Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:6]([CH2:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)[CH:7]=[CH:8][CH:9]=1)=[O:4].[OH-:25].[Na+].Cl.[CH3:28]O>O>[O:22]=[C:11]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1)[CH2:10][N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3]([O:4][CH3:28])=[O:25]
Reactant: O=C(Cn1cccc1C(=O)C(Cl)(Cl)Cl)c1ccc(C(F)(F)F)cn1
Reactant: [OH-]
Reactant: CO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cccn1CC(=O)c1ccc(C(F)(F)F)cn1
Reaction time: 1 h

Procedure:
To a chilled (0° C.) solution of 2,2,2-trichloro-1-(1-{2-oxo-2-[5-(trifluoromethyl)pyridin-2-yl]ethyl}-1H-pyrrol-2-yl)ethanone (105 mg, 0.26 mmol) in MeOH (7 mL) was added an aqueous solution of sodium hydroxide (1 M), (0.26 mL, 0.26 mmol). The solution was allowed at room temperature. After one hour the reaction was complete (monitored by LCMS). The mixture was acidified with 1 M HCl (aq), diluted with water (10 mL) and partially concentrated in vacuo to remove the MeOH. The aqueous mixture was then extracted with CH2Cl2 (3×4 mL). The organic layers were combined, dried (MgSO4), filtered and the filtrate concentrated in vacuo to yield methyl 1-{2-oxo-2-[5-(trifluoromethyl)pyridin-2-yl]ethyl}-1H-pyrrole-2-carboxylate as a brown oil (85 mg, quantitative yield) ESI-MI m/z [M+H]+ 312.9.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C@H:9]3[CH2:13][NH:12][C:11](=O)[C@@H:10]3[C:4]=2[CH:3]=1.Cl.C(O)C>O1CCCC1>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C@H:9]3[CH2:13][NH:12][CH2:11][C@@H:10]3[C:4]=2[CH:3]=1
Reactant: O=C1NC[C@@H]2c3ccccc3Oc3ccc(Cl)cc3[C@@H]12
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)[C@H]1CNC[C@@H]1c1ccccc1O2
Temperature: -2 °C
Reaction time: 20.5 h

Procedure:
0.53 g (1.9 mmol) of trans-11-chloro-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one (compound trans-XVIIa) was suspended in 5 mL of anhydrous tetrahydrofuran and cooled to −2° C. 8.8 mL of borane-tetrahydrofuran complex (8.7 mmol) were added dropwise and the obtained solution was allowed to warm up to room temperature. The reaction mixture was stirred for 20.5 h and 5 mL of anhydrous tetrahydrofuran were added. After further 25 h at room temperature, 8.8 mL of borane-tetrahydrofuran complex (8.7 mmol) were added and the mixture stirred for 4 h before adding 1.25 M hydrogen chloride in ethanol (25.2 mL, 31.5 mmol). After 3 days the reaction mixture was rotary evaporated and toluene (25 mL) and 1 M sodium hydroxide (10.5 mL) were added to the residue. More toluene (25 mL) and water (10 mL) were added and the mixture vigorously stirred for about 2.5 h. Then the layers were separated and the aqueous layer was extracted with toluene (25 mL), twice. The organic layers were combined and washed with 0.1 M sodium hydroxide (4 mL), dried with anhydrous sodium sulfate, filtered and rotary evaporated.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C.[C:22](Cl)([Cl:24])=[O:23]>C(OCC)C>[C:9]1([N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:22]([Cl:24])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=1
Reactant: Cc1ccccc1N=C1CCCCC1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccccc1N(C(=O)Cl)C1=CCCCC1

Procedure:
187 parts of cyclohexanone-o-methylphenylimine and 120 parts of triethylamine are added in portions and at 0° to 10° C. to a solution of 120 parts of phosgene in 400 parts of diethyl ether over a period of 1 hour in a manner analogous to that employed in Example 10. The mixture is stirred for another hour. The end product is then isolated analogously to Example 10. 216 parts (87% of the theory) of N-1-cyclohexenyl-N-o-methylphenylcarbamyl chloride is obtained having a boiling point of 132° C. at 0.3 mm.
Reaction SMILES: [F-:1].CC(CC(O)CO)C.Cl[C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].C1(C)C(C)=CC=CC=1>>[Cl:17][C:16]1[C:11]([F:1])=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=[CH:14][CH:15]=1
Reactant: [F-]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: CC(C)CC(O)CO
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1cccc(Cl)c1F
Temperature: 100 °C
Reaction time: 24 h

