19]3[CH2:20][CH2:21][CH:22]([C:25]4[CH:26]=[C:27]([N:31]5[CH2:35][CH2:34][CH2:33][C:32]5=[O:36])[CH:28]=[CH:29][CH:30]=4)[CH2:23][CH2:24]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2cc(C(C)=O)ccc21
Reactant: O=C1CCCN1c1cccc(C2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCn1c2ccccc2c2cc(CN3CCC(c4cccc(N5CCCC5=O)c4)CC3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.2 %

Procedure:
Prepared by Scheme R and Procedure F. A solution of 1-(9-ethyl-9H-carbazol-3-yl)ethanone (22.3 mg, 0.100 mmol) and 1-[3-(4-piperidinyl)phenyl]-2-pyrrolidinone (27.2 mg, 0.100 mmol) in 1,2-dichloroethane (1.00 mL) was treated with sodium triacetoxyborohydride (63.6 mg, 0.300 mmol) and HOAc (5.70 uL, 0.100 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was treated with a saturated aqueous NaHCO3 solution (10 mL). The aqueous layer was extracted with CH2Cl2 (3×10 mL) and the combined organic layers were washed with brine (10 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC using 5% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product 1-(3-{1-[(9-ethyl-9H-carbazol-3-yl)methyl]-4-piperidinyl}phenyl)-2-pyrrolidinone (4.60 mg, 9.43%): 1H NMR (400 MHz, CDCl3) δ 8.04 (d, 1H, J=7.4 Hz), 7.99 (s, 1H), 7.43–7.28 (m, 5H), 6.96 (d, 1H, J=7.4 Hz), 4.31 (q, 2H, J=6.8 Hz), 3.77 (t, 2H, J=7.3 Hz), 3.70 (s, 2H), 3.06 (d, 2H, J=10.6 Hz), 2.56–2.42 (m, 3H), 2.07 (m, 4H), 1.77 (m, 4H), 1.36 (m, 3H) ESMS m/e: 452.5 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][CH2:17][CH2:18]Cl)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C[N:21](C)[CH:22]=[O:23]>>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:17][CH2:18][NH:21][C:22]2=[O:23])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(NCCCl)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(N2CCNC2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (59 mg, 60% dispersion in oil, 1.5 mmol) was added to a solution of 1-t-butoxycarbonyl-4-(2-chloroethylamino)piperidine (305 mg, 0.98 mmol) in dimethylformamide (5 mL), and the reaction stirred at room temperature overnight. The reaction was quenched with water, filtered and purified by reverse phase HPLC(C-18, 5% to 95% 0.1% trifluoroacetic acid/acetonitrile in 0.1% aqueous trifluoroacetic acid, gradient elution), to give the title compound (30 mg). 1H NMR (500 MHz, CDCl3) □ 4.22 (br s, 3H), 3.88 (tt, J=4, 12 Hz, 1H), 3.52 (m, 2H), 3.46 (m, 2H), 2.79 (br t, 11 Hz, 2H), 1.72 (d, J=12 Hz, 2H), 1.56 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=3)[C:14]([O:16]C)=[O:15])[N:9]=2)[CH:4]=[CH:3][C:2]=1[C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26]C)=[O:25]>C1COCC1.CO.[OH-].[Na+]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=3)[C:14]([OH:16])=[O:15])[N:9]=2)[CH:4]=[CH:3][C:2]=1[C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([OH:26])=[O:25]
Reactant: COC(=O)c1cccc(-c2ccc3ccc(-c4cccc(C(=O)OC)c4)nc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(-c2ccc3ccc(-c4cccc(C(=O)O)c4)nc3n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.0 g dimethyl 3,3′-(1,8-naphthyridine-2,7-diyl)dibenzoate was dissolved in 60 mL of mixed solvent of THF and MeOH (v/v=1:1), 20 mL of 2N NaOH aqueous solution was added. The mixture was stirred at room temperature overnight. After the organic phase was removed, the aqueous phase was acidified with dilute hydrochloric acid to give white precipitate, which was filtered and washed with water several times. Yield: 1.73 g, 93%. 1H NMR (300 MHz, DMSO-d6): δ 7.74 (t, 2H), 8.12 (d, 2H), 8.36 (d, 2H), 8.60 (d, 2H), 8.64 (d, 2H), 8.97 (s, 2H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)[CH3:4].O[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=2)[C:20](=[O:31])[N:19]1[CH2:32][C:33]([F:36])([F:35])[F:34].CC(=O)OCC>COCCOC>[CH2:3]([O:5][C:6](=[O:16])[CH2:7][CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:25]=2)[C:20](=[O:31])[N:19]1[CH2:32][C:33]([F:34])([F:36])[F:35])[CH3:4]
Reactant: CS(=O)(=O)c1ccc2c(c1)C(O)N(CC(F)(F)F)C2=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)CC1c2cc(S(C)(=O)=O)ccc2C(=O)N1CC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.56 g of a 60% suspension of NaH in mineral oil were suspended in 20 ml of DME. Afterwards, 2.8 ml of (diethoxy-phosphoryl)-acetic acid ethyl ester were added dropwise at ambient temperature and the mixture stirred for 1 h at that temperature. A solution prepared of 3-hydroxy-5-methanesulfonyl-2-(2,2,2-trifluoro-ethyl)-2,3-dihydro-isoindol-1-one using 30 ml of DME was then added and the mixture was heated up to reflux. The mixture was refluxed for 4 h and then allowed to cool to ambient temperature. 300 ml of EA were added and the mixture was washed 3 times using 100 ml of saturated aqueous NaHCO3 solution each time. The aqueous layer was then extracted twice using 100 ml of EA each time. The combined EA layers were dried over Na2SO4 and the solvent was removed in vacuo. Chromatography on silica gel using MTB yielded 1.1 g of a colorless oil (Rf (MTB)=0.40; MS (DCI): 380 (M+1)+).
Reaction SMILES: [Br:1]Br.[CH:3]1([S:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[CH2:5][CH2:4]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.[Cl-].[Na+].O>[Br:1][C:10]1[CH:11]=[CH:12][C:7]([S:6][CH:3]2[CH2:5][CH2:4]2)=[C:8]([CH3:13])[CH:9]=1
Reactant: Cc1ccccc1SC1CC1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(Br)ccc1SC1CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 80 %

