Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[CH:6]=[CH:5]2.CS(C)=O.[C-:15]#[N:16].[Na+]>CC(OC)(C)C>[C:15]([CH2:2][CH2:3][C:4]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[CH:6]=[CH:5]2)#[N:16]
Reactant: ClCCC12C=CC(CC1)C2
Reactant: [C-]#N
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: N#CCCC12C=CC(CC1)C2
Temperature: 80 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A 1 L, 4 neck RBF was equipped with a thermowell, condenser with a nitrogen inlet, stopper and mechanical stirrer. The RBF was charged with chloroethylnorbornene (100 g, 0.64 mol), 300 mL DMSO and solid NaCN (43.8 g, 0.89 mol). An extra 20 mL DMSO was added to rinse in the NaCN. The reaction mixture was stirred at ˜80° C. for 2 hours. GC analysis of an aliquot indicated all starting material had been consumed and the reaction was completed. The reaction mixture was cooled to room temperature. Approximately 200 mL water was poured into the flask and diluted with 100 mL MTBE. The organic phase was separated and the aqueous layer was re-extracted with (3×200 mL) MTBE. The organic phases were combined and washed with (3×500 mL) tap water until the aqueous wash reached pH=6. The MTBE solution was dried over anhydrous sodium sulfate overnight, filtered, and rotary evaporated to give 93.5 g (99.5% yield) with 99.3% purity by GC. NMR analysis indicated the material contained ˜1% MTBE. The crude product was used for the next reaction without further purification. Data: GC analysis done on a DB5 Column, 30 meters, 0.32 mm ID, 0.25 μm film, 75° C. to 300° C. at 25° C./min., hold for 2 min at 300° C., Injector temperature: 275° C., Detector temperature: 350° C.
Reaction SMILES: Br.[N+:2]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][NH:6]1)([O-:4])=[O:3]>CC(O)=O>[N+:2]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1)([O-:4])=[O:3]
Reactant: O=[N+]([O-])C1NC=Cc2ccccc21
Agent: Br
Solvent: CC(=O)O
Product: O=[N+]([O-])c1nccc2ccccc12
Temperature: 25 °C
Yield: 28.5 %