Procedure:
In a 1.5 liter flange flask and fitted with a distillation bridge and impeller stirrer, 279 g (4.8 tool) of fluoride, 218.5 g (0.3 mol) of trimethyl(ethoxypolyoxypropyl)ammonium chloride and 11.5 g (0.023 mol) of polyethylene glycol dimethyl ether 500 were introduced at 100° C. into the melt of 768 g (4 mol) of 2,3-dichloronitrobenzene. Subsequently, the mixture was azeotropically dried using 200 g (1.9 mol) of xylene and stirred for 24 hours at a temperature of 100° C. Amount of 3-chloro-2-fluoronitrobenzene formed: after 5 hours: 18 GC area-%. after 24 hours: 47 GC area-%.
Reaction SMILES: [OH:1][CH:2]1[C:7]2[CH:8]=[C:9]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])[S:10][C:6]=2[S:5](=[O:20])(=[O:19])[NH:4][CH2:3]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.OS(O)(=O)=O>CC(C)=O.O>[CH3:18][C:15]([NH:14][S:11]([C:9]1[S:10][C:6]2[S:5](=[O:20])(=[O:19])[NH:4][CH2:3][C:2](=[O:1])[C:7]=2[CH:8]=1)(=[O:13])=[O:12])([CH3:16])[CH3:17]
Reactant: CC(C)(C)NS(=O)(=O)c1cc2c(s1)S(=O)(=O)NCC2O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1cc2c(s1)S(=O)(=O)NCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of 3,4-dihydro-4-hydroxy-N-(1,1-dimethylethyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide (3.36 g, 9.87 mmol) in acetone (15 mL) at room temperature was added Jones reagent [2 mL (prepared by dissolving CrO3 (7 g) in H2O (50 mL) and adding H2SO4 (6.1 mL)]. The mixture was stirred at room temperature for one hour, solvent was evaporated and the residue dissolved in ethyl acetate (75 mL). This solution was washed with saturated aqueous sodium bicarbonate until the the organic layer was neutral. The aqueous layer was separated and washed with ethyl acetate (3'25 mL). The combined extracts were dried (NaSO4) and evaporated to provide a residue which was purified by column chromatography (silica, 40% ethyl acetate in hexane) to give an off-white solid (2.74 g, 82%): mp 170°-172° C.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17](OCC)=[O:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:24]([Mg]Br)[CH3:25].[CH2:28]1COC[CH2:29]1>>[F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([OH:18])([CH2:24][CH3:25])[CH2:28][CH3:29])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: C1CCOC1
Reactant: CC[Mg]Br
Reactant: CCOC(=O)CCN1CCC(c2noc3cc(F)ccc23)CC1
Product: CCC(O)(CC)CCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 17 h
Yield: 61 %

Procedure:
To a solution of ethyl 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propionate (3.9 g, 12.0 mmol) in THF (100 ml) was added ethylmagnesium bromide (12.0 ml, 36.0 mmol, 3.0M in ether) at room temperature under nitrogen (mild exotherm). The reaction mixture was stirred for 17 hours at which time it was carefully quenched with NH4Cl (sat., 20 ml). The precipitated salts were dissolved into water (25 ml) and the layers were separated. The aqueous phase was extracted with EtOAc (2×) and the combined organics were washed with brine and dried (Na2SO4). Filtration and concentration gave the crude product which was purified via flash column chromatography (silica gel, 1% MeOH/DCM) to give 2.4 g (61%) of the desired product as an oil which solidified on standing, m.p.=50°-53° C.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([CH:7]2[NH:11][CH2:10][CH2:9][CH2:8]2)[CH:2]=1.C=O.[CH:14](O)=O.[OH-].[Na+]>O>[CH3:14][N:11]1[CH:7]([C:3]2[CH:2]=[CH:1][CH:6]=[N:5][CH:4]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: O=CO
Reactant: c1cncc(C2CCCN2)c1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCCC1c1cccnc1
Temperature: 85 °C
Reaction time: 20 h
Yield: 81.2 %