Procedure:
Bromine (0.42 mL) was added to a solution of 1-(cyclopropylsulfanyl)-2-methylbenzene (1.35 g) in acetic acid (10 mL) under ice-cooling, and the mixture was stirred at room temperature for 17 hours. The reaction solution was ice-cooled and a saturated sodium thiosulfate solution and brine were added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane only) and the solvent was evaporated under reduced pressure. The precipitated solid was filtered and washed with hexane, after which the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane only) to give the title compound as a pale yellow oil (1.59 g, 80%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH2:14][C:15]#[N:16].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>C(O)C.C(OCC)(=O)C>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[C:2]([CH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH2:14][CH2:15][NH:16][CH2:19][CH2:18][C:17]([O:21][CH2:22][CH3:23])=[O:20])#[N:1]
Reactant: C=CC(=O)OCC
Reactant: COc1cc(CC#N)c(CCN)cc1OC
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCNCCc1cc(OC)c(OC)cc1CC#N
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.3 %

Procedure:
A mixture of [2-(2-aminoethyl)-4,5-dimethoxyphenyl]acetonitrile (6.5 g, 29.5 mmol) and ethyl acrylate (3.9 ml, 36 mmol, 1.2 eq.) in 120 mL of ethanol is stirred for 20 hours at ambient temperature. The reaction mixture is subjected to drying in vacuo; then the crude reaction mixture is taken up in a mixture of ethyl acetate (133 mL) and ethanol (13 mL) and is heated at reflux in the presence of oxalic acid (2.52 g, 28 mmol, 0.95 eq.). Precipitation from the mixture occurs during contact at reflux. After returning to ambient temperature, the mixture is filtered and washed with 19 ml of ethyl acetate to obtain a white powder (9 g) corresponding to the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:3]=1.C([Li])CCC.[O:21]1[CH2:25][CH2:24]OS1(=O)=O.Cl>C1COCC1>[Cl:8][C:6]1[C:7]([CH2:24][CH2:25][OH:21])=[C:2]([Cl:1])[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:5]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)cc(Cl)n1
Reactant: O=S1(=O)OCCO1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H]1COCCN1c1nc(Cl)c(CCO)c(Cl)n1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3S)-4-(4,6-dichloropyrimidin-2-yl)-3-methylmorpholine (992 mg, 4.0 mmol) in THF (20 mL) was added n-butyllithium (1.56 mL, 1.6 M) dropwise at −78° C. and the mixture was stirred for 30 min. 1,3,2-dioxathiolane 2,2-dioxide (672 mg, 5.41 mmol) was added, and stirring was continued for 30 min, whereupon 6 N HCl (13.3 mL) was added. The reaction mixture was stirred for 18 h and then heated at 40° C. for 4 h. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried with MgSO4, filtered and concentrated by rotary evaporation.
Reaction SMILES: [C:1]1([C:7]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:11][C:10](=[O:12])[N:9]([CH2:13][OH:14])[C:8]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22][CH:23]([CH3:27])[C:24](Cl)=[O:25]>C(OCC)C>[Br:22][CH:23]([CH3:27])[C:24]([O:14][CH2:13][N:9]1[C:8](=[O:15])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:11][C:10]1=[O:12])=[O:25]
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CO
Reactant: CC(Br)C(=O)Cl
Solvent: CCOCC
Product: CC(Br)C(=O)OCN1C(=O)NC(c2ccccc2)(c2ccccc2)C1=O