Procedure:
Hydrobromic acid (3.0 M in HOAc, 1 mL) was added to a suspension of the dihydronitroisoquinoline (0.83 g) in glacial HOAc (2 mL). The mixture was heated to 100° C. for 1 day with occasional addition of more hydrobromic acid solution (3 mL overall). After the reaction, the mixture was allowed to cool to room temperature, concentrated in vacuo, diluted by water, and extracted twice with ethyl ether. Combined organics were washed by saturated NaHCO3 solution, dried over Na2SO4, filtered, concentrated in vacuo, and chromatographed on silica gel (5% to 10% ethyl acetate in hexane) to give 234 mg of nitroisoquinoline (35%) as solids, along with 95 mg of 4-bromo-1(2,4,6-trimethylphenyl)isoquinoline (13%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][OH:11])=[CH:4][CH:3]=1.COCCO[AlH2-]OCCOC.[Na+].C1(C)C=CC=CC=1.C(OCC)(=O)C.[I:37]I>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[I:37])=[CH:9]/[CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: OCC#Cc1ccc(Br)cc1
Reactant: II
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC/C=C(\I)c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A solution of 1-(4-bromophenyl)-1-propyne-3-ol B (6.58 g, 31.2 mmol) in anhydrous tetrahydrofuran (THF, 66 mL) was chilled in an ice bath. A 65% w/w solution of Red-Al in toluene (PhMe, 18.7 mL, 19.4 g, 62.4 mmol) was added dropwise over 15 minutes. After 1 hour ethyl acetate (EtOAc, 3.0 mL, 2.75 g, 31.2 mmol) was added. The reaction mixture was chilled in a dry-ice/acetone bath. A solution of I2 (12.7 g, 49.9 mmol) in anhydrous THF (66 mL) was added dropwise. The reaction mixture was allowed to slowly warm to room temperature overnight. The reaction was quenched with saturated Na2SO3 and filtered through Celite. The filter cake was washed well with EtOAc. The filtrate was washed with water and brine, dried (MgSO4), filtered, and concentrated. Column chromatography (20% EtOAc/hexanes) provided (Z)-1-(4-bromophenyl)-1-iodopropene-3-ol C (8.82 g, 83%) as a yellow solid. 1H NMR (300 MHz, CDCl3) 1.82 (t, 1H), 4.37 (collapsed dd, 2H), 6.25 (t, 1H), 7.34 (d, 2H), 7.44 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[C:11]([CH3:16])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:3]=1.C([Li])CCC.[F:22][C:23]([F:41])([F:40])[C:24]1[CH:25]=[C:26]([C:34]([CH3:39])([CH3:38])[C:35](Cl)=[O:36])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1.[OH-].[Na+]>C1COCC1>[F:33][C:30]([F:31])([F:32])[C:28]1[CH:27]=[C:26]([C:34]([CH3:38])([CH3:39])[C:35]([N:8]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]2[C:11]([CH3:16])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])=[O:36])[CH:25]=[C:24]([C:23]([F:40])([F:22])[F:41])[CH:29]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnc(Cl)cc1-c1cccnc1C
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ncccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a solution of (6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-yl)-methyl-amine in THF is added a solution of n-butyllithium in hexanes at about −78° C. After 15 min 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride is added. The reaction mixture is allowed to warm to room temperature during 30 min. After addition of an aqueous sodium hydroxide solution, the mixture is extracted with dichloromethane, dried and concentrated to give the compound 2-(3,5-Bis-trifluoromethyl-phenyl)-N-(6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-yl)-N-methyl-isobutyramide of formula II-2.
Reaction SMILES: [N:1]([CH2:4][C:5]([N:7]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[CH3:29])[C:8]1[N:9]=[C:10]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[S:11][C:12]=1[C:13]#[N:14])=O)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])(O)=[O:50].[Na+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>O1CCCC1.O.C(Cl)Cl>[NH2:1][CH2:4][C:5]1[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[CH3:29])[C:8]2[N:9]=[C:10]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[S:11][C:12]=2[C:13](=[O:50])[N:14]=1
Reactant: Cc1c(Cl)cccc1CN(C(=O)CN=[N+]=[N-])c1nc(N2CCOCC2)sc1C#N
Reactant: O=C([O-])O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Cc1c(Cl)cccc1Cn1c(CN)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-azido-N-[(3-chloro-2-methylphenyl)methyl]-N-[5-cyano-2-(4-morpholinyl)-1,3-thiazol-4-yl]acetamide (300 mg, 0.695 mmol) in Tetrahydrofuran (THF) (20 mL) and H2O (2 mL) was added Ph3P (547 mg, 2.084 mmol). The mixture was stirred at rt for 5 hr before removal of the solvent. To the residue was added 50 mL DCM and 20 mL NaHCO3 (sat.), followed by Boc2O (0.323 mL, 1.389 mmol). The mixture was stirred at rt for 17 hrs. The organic layer was concentrated and purified on a silica column to give the titled compound 150 mg. (43%) LC/MS (ES) m/z=505.9 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]2=[O:31])=[C:4]([OH:32])[CH:3]=1.[C:33]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:19]1([CH:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]3([C:5]4[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=4[O:32][CH2:33]3)[C:10]2=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2cc(F)c(F)cc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(F)c(F)cc12

