Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH2:14][CH2:15][OH:16])=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].[CH2:17]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)N)[CH3:18]>>[CH2:17]([C:19]1[CH:20]=[C:21]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([O:13][CH2:14][CH2:15][OH:16])[C:3]=23)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH3:18]
Reactant: CCc1cc(N)ccc1OCc1ccccn1
Reactant: CN(C)C=Nc1[nH]nc(OCCO)c1C#N
Product: CCc1cc(Nc2ncnc3[nH]nc(OCCO)c23)ccc1OCc1ccccn1
Yield: 54.5 %

Procedure:
The procedure described in Example 1 was repeated using N′-[4-cyano-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide (655 mg, 2.82 mmol) and 3-ethyl-4-(pyridin-2-ylmethoxy)aniline (786 mg, 3.10 mmol) to give the title compound as a white solid (625 mg, 55%); NMR spectrum: 1.20 (t, 3H), 2.66 (q, 2H), 3.79 (d, 2H), 4.30 (td, 2H), 5.21 (s, 2H), 7.02 (d, 1H), 7.36 (m, 2H), 7.43 (dd, 1H), 7.85 (td, 1H), 8.20 (s, 1H), 8.35 (s, 1H), 8.60 (d, 1H); Mass Spectrum: 407 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].C([Li])CCC.[CH2:16]1[O:18][CH2:17]1>O1CCCC1.CCCCCC>[OH:18][CH2:17][CH2:16][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[O:9][CH3:10]
Reactant: C1CO1
Reactant: COc1ccccc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(CCO)c1OC
Reaction time: 17 h
Yield: 18.9 %

Procedure:
To 20 g (0.145 mol) of 1,2-dimethoxybenzene in 300 mL of anhydrous tetrahydrofuran stirred at room temperature under argon was added 90 mL (0.145 mol) of 1.6M butyl lithium in hexane over 30 minutes. The reaction mixture was stirred and heated at 40° for 4 hours and then cooled in an ice bath. Ethylene oxide (14 mL, 0.29 mol) was allowed to distill into the ice cooled reaction mixture over 45 minutes. The reaction mixture was stirred with ice bath cooling for 1.5 hours and then at room temperature for 17 hours. Most of the solvent was removed under reduced pressure and water was added to the residue. The product was extracted with ether and the dried extract was concentrated under reduced pressure to an oil. The remaining 1,2-dimethoxybenzene (7.5 g) was removed by distillation (bp 45°-60°/0.2 mm) and the residue was purified by HPLC using 20% ethylacetate-toluene to give 5 g (19% yield) of 1-(2-hydroxyethyl)-2,3-dimethoxybenzene. This intermediate (5 g, 0.028 mol) was dissolved in 100 mL of anhydrous methylene chloride and the solution was cooled in an ice bath. Triethylamine (7.7 mL, 0.056 mol) was added and followed by 2.6 mL (0.033 mol) of methane sulfonyl chloride added dropwise. The reaction mixture was stirred with ice bath cooling for two hours and then was washed with water, with sodium bicarbonate solution, dried and concentrated under reduced pressure to give (7.2 g) of 1-[(2-methanesulfonyloxy)ethyl]-2,3-dimethoxybenzene as an oil which was used without purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=[O:6].[F:14]C1C=C(C=CC=1O)C=O>>[F:14][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: O=Cc1cc(Cl)c(O)c([N+](=O)[O-])c1
Product: O=Cc1cc(F)c(O)c([N+](=O)[O-])c1
Yield: 53 %

Procedure:
Followed procedure described for Intermediate 59, starting with 3-fluoro-4-hydroxybenzaldehyde. Desired product isolated in 53% yield.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10](=[O:20])[C:11](=[C:17]([CH3:19])[CH3:18])[O:12]2.[Cl:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][CH:24]=1>CC(=O)CC>[Cl:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][O:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[O:20])[C:11](=[C:17]([CH3:18])[CH3:19])[O:12]3)=[CH:25][CH:24]=1
Reactant: ClCc1ccc(CCl)cc1
Reactant: CC(C)=C1Oc2cccc(O)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)=C1Oc2cccc(OCc3ccc(CCl)cc3)c2C1=O
Yield: 19.8 %