Procedure:
To a solution of nornicotine (50 g 0.338 mol) in 100 ml water a mixture of 37% formaldehyde (49.7 g, 1.656 mol) and 85% formic acid (37.26 g 0.81 moles) was added and stirred at 85° C. for 20 hrs. The reaction was cooled and pH adjusted to >13 using NaOH, extracted with dichloromethane (100 ml×3) dried over Na2SO4 and solvent removed completely to get crude oil (52.5 g, 94.33% purity by GC). It was further purified by high vacuum distillation at 0.1 mm Hg to obtain colorless (R,S)-nicotine (44.54 g, 81.3% yield, 99.1% purity by GC). 1H NMR (CDCl3): δ 1.72-2.0 (3H, m), 2.1 (3H, s), 2.25 (1H, m), 2.3 (1H, m), 3.08 (1H, m), 3.23 (1 h, t), 7.25 (1H, m), 7.69 (1H, dt), and 8.5 (2H, m). 13C-NMR (CDCl3): 149.71, 148.76, 139, 134.97, 123.7, 68.9, 57.1, 40.5, 35.5, and 22.83. IR: 3233, 1642, and 1402 Cm−1.
Reaction SMILES: [Cl-].[Br:2][C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8][OH:9])=[CH:5][CH:4]=1.[CH2:12]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.O>O1CCCC1>[CH2:12]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:9][N:8]=[C:7]([C:6]3[CH:10]=[CH:11][C:3]([Br:2])=[CH:4][CH:5]=3)[CH:25]=2)=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: ON=Cc1ccc(Br)cc1
Reactant: C#Cc1ccc(OCCCCC)cc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCOc1ccc(-c2cc(-c3ccc(Br)cc3)no2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
To a solution of 4-bromobenzaldehyde oxime chloride (647 mg) and 4-n-pentyloxy-phenylacetylene (650 mg) in tetrahydrofuran (7 ml) was added triethylamine (0.5 ml) in tetrahydrofuran (5 ml) dropwise at 40° C. The solution was stirred at 40° C. for 30 minutes, poured into water and extracted with ethyl acetate. The organic layer was washed with H2O, brine and dried over magnesium sulfate. The solvents were removed under reduced pressure and the residue was triturated with acetonitrile. The precipitate was collected by filtration and dried to give 4-[5-(4-n-pentyloxyphenyl)isoxazol-3-yl]bromobenzene (0.59 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.O=S(Cl)Cl.CCOC(C)=O.[NH4+:25].[OH-]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:5]([C:6]([NH2:25])=[O:7])=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: O=C(O)c1cnc(Cl)cc1C(F)(F)F
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)c1cnc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
6-Chloro-4-(trifluoromethyl)nicotinic acid (1.0 g, 4.4 mmol, Oakwood) was dissolved in DCM (44 mL) to give a clear solution. SOCl2 (3.2 mL, 44 mmol) was added drop-wise and the reaction mixture was stirred at room temperature overnight and then at reflux for about 16 h. The mixture was concentrated under reduced pressure to give a yellow oil that was dissolved into EtOAc (10 mL). The solution was added drop-wise to a rapidly stirred mixture of EtOAc (20 mL) and concentrated aqueous NH4OH (22 mL, 580 mmol). The resulting cloudy mixture was stirred for about 2 h and separated. The aqueous layer was further extracted with EtOAc (30 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 6-chloro-4-(trifluoromethyl)nicotinamide (0.85 g, 85%) as off-white solid: LC/MS (Table 2, Method a) Rt=1.62 min; MS m/z: 223 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[C:19]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[CH2:23][CH2:22]2)=[O:20])=[CH:5][CH:4]=1.Cl.[CH3:43][N:44]([CH3:48])[CH2:45][CH2:46]Cl>>[CH3:41][O:40][C:37]1[CH:36]=[CH:35][C:34]([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:46][CH2:45][N:44]([CH3:48])[CH3:43])[C:11]=2[C:19]([N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[CH2:25][CH2:26]2)=[O:20])=[CH:39][CH:38]=1
Reactant: COc1ccc(C(c2ccc(OC)cc2)c2c(C(=O)N3CCN(c4ccccc4Cl)CC3)[nH]c3ccccc23)cc1
Reactant: CN(C)CCCl
Agent: Cl
Product: COc1ccc(C(c2ccc(OC)cc2)c2c(C(=O)N3CCN(c4ccccc4Cl)CC3)n(CCN(C)C)c3ccccc23)cc1
Yield: 66.5 %