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (70%) as a colorless solid: mp 213-216° C.; 1H NMR (300 MHz, CDCl3) δ 7.41-7.26 (m, 10H), 7.15-7.12 (m, 1H), 7.08-6.97 (m, 3H), 6.78 (dd, J=10.5, 6.3 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 6.44 (dd, J=9.0, 7.8 Hz, 1H), 5.03 (d, J=9.0 Hz, 1H), 4.77 (d, J=9.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 176.8, 156.6 (d, J=11.0 Hz), 151.2 (dd, JC-F=248.2, 14.5 Hz), 145.6 (dd, JC-F=241.5, 13.9 Hz), 141.7, 137.4, 137.1, 131.5, 128.8, 128.8, 128.7, 128.3, 128.3, 128.1, 128.0, 124.2 (dd, J=6.4, 3.3 Hz), 123.8, 123.3, 112.4, 111.5 (dd, J=20.4, 1.6 Hz), 100.1 (d, J=22.4), 80.8, 58.9, 57.5; MS (ES+) m/z 440.2 (M+1).
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[NH2:2].C(O[CH:15]=[C:16]([C:22]#[N:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C(O)C>[NH2:23][C:22]1[N:1]([C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=2)[C:6]([OH:8])=[O:7])[N:2]=[CH:15][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNc1cccc(C(=O)O)c1
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2cccc(C(=O)O)c2)c1N
Yield: 66.3 %

Procedure:
The mixture of 3-hydrazinobenzoic acid (5.0 g) and ethyl 2-ethoxymethylene-2-cyanoacetate (5.6 g) in ethanol (50 ml) was heated under reflux for 2 hours under stirring, and then the mixture was evaporated in vacuo. To the residue was added a mixture of ethyl acetate and water, and the mixture was adjusted to pH 8 with 20% aqueous potassium carbonate solution. The separated aqueous layer was adjusted to pH 4 with 6N-hydrochloric acid and extracted with ethyl acetate. The extract layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with a solution of ethyl acetate and diisopropyl ether and the precipitate was collected by filtration to give 3-(5-amino-4-ethoxycarbonylpyrazol-1-yl)benzoic acid (6.0 g).
Reaction SMILES: [CH:1]([C:3]1[N:4]([CH3:20])[C:5]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[N:4]([CH3:20])[C:5]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: Cn1c(C=O)nc(-c2ccccc2)c1-c1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1c(CO)nc(-c2ccccc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-formyl-1-methyl-4-phenyl-5-[4-pyridyl]imidazole (0.830 g, 3.15 mmol) in MeOH at 0° C. was added NaBH4 (0.143 g, 3.78 mmol). The mixture was stirred at rt for 0.5 h when the solvent was evaporated in vacuo and the residue was partitioned between CH2Cl2 and H2O. The organic extract was washed with aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography eluting with 25:1 CH2Cl2/MeOH. The title compound was obtained as a white solid (0.608 g, 73%): mp 236-238° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C@@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])=[O:17])[CH2:12][CH2:11]2)[N:3]=1.[NH2:30][CH2:31][CH2:32][OH:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:33][CH2:32][CH2:31][NH:30][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C@@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])=[O:17])[CH2:12][CH2:11]2)[N:3]=1
Reactant: Cc1nc(Cl)nc(N[C@H]2CC[C@@H](C(=O)NCc3ccccc3C(F)(F)F)CC2)n1
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc(NCCO)nc(N[C@H]2CC[C@@H](C(=O)NCc3ccccc3C(F)(F)F)CC2)n1

Procedure:
A mixture of cis-4-[(4-chloro-6-methyl-1,3,5-triazin-2-yl)amino]-N-{[2-(trifluoromethyl)phenyl]methyl}cyclohexanecarboxamide (70 mgs, 0.16 mmol, 1.0 equiv), 2-aminoethanol (15 mgs, 0.25 mmol, 1.5 equiv), and potassium carbonate (34 mgs, 0.25 mmol, 1.0 equiv) in acetonitrile (3 ml) was heated to reflux for 16 h. The solvent was removed under reduced pressure, and the residue was extracted with CH2Cl2 and washed with water. The organic layer was dried over sodium sulfate and concentrated. The residue was purified via reverse-phase HPLC purification to afford the title compound. MS (ES+): m/e 453.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[CH3:25])=[CH:20][CH:19]=1>>[Cl:16][C:13]1[CH:12]=[C:3]2[C:2](=[CH:15][CH:14]=1)[N:1]=[C:24]([C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)[CH:25]=[C:4]2[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CC(=O)c1ccc(F)cc1
Product: Fc1ccc(-c2cc(-c3ccccc3)c3cc(Cl)ccc3n2)cc1
Temperature: 165 °C