Procedure:
2.8 g Potassium carbonate is added over 3 hours to a mixture of 3.8 g 4-hydroxy-2-isopropylidenecoumaran-3-one, 3.5 g 1,4-bis-(chloromethyl)benzene and 150 ml butanone at 70-75° C. The mixture is refluxed for 16 hours, then filtered, the filtrate evaporated and the residue purified by silica gel chromatography (eluent isohexane/ethyl acetate 3:1) to give 1.3 g of the desired intermediate.
Reaction SMILES: [NH2:1][CH:2]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)[OH:4].[C:23]1([C:33](Cl)=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH:2]([NH:1][C:33]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)=[O:34])[CH:3]([OH:4])[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][CH:6]=2)=[CH:21][CH:20]=1
Reactant: NC(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (15 ml) were added 1-naphthoyl chloride (282 ml, 1.87 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml), and the mixture was stirred at room temperature for 2 hrs. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (614 mg, 91%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:21][CH2:22][N:23]3[C@H:28]4[CH2:29][CH2:30][C@@H:24]3[CH2:25][CH:26]([N:31]3[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[N:33]=[C:32]3[CH3:40])[CH2:27]4)[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]([NH2:20])[CH:17]([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:41][CH:42]([Cl:46])[C:43](Cl)=[O:44].CCN(C(C)C)C(C)C>>[Cl:41][CH:42]([Cl:46])[C:43]([NH:20][C@H:16]([C:14]([N:11]1[CH2:12][CH2:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)([CH2:21][CH2:22][N:23]2[C@H:24]3[CH2:30][CH2:29][C@@H:28]2[CH2:27][CH:26]([N:31]2[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=[C:32]2[CH3:40])[CH2:25]3)[CH2:9][CH2:10]1)=[O:15])[CH:17]([CH3:18])[CH3:19])=[O:44]
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H](N)C(C)C)CC1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H](NC(=O)C(Cl)Cl)C(C)C)CC1

Procedure:
2,2-dichloro-N-{(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2-methylpropyl}acetamide was obtained from treating 1,1-dimethylethyl {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-2-methylpropyl}carbamate (0.614 g, 0.95 mmol) with HCl as outlined in the procedure for Example 890 to form {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S) 3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-2-methylpropyl}amine (0.512 g, 99%). {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-2-methylpropyl}amine (0.050 g, 0.09 mmol), Dichloro-acetyl chloride (0.013 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2,2-dichloro-N-(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2-methylpropyl}acetamide (0.031 g, 53%) as an oil. ES-LCMS m/z 656 (M+1).
Reaction SMILES: [CH:1]1(O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:26](C(OC(C)(C)C)=O)=[N:27]C(OC(C)(C)C)=O.[ClH:42].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>O1CCCC1.O>[ClH:42].[ClH:42].[CH:1]1([NH:26][NH2:27])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCC1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NNC1CCCC1
Temperature: 5 °C
Reaction time: 5 h