Procedure:
5,5-Diphenyl-3-hydroxymethyl-2,4-imidazolidinedione (2 g, 0.0071 mol) was dissolved in 2-bromopropionyl chloride (8.5 g, 5 mL, 0.05 mol) by heating for 30 minutes on a 100°-110° C. oil bath. The reaction mixture was cooled, 20 mL of ethyl ether were added, and the resultant solution was extracted with aqueous potassium carbonate, dried and then crystallized. The product was obtained as a solid white substance (1 g, 34%), m.p. 112°-115° C. Anal. calc. for C19H17N2O4Br: C, 54.69; H, 4.11; N, 6.72; Br, 19.15. Found: C, 54.77; H, 4.15; N, 6.69; Br, 19.25. The product had the formula: ##STR77##
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[CH2:9][C@@H:10]3[C@H:14]([CH2:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C@@H:11]3[C:12]=2[CH:13]=1)=[O:5])C.[OH-].[Li+].CO>C1COCC1>[CH2:15]([C@H:14]1[C@H:10]2[CH2:9][C:8]3[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:13][C:12]=3[C@@H:11]12)[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1cc2c([nH]1)C[C@@H]1[C@H](CCc3ccccc3)[C@H]21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)C[C@@H]1[C@H](CCc3ccccc3)[C@H]21

Procedure:
The title compound was synthesized from ±(1S,1aS,5aR)-1-phenethyl-1a,4,5,5a-tetrahydro-1H-4-aza-cyclopropa[α]pentalene-3-carboxylic acid ethyl ester (295 mg, 1.0 mmol) and lithium hydroxide (419 mg, 10.0 mmol in 7 mL water) according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (14 mL) was used. The resulting product was purified by chromatography, eluting with heptane-EtOAc, 0 to 50% EtOAc. 225 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.93-1.06 (m, 1H), 1.07-1.17 (m, 1H), 1.24-1.38 (m, 1H), 1.98 (q, J=6.90 Hz, 1H), 2.20 (t, J=6.74 Hz, 1H), 2.50 (d, J=17.33 Hz, 1H), 2.53-2.61 (m, 2H), 2.88 (dd, J=17.23, 7.13 Hz, 1H), 6.80 (d, J=1.51 Hz, 1H), 7.07 (d, J=7.08 Hz, 2H), 7.16 (d, J=7.32 Hz, 1H), 7.24 (t, J=7.39 Hz, 2H), 8.81 (br. s, 1H). LCMS m/e 268 (M+H). Purity 98% (HPLC).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].C1(CNC([C:18]2[CH:35]=[CH:34][C:21]3[NH:22][C:23]([C:25]4[C:33]5[C:28](=CC=CC=5)[NH:27][N:26]=4)=[N:24][C:20]=3[CH:19]=2)=O)CCCCC1>>[CH2:3]([O:4][C:28]1[NH:27][N:26]=[C:25]([C:23]2[NH:22][C:21]3[CH:34]=[CH:35][CH:18]=[CH:19][C:20]=3[N:24]=2)[CH:33]=1)[CH3:2]
Reactant: O=C(NCC1CCCCC1)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Reactant: O=C(O)C(F)(F)F
Product: CCOc1cc(-c2nc3ccccc3[nH]2)n[nH]1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
A mixture of trifluoroacetic acid (6 mL) and 2-(5-ethoxy-1H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (300 mg, Reference Example 11) was stirred at 50° C. for 1.5 hours. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and water (pH 10). The organic layer was dried and then evaporated. The residue was subjected to chromatography on silica eluting with a mixture of dichloromethane and methanol (9:1, v/v) and then recrystallised from toluene to give 2-(5-ethoxy-1H-pyrazol-3-yl)-1H-benzoimidazole (0.1 g) as a colourless solid, mp 217-219.5° C. [Elemental analysis: C, 62.26%; H, 5.23%; N, 23.44%. Calculated for C12H12N4O: C, 63.15%; H, 5.30%; N, 24.55%].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4](=[O:8])[CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: O=c1cc(Br)cc[nH]1
Product: CCOC(=O)Cn1ccc(Br)cc1=O

Procedure:
5.0 g (28.7 mmol) of 4-bromopyridin-2(1H)-one and 5.3 g (31.6 mmol) of ethyl bromoacetate were reacted according to General Method 4B. Yield: 6.2 g (83% of theory)