Procedure:
A three-necked, 2 L round-bottomed flask equipped with a thermometer, a mechanical stirrer, and a distillation unit fitted with a nitrogen inlet valve was charged with 2-amino-5-chlorobenzophenone (695.0 g, 3.00 mol), 4'-fluoroacetophenone (456.0 g, 3.30 mol), and p-tosic acid (47.62 g, 0.25 mol). The reaction mixture was heated under nitrogen at 165° C. (44 h). The yellow 4'-acetophenone that co-distilled with the water was separated and reintroduced to the reaction mixture through the heating period. The mixture was further heated to 190° C. (2 h). The mixture was cooled to 120° C. and poured into 95% ethanol (10 L) while vigorously stirring with a mechanical stirring rod setup. The mixture was filtered and the precipitate washed with ethanol (1 L). The solid was dried in a vacuum oven at 80° C. (16 h). Yield 969 g., 97%; mp 141.0°-142.1° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[CH2:10][NH:11][C:12]([CH:14]1[CH2:18][NH:17][C:16](=[O:19])[N:15]1[CH3:20])=[O:13].I[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)[C@@H]1CCCC[C@H]1N>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[CH2:10][NH:11][C:12]([CH:14]1[CH2:18][N:17]([C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)[C:16](=[O:19])[N:15]1[CH3:20])=[O:13]
Reactant: CN1C(=O)NCC1C(=O)NCc1ccc(F)c(F)c1Cl
Reactant: Cn1nccc1I
Agent: [Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CN1C(=O)N(c2ccnn2C)CC1C(=O)NCc1ccc(F)c(F)c1Cl
Temperature: 25 °C
Yield: 23.5 %

Procedure:
To a stirred mixture of N-[(2-chloro-3,4-difluorophenyl)methyl]-3-methyl-2-oxo-4-imidazolidinecarboxamide (60.7 mg, 0.2 mmol) (prepared as described in Example 28), 5-iodo-1-methyl-1H-pyrazole (41.6 mg, 0.2 mmol) in 1,4-dioxane (4 ml) was added potassium phosphate (212 mg, 1 mmol), copper (I) iodide (38.1 mg, 0.2 mmol) and trans-N,N-dimethylcyclohexane-1,2-diamine (0.032 ml, 0.2 mmol) and the mixture was heated at reflux under argon for 1 h. The mixture was cooled to room temperature and partitioned between saturated sodium hydrogen carbonate solution and dichloromethane. The organic extracts were separated, washed with water and brine, dried and evaporated. The residue was purified by mass-directed automated HPLC to give N-[(2-chloro-3,4-difluorophenyl)methyl]-3-methyl-1-(1-methyl-1H-pyrazol-5-yl)-2-oxo-4-imidazolidinecarboxamide (18 mg, 23%). LC/MS [M+H]+=384, retention time=2.22 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[CH:15]=[C:16]([C:31](O)=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH:34]1[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]1>>[F:8][C:6]1[CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[CH:15]=[C:16]([C:31]([N:34]3[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]3)=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)=[CH:20][C:19]3=[O:30])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: OC1CCNCC1
Reactant: O=C(O)c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Product: O=C(c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCC(O)CC1
Yield: 66.2 %