Procedure:
Substantially the same procedure as in Example 2 was repeated using Compound 29 (1.0 g, 1.77 mmol) obtained in Example 29 and 2-dimethylaminoethylchloride hydrochloride (266 mg, 1.85 mmol) to give 0.75 g (yield: 67%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:3][CH2:4][NH2:5].[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22].[N:33]1([CH2:39][C:40]2[CH:41]=[C:42]([CH:48]=[CH:49][CH:50]=2)[O:43][CH2:44][CH2:45][CH2:46][NH2:47])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(OCC)(=O)C>O1CCCC1>[C:15]1([CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:6][N:2]([CH2:3][CH2:4][NH:5][C:21]([NH:47][CH2:46][CH2:45][CH2:44][O:43][C:42]2[CH:48]=[CH:49][CH:50]=[C:40]([CH2:39][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:41]=2)=[O:22])[CH3:1])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(CCN)CCC(c1ccccc1)c1ccccn1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(CCNC(=O)NCCCOc1cccc(CN2CCCCC2)c1)CCC(c1ccccc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.33 g (1.2 mmol) of N-methyl-N-[3-phenyl-3-(2-pyridyl)propyl]-1,2-ethanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.4 g (1.6 mmol) of 3-[3-(piperidinomethyl)phenoxy]propaneamine in 10 ml of absolute tetrahydrofuran as starting materials. Working up by chromatography (eluant: ethyl acetate) analogously to Example 63 yields the purified title compound in the form of an oil; MS (EI-80 eV): m/z (rel. int.[%])=543 ([M]+, 1), 84 (100). For analytical purposes a sample is converted into the hydrochloride and recrystallised from ether/ethanol; m.p.: from 130° C. with decomposition.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([N+:18]([O-])=O)[C:5]=1[CH:21]=[CH:22][C:23]([O:25]C)=O)(=[O:3])[CH3:2].[H][H]>C(O)C.[Ni]>[C:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]2[C:5]=1[CH2:21][CH2:22][C:23](=[O:25])[NH:18]2)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COC(=O)C=Cc1c(C(C)=O)cc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CC(=O)c1cc(OCc2ccccc2)cc2c1CCC(=O)N2
Reaction time: 2 h

Procedure:
A suspension of methyl 3-(2-acetyl-4-benzyloxy-6-nitrophenyl)-acrylate (5.0 g, 14.07 mmol) in ethanol (100 mL) is hydrogenated with Raney nickel (3 g) at ambient temperature and 4 bar hydrogen pressure. After 6 hours more Raney nickel (2 g) is added and the mixture is hydrogenated for a further 2 hours. The catalyst is separated off and the filtrate is combined with 2 M aqueous hydrochloric acid (15 mL). The product that crystallises out is filtered off and dried.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.B1([O-])OO1.[OH2:15].[OH2:16].O.O.[Na+]>C(O)(C(F)(F)F)=O.CC(O)=O>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([N+:6]([O-:16])=[O:15])=[C:4]([F:10])[CH:3]=1
Reactant: O
Reactant: Nc1c(F)cc(Br)cc1F
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1c(F)cc(Br)cc1F
Temperature: 60 °C
Yield: 42 %

Procedure:
A solution of 4-bromo-2,6-difluoroaniline (4.75 g, 22.8 mmol) in TFA (50.2 mL) and AcOH (50.2 mL) was charged with sodium perborate tetrahydrate (16.0 g, 104 mmol). The reaction was warmed to 60° C. and heated for 24 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (15 mL). The organic layer was washed with brine (10 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure to yield a yellow solid. The material was purified by silica gel chromatography on an ISCO combi-flash Rf system using Heptane/EtOAc (100:0→90:10) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a white solid, 2.28 g (42% yield). 1H NMR (CDCl3, 400 MHz): δ=7.31-7.35 (m, 2 H).
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]=[C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([C:20]3[NH:24][N:23]=[C:22]([C:25]([OH:27])=O)[CH:21]=3)=[CH:19][C:13]=2[O:12]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:50][CH2:51][C:52]([N:54]1[CH2:59][CH2:58][N:57]([C:60](=[O:72])[C:61]2[CH:66]=[C:65]([F:67])[CH:64]=[CH:63][C:62]=2[C:68]([F:71])([F:70])[F:69])[CH2:56][CH2:55]1)=[O:53]>CN(C=O)C.O>[F:67][C:65]1[CH:64]=[CH:63][C:62]([C:68]([F:70])([F:69])[F:71])=[C:61]([CH:66]=1)[C:60]([N:57]1[CH2:58][CH2:59][N:54]([C:52](=[O:53])[CH2:51][NH:50][C:25]([C:22]2[CH:21]=[C:20]([C:18]3[CH:17]=[CH:16][C:14]4[NH:15][C:11](=[O:10])[O:12][C:13]=4[CH:19]=3)[NH:24][N:23]=2)=[O:27])[CH2:55][CH2:56]1)=[O:72]
Reactant: O=C(O)c1cc(-c2ccc3[nH]c(=O)oc3c2)[nH]n1
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1cc(-c2ccc3[nH]c(=O)oc3c2)[nH]n1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 21.3 %