Procedure:
Cyclopentanol (6.127 kg, 71.1 moles) and triphenylphosphine (18.667 kg, 71.25 moles) were dissolved in tetrahydrofuran (40 gal) in a clean and dry, nitrogen purged 100 gallon tank and the reaction mixture was cooled to 5° C. A solution of di-t-butyl azodicarboxylate (14.9 kg, 64.7 moles) in tetrahydrofuran (36 L) was added over about 2 hours keeping the temperature <6° C. The reaction was allowed to stir for 5 hours as the temperature was allowed to slowly increase to 20-25° C. 6N HCl (26.5 L) was added to the reaction which was at 20° C. The reaction was allowed to stir 24 hours at 20-25° C. at which point the starting material had reacted. Water (10 gal, 37.85 L) was added and the tetrahydrofuran was removed by vacuum distillation. During the concentration, triphenylphosphine oxide precipitated and an additional 20 gal (75.7 L) of water was added. The reaction was cooled and methylene chloride (30 gal, 113.6 L) was added. The layers were separated and the aqueous was extracted twice more with methylene chloride (10 gal, 37.85 L) The aqueous was distilled to remove water. As the volume was reduced, isopropanol (3×20 gal (75.7 L)) was added to azeotrope the residual water. The resulting slurry was filtered and the solids were vacuum oven dried to give 7.682 kg (68.6% of theoretical) over multiple crops. This material was characterized to be the dihydrochloride salt; mp 189-194° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[CH2:7]([N:9]1[C:13]2[CH:14]=[CH:15]C(C([O-])=O)=[CH:17][C:12]=2[N:11]=[C:10]1[CH2:21][C:22]1[N:23]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[N:24]=[CH:25][CH:26]=1)[CH3:8]>CN(C=O)C.ClCCl>[CH2:10]([NH:9][C:1]([C:2]1[CH:15]=[CH:14][C:13]2[N:9]([CH2:7][CH3:8])[C:10]([CH2:21][C:22]3[N:23]([C:27]4[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=4[F:34])[N:24]=[CH:25][CH:26]=3)=[N:11][C:12]=2[CH:17]=1)=[O:5])[C:21]#[CH:22]
Reactant: CCn1c(Cc2ccnn2-c2cc(F)ccc2F)nc2cc(C(=O)[O-])ccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C#CCNC(=O)c1ccc2c(c1)nc(Cc1ccnn1-c1cc(F)ccc1F)n2CC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (2.5 eq of 2M in dichloromethane) is added dropwise to a solution of 1-ethyl-2-{[2-(2,5-difluorophenyl)-pyrazol-3-yl]methyl}-1H-benzimidazole-5-carboxylate (368 mg) in DMF (5 drops) and dichlormethane (30 mL) at 0° C. The mixture is stirred at 0° C. for 0.5 h, then at room temperature for 1 h. The solution is concentrated, the residue taken up in DMF (30 ml), excess propargylamine added, and the mixture stirred for 6 h. Dilute aqueous sodium bicarbonate is added then extracted with dichloromethane (3×), the combined organic layers washed with saturated aqueous sodium chloride, dried (MgSO4), and concentrated to give 462 mg of crude N-propargyl 1-ethyl-2-{[2-(2,5-difluorophenyl)-pyrazol-3-yl]methyl}-1H-benzimidazole-5-carboxamide.
Reaction SMILES: [NH2:1][N:2]1[C@H:6]([CH2:7][O:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][C:3]1=O.[CH:29]([NH2:31])=O>CN(C=O)C.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[C:9]([O:8][CH2:7][C@H:6]1[N:2]2[N:1]=[CH:29][N:31]=[C:3]2[CH2:4][CH2:5]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NN1C(=O)CC[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(C(OC[C@@H]2CCc3ncnn32)(c2ccccc2)c2ccccc2)cc1
Temperature: 160 °C
Yield: 48.8 %

Procedure:
To a stirred solution of 0.540 g (1.45 mmol) of (5S)-1-amino-5-[(trityloxy)methyl]pyrrolidin-2-one from step A above in 5 mL of anhydrous DMF was added 0.327 g (7.25 mmol) of formamide followed by 0.050 g (0.36 mmol) of zinc(II) chloride. The resulting mixture was heated to 160° C. for 48 h, cooled to ambient temperature and diluted with 25 mL of ethyl acetate. The solution was washed sequentially with an aqueous sodium bicarbonate solution, water and then brine and the organic layer dried over magnesium sulfate. The mixture was then filtered, evaporated to dryness in vacuo and purified by silica gel chromatography eluting with a 0-100% ethyl acetatae in hexanes gradient to afford the title compound (0.27 g, 49%). LC-MS: m/z (ES) 382 (MH)+.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[N:25](OCCCC)=O>C(#N)C>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[N:14]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[N:25]=[N:24][C:8]=12)[CH2:4][CH3:5])[CH3:2]
Reactant: CCCCON=O
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Solvent: CC#N
Product: CCC(CC)Oc1cc(C)nc2c1nnn2-c1c(C)cc(C)cc1C
Temperature: 65 °C
Yield: 112 %