Procedure:
Title compound was prepared using an analogous procedure to that described in Example 1.01. 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (105 mg, 0.21 mmol) was reacted with piperidin-4-ol (22.48 mg, 0.22 mmol) to afford 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-6-(4-hydroxypiperidine-1-carbonyl)-2-morpholino-4H-chromen-4-one (75 mg, 66%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:15]=[CH:14]/[C:13]([O:17][CH3:18])=[O:16])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1
Reactant: FC(F)(F)c1cc(Cl)ccc1I
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 96 h
Yield: 100.4 %

Procedure:
The mixture of 4-chloro-1-iodo-2-(trifluoromethyl)-benzene (15 g), methyl acrylate (6.74 g), tetrabutylammonium chloride (14 g), palladium acetate (0.22 g) and potassium carbonate (13.6 g) in DMF (150 ml) was stirred at room temperature for 4 days. After diluting with ether (1 L), the mixture was washed with water (5×200 ml), then dried over sodium sulphate and solvent removed under reduced pressure. The residue was columned on silica gel using 5:1 heptane:EtOAc as eluant to give (E)-methyl 3-(4-chloro-2-(trifluoromethyl)-phenyl)-acrylate (13 g).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]([O-])([CH3:22])[CH3:21].[K+].BrCC(C)=C>C1COCC1.O>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([O:12][CH2:21][C:20]([CH3:22])=[CH2:19])[CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)[O-]
Agent: C=C(C)CBr
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)COC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A solution of 1-diphenylmethylazetidin-3-ol (239 mg, 1.0 mmol) in THF (3.6 mL) was cooled to 0° C. t-BuOK (1M in THF, 3.6 mL) was added dropwise and the reaction mixture was stirred at room temperature for 1 h then cooled to 0° C. 3-Bromo-2-methyl-1-propene (504 μL, 5.0 mmol) was added and the solution was stirred from 0° C. to room temperature overnight. The reaction mixture was diluted with H2O and extracted twice with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated to dryness to give the title compound (276 mg, 94%) as a yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][CH3:15])[CH:6]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCOCC1>[CH3:15][O:14][C:7]1[CH:6]=[C:5]([C:4]#[C:3][CH2:2][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12]
Reactant: C1CCNCC1
Reactant: COc1cc(C#CCCl)ccc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: COc1cc(C#CCN2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 96.4 %

Procedure:
To 4-(3-chloro-1-propyn-1-yl)-2-(methyloxy)-1-nitrobenzene (0.250 g, 1.1 mmol) in 10 mL of dioxane was added, piperidine (0.26 g, 3.1 mmol). The mixture was heated to 110° C. for 3 h. The mixture was purified by flash chromatography to give the title compound of step C (0.29 g, 1.06 mmol, 95%). 1H NMR (400 MHz, CDCl3) δ ppm 7.79 (d, J=8.42 Hz, 1H), 7.11 (d, J=1.47 Hz, 1H), 7.06 (dd, J=8.33, 1.56 Hz, 1H), 3.94 (s, 3H), 3.50 (s, 2H), 2.54-2.63 (m, 4H), 1.62-1.70 (m, 4H), 1.41-1.50 (m, 2H).
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][C:4]([N:7]2[CH:11]=[CH:10][C:9]([C:12]3[CH:25]=[CH:24][C:15]([O:16][C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=4)=[CH:14][CH:13]=3)=[N:8]2)=[CH:3][CH:2]=1.Br[C:28]1([CH2:37][CH2:38][O:39][CH2:40]C)[C:33](=[O:34])[NH:32][C:31](=[O:35])[NH:30][C:29]1=[O:36]>>[CH3:40][O:39][CH2:38][CH2:37][C:28]1([O:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[CH:24]=[CH:25][C:12]([C:9]4[CH:10]=[CH:11][N:7]([C:4]5[CH:3]=[CH:2][C:1]([CH3:26])=[CH:6][CH:5]=5)[N:8]=4)=[CH:13][CH:14]=3)=[CH:18][CH:19]=2)[C:29](=[O:36])[NH:30][C:31](=[O:35])[NH:32][C:33]1=[O:34]
Reactant: Cc1ccc(-n2ccc(-c3ccc(Oc4ccc(O)cc4)cc3)n2)cc1
Reactant: CCOCCC1(Br)C(=O)NC(=O)NC1=O
Product: COCCC1(Oc2ccc(Oc3ccc(-c4ccn(-c5ccc(C)cc5)n4)cc3)cc2)C(=O)NC(=O)NC1=O