Procedure:
DIPEA (120 mg, 0.16 mL, 0.927 mmol) was added to a stirred solution of 5-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-1H-pyrazole-3-carboxylic acid (65 mg, 0.26 mmol) in DMF (2.5 mL). HOBT (37.6 mg, 0.27 mmol) and EDCI (53.4 mg, 0.2783 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (98 mg, 0.265 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue recrystallized from EtOAc to afford 31 mg (21% yield) of 5-(2-Oxo-2,3-dihydro-benzooxazol-6-yl)-1H-pyrazole-3-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 80.27%. 1H NMR (DMSO-d6): δ 13.7 (s, 1H), 11.8 (s, 1H), 8.0 (m, 1H), 7.9 (m, 1H), 7.7 (m, 1H), 7.5 (m, 3H), 7.06 (m, 2H), 4.1 (m, 2H), 3.4 (m, 6H), 3.1 (m, 2H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]#[C:17][Si](C)(C)C)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.O1CCCC1.Cl>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]#[CH:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(C#C[Si](C)(C)C)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc2[nH]c(CCCC)nc(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a solution of 0.70 g of 2-butyl-6-[(trimethylsilyl)ethynyl]-4(1H)-quinazolinone in 20 ml of methanol and 20 ml of tetrahydrofuran is added 10.0 ml of 1.0N sodium hydroxide solution. The reaction is stirred at room temperature for 2 hours and then diluted with 5% hydrochloric acid solution until the pH is 2. The resulting tan precipitate is collected filtration and dried in vacuo to yield 0.50 g of the desired product.
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4].[OH-].[K+].C1(C)C=CC=CC=1.[C:17](Cl)(Cl)=[O:18]>O>[CH3:6][CH:5]([C@H:2]1[CH2:3][O:4][C:17](=[O:18])[NH:1]1)[CH3:7]
Reactant: CC(C)[C@H](N)CO
Reactant: O=C(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)[C@H]1COC(=O)N1
Reaction time: 0.5 h

Procedure:
A mixture of 9.4 grams (0.091 mole) of (S)-2-amino-3-methyl-1-butanol, 36 grams (0.0546 mole) of 85% potassium hydroxide, 175 mL of toluene, and 240 mL of water was stirred rapidly as 140 mL (0.273 mole) of a toluene solution containing 20% phosgene was added dropwise during a 15 minute period. Upon completion of addition, the resulting hot solution was stirred an additional 30 minutes. The reaction mixture was cooled, and the organic and aqueous layers were separated. The organic layer was washed with water and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure, yielding 15.0 grams of (S)-4-(1-methylethyl)-2-oxazolidinone as a solid. Recrystallization from cyclohexane yielded purer compound, m.p. 71.5°-72.5° C.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:20]=4[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:20]=4[N:19]([CH3:27])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2c1CCCCC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2c1CCCCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.2 %

Procedure:
To a solution of 2-(1-methyl-1,4,5,6,7,8-hexahydrocycloheptapyrazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (40 mg, 0.08 mmol) in CH2Cl2 (2 mL) was added TFA (1.0 mL, 13.0 mmol). The yellow reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in CH2Cl2 (2 mL) and ethylenediamine (0.1 mL, 1.48 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 h then concentrated and directly purified by silica gel chromatography with 0% to 3% MeOH/EtOAc to isolate 20 mg (68%) of 2-(1-methyl-1,4,5,6,7,8-hexahydrocycloheptapyrazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as an off-white solid. MS: (M+Na)+=389; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.63 (br. s., 1H), 8.80 (s, 1H), 8.27 (s, 1H), 7.83 (s, 1H), 3.81 (s, 3H), 3.02-3.12 (m, 2H), 2.74-2.83 (m, 2H), 1.82 (br. s., 2H), 1.57-1.73 (m, 4H), 1.44 (s, 9H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[S:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.N(OCCCC)=O>>[C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:15]1[S:14][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccsc1
Reactant: Nc1ccccc1-c1ccccc1
Agent: CCCCON=O
Product: c1ccc(-c2ccccc2-c2cccs2)cc1
Reaction time: 192 h
Yield: 34.8 %

Procedure:
In a 4-l Erlenmeyer flask were placed 100 g (0.600 mole) of Pfalz and Bauer o-aminobiphenyl, m.p. 49°-51° C., 3000 ml (38.2 moles) of thiophene and 90 ml (0.80 mole) of n-butyl nitrite. The mixture was thoroughly stirred and then allowed to stand at room temperature for eight days. Unreacted thiophene was removed by distillation. The residue was distilled at reduced pressure to give 49.4 g (34.8%) of 2-(o-biphenylyl)thiophene b.p. 138°-155° C. (0.1 mm), ND20 1.6465.