Procedure:
A mixture of 4-(1-Ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diamine (50 mg, 0.153 mmol) and butyl nitrite (24 mg, 0.229 mmol) in 4 ml acetonitrile was heated at 65° C. for 2 hours. An additional 0.13 ml of butyl nitrite was added and the resulting mixture was heated at 65° C. for 2 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 58 mg of brown oil. The oil was purified through silica gel column chromatography using 5% ethyl acetate in hexane as eluent to give 46 mg (88%) of the title compound as a light yellow oil. 1H NMR (CDCl3) ä 7.04(s, 2H), 6.60(s, 1H), 5.26(m, 1H), 2.57(s, 3H), 2.38(s, 3H), 1.94(s, 6H), 1.8-2.0(m, 4H), 1.07(t, 6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11](=[O:24])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH3:9])=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:11]([NH:10][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:3][CH:4]=2)[CH3:9])=[O:24])=[CH:19][CH:18]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](NC(=O)COc1ccc(C(C)(C)C)cc1)c1ccc(N)cc1
Solvent: c1ccncc1
Product: C[C@@H](NC(=O)COc1ccc(C(C)(C)C)cc1)c1ccc(NS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
To a pyridine (5.0 ml) solution of N-[(1R)-1-(4-aminophenyl)ethyl]-2-(4-tert-butylphenoxy)acetamide (420 mg, 1.0 mmol), methanesulfonyl chloride (114 mg, 1.0 mmol) was added at 0° C. and the mixture was stirred for 3 hours at 0° C. The reaction mixture was then quenched with 2 M HCl and then crude products were extracted with methylene dichloride The organic layer was then washed with brine, dried over Na2SO4. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with methylene dichloride/ethylacetate=1/1 to furnish 120 mg (29% yield) of the title as a white solid.
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: N#Cc1cccnc1F
Product: N#Cc1cccnc1NCc1ccccc1
Yield: 66 %

Procedure:
Prepared in 66% yield from 2-fluoronicotinonitrile and benzylamine according to the procedure described for Example 178A. MS (ESI+) m/z 210.0 (M+H)+; 1H NMR (DMSO-d6) δ 4.59 (d, J=6.1 Hz, 2H), 6.64 (dd, J=7.6, 4.9 HZ, 1H), 7.16-7.24 (m, 1H), 7.26-7.32 (m, 5H), 7.71 (dd, J=5.9, 5.9 Hz, 1H), 7.91 (dd, J=7.6, 1.9 Hz, 1H), 8.23 (dd, J=4.9, 1.9 Hz, 1H).
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:7][CH2:6][CH:5]([CH2:8][C@H:9]2[CH2:14][C@H:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH2:4][CH2:3]1.[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1([F:27])[CH2:7][CH2:6][CH:5]([CH2:8][C@H:9]2[CH2:14][C@H:13]([C:15]3[O:22][NH:30][C:17](=[O:18])[CH:16]=3)[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH2:4][CH2:3]1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](CC2CCC(F)(F)CC2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1CC1CCC(F)(F)CC1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 96.8 %

Procedure:
Trans-methyl 2-((4,4-difluorocyclohexyl)methyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (300 mg, 0.77 mmol) (from example 89, step 1) was dissolved in MeOH (3 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.227 mL, 0.77 mmol) dissolved in water (0.300 mL) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.047 mL, 0.77 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h 15 min. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (4 mL, 24.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield crude trans-methyl 2-((4,4-difluorocyclohexyl)methyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (267 mg, 97%) as a slightly yellow solid. MS m/z 357 (M−H)−
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.[CH:12]1([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=2)[CH2:14][CH2:13]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[Br:1][C:24]1[C:15]([CH:12]2[CH2:14][CH2:13]2)=[CH:16][C:17]([O:25][CH2:26][CH3:27])=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOc1cc(C2CC2)ccc1C(=O)OC
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(C2CC2)c(Br)cc1C(=O)OC
Temperature: 90 °C
Reaction time: 1 h
Yield: 154 %

Procedure:
Dibromoisocyanuric acid (2.54 g) was added at room temperature to a DMF (60 mL) solution of methyl 4-cyclopropyl-2-ethoxybenzoate (3.25 g), and the mixture was stirred at 90° C. for 1 hour in a nitrogen atmosphere. Dibromoisocyanuric acid (423 mg) was added to the reaction mixture, and the mixture was stirred at 90° C. for 30 minutes in a nitrogen atmosphere. An aqueous sodium thiosulfate solution was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (4.08 g).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12]>C(OCC)(=O)C>[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:12]
Reactant: O=C(Cl)CCCCBr
Reactant: CS(N)(=O)=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC(=O)CCCCBr
Temperature: 87.5 °C
Yield: 88.3 %