Procedure:
By the same procedure as Example 1, Part C, 4-[4-(1-p-Tolyl-1H-pyrazol-3-yl)-phenoxy]-phenol and 5-bromo-5-(2-methoxyethyl)-pyrimidine-2,4,6-trione (from Preparation 3B) were converted to the title compound. MS m/z: ESI+ 527.2 (M+H)+, ESI− 525.4 (M−H)−.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([CH3:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:10][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH2:11][Br:12])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(C)(=O)=O)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
Methyl p-tolyl sulfone (24 g, 0.14 mol) in 550 ml CCl4 was heated to reflux temperature, N-bromosuccinimide (17.8 g, 0.14 mol) was added in portions and the mixture was refluxed for 3 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to yield 4-methanesulfonylbenzyl bromide as a crystalline solid (32.9 g), 1H-NMR (CDCl3) δ 8.05 (d, 2H), 7.70 (d, 2H), 4.45 (s, 2H), 3.09 (s, 3H). To the crude product in water (200 ml) were added sodium sulfite (33.2 g, 264 mmol) and tetrabutylammonium bromide (0.41 g, 1.64 mmol), and the mixture was refluxed for 2 h. After cooling to room temperature the solution was extracted with ethyl acetate, the aqueous phase was then concentrated to half the volume and cooled. The precipitate was filtered off and dried under vacuum at 70° C. to yield sodium 4-methanesulfonyl-benzylsulfonate (33.3 g, quant.).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=1)[C@H:11]([NH:30]C(=O)OC(C)(C)C)[C:12]([NH:14][C:15]1[S:16][C:17]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[N:25][CH:24]=[CH:23]3)=[N:18][N:19]=1)=[O:13])(C(C)(C)C)(C)C.[ClH:48]>O1CCOCC1>[ClH:48].[NH2:30][C@@H:11]([C@H:10]([C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[CH:40][CH:39]=1)[CH2:9][OH:8])[C:12]([NH:14][C:15]1[S:16][C:17]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[N:25][CH:24]=[CH:23]3)=[N:18][N:19]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)Nc1nnc(-c2ccc3cnccc3c2)s1)[C@@H](CO[Si](C)(C)C(C)(C)C)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](C(=O)Nc1nnc(-c2ccc3cnccc3c2)s1)[C@@H](CO)c1ccc(C(F)(F)F)cc1
Reaction time: 1.5 h
Yield: 12 %

Procedure:
tert-Butyl (2S,3S)-4-(tert-butyldimethylsilyloxy)-1-(5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-ylamino)-1-oxo-3-(4-trifluoromethylphenyl)butan-2-ylcarbamate (0.014 g, 0.020 mmol) was taken up in 2 mL of 4 N HCl in dioxane. After 1.5 hours, a white precipitate formed. The precipitate was collected by filtration to provide (2S,3S)-2-amino-4-hydroxy-N-(5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-yl)-3-(4-(trifluoromethyl)phenyl)butanamide hydrochloride (1.2 mg, 12%). LCMS (M+H) 474 calc. for C22H19F3N5O2S 474.1. 1H NMR (400 MHz, CD3OD): δ ppm 9.84-9.78 (m 1H), 8.90-8.55 (m, 6H), 7.80-6.58 (m, 3H), 4.83-4.72 (m 2H), 4.09-3.90 (m, 1H), 3.72-3.54 (m, 1H). 4H not detected.