Procedure:
A mixture consisting of methanesulfonamide (4.76 g) and 5-bromovaleric acid chloride (10 g) was heated at 85-90° C. for one hour, was cooled to room temperature, and was diluted with ethyl acetate (75 mL). The solution was washed with water, brine, and dried over sodium sulfate. The solution was filtered and evaporated to 40 mL of solvent, then cooled to −15° C. A white precipitate formed, which was collected by filtration to afford the title intermediate (11.4 g, 88%) as a white solid; melting point 98-100° C.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:48][C:49]1[CH:54]=[CH:53]C=[CH:51][C:50]=1O)[C:6]([NH:8][CH:9]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH:18]([C:30](=[O:33])[NH:31][CH3:32])[CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[CH2:14][CH:13]1[CH2:34][CH2:35][O:36]C(=O)C)=[O:11])=[O:7])(=[O:3])[CH3:2].[O:56]([CH3:58])[Na]>CO>[C:1]([NH:4][CH:5]([CH2:48][C:49]1[CH:54]=[CH:53][C:58]([OH:56])=[CH:51][CH:50]=1)[C:6]([NH:8][CH:9]([CH2:40][C:41]1[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH:18]([CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[C:30]([NH:31][CH3:32])=[O:33])[CH2:14][CH:13]1[CH2:34][CH2:35][OH:36])=[O:11])=[O:7])(=[O:3])[CH3:2]
Reactant: CO[Na]
Reactant: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(Cc2ccc(F)cc2)NC(=O)C(Cc2ccccc2O)NC(C)=O)C(CCOC(C)=O)C1
Solvent: CO
Product: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(Cc2ccc(F)cc2)NC(=O)C(Cc2ccc(O)cc2)NC(C)=O)C(CCO)C1
Reaction time: 8 h

Procedure:
To a solution acetic acid 2-[1-{2-[2-acetylamino-3-(hydroxyphenyl)propionylamino]-3-(4-fluorophenyl)propionyl}-4-(1-methylcarbamoyl-2-naphthalen-2-ylethyl)piperazin-2-yl]ethyl ester, 65, (7.5 g, 10 mmol) in methanol (50 mL) is added freshly prepared NaOCH3 (0.55 g, 10.1 mmol) and the solution stirred overnight. The solution is concentrated in vacuo, the resulting residue partitioned between dichloromethane and water, the organic layer is dried and concentrated in vacuo to afford the desired product.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C@@:3]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[CH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1)(O)[CH2:4][C:5]1[NH:6][CH:7]=[C:8]([CH2:10][C:11]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12]2)[N:9]=1.C(OC(=O)C)(=O)C.[OH-].[Na+]>C(O)(=O)C>[F:31][C:2]([F:1])([F:30])/[C:3](/[C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH:29]=[CH:28][CH:27]=[N:26]2)=[CH:23][CH:24]=1)=[CH:4]\[C:5]1[NH:6][CH:7]=[C:8]([CH2:10][C:11]2([C:14]([F:15])([F:16])[F:17])[CH2:12][CH2:13]2)[N:9]=1
Reactant: O[C@](Cc1nc(CC2(C(F)(F)F)CC2)c[nH]1)(c1ccc(-n2cccn2)cc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: FC(F)(F)/C(=C\c1nc(CC2(C(F)(F)F)CC2)c[nH]1)c1ccc(-n2cccn2)cc1

Procedure:
A suspension of (2R)-1,1,1-trifluoro-2-[4-(1H-pyrazol-1-yl)phenyl]-3-(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1H-imidazol-2-yl)propan-2-ol in acetic acid (10 mL)/acetic anhydride (10 mL) was heated to reflux. The reaction mixture was poured into 1M sodium hydroxide solution until basic and extracted with diethyl ether. The crude product was dissolved in a mixture of methanol and acetonitrile and charged with 1M sodium hydroxide. It was heated to reflux overnight, and the reaction mixture was extracted with diethyl ether. The combined organic extracts were washed with brine, dried (potassium carbonate) and concentrated in vacuo to afford 1-{4-[(Z)-1-(trifluoromethyl)-2-(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1H-imidazol-2-yl)vinyl]phenyl}-1H-pyrazole, which was used without further purification.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: NCc1ccc(F)cc1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NCc3ccc(F)cc3)cc2c1=O
Yield: 12.5 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 4-fluoro-benzylamine according to the GPA affording 5 mg (12.5%) of a red powder. Rt=5.00 min.