Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[Cl-].[C:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH2:21][CH:20]([N:25]1[CH2:30][CH2:29][NH2+:28][CH2:27][CH2:26]1)[CH2:19]2)#[N:15].C(N(C(C)C)C(C)C)C>C(#N)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:28]2[CH2:27][CH2:26][N:25]([CH:20]3[CH2:19][C:18]4[C:22](=[CH:23][CH:24]=[C:16]([C:14]#[N:15])[CH:17]=4)[CH2:21]3)[CH2:30][CH2:29]2)=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: N#Cc1ccc2c(c1)CC(N1CC[NH2+]CC1)C2
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc2c(c1)CC(N1CCN(CCc3ccc([N+](=O)[O-])cc3)CC1)C2
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a 12 mL reaction vial was added 1-(2-bromoethyl)-4-nitrobenzene (42 mg, 0.18 mmol), 4-(5-cyano-2,3-dihydro-1H-inden-2-yl)piperazin-1-ium chloride (33 mg, 0.12 mmol) and acetonitrile (2 mL). To a stirred solution of above mixture was added N-ethyl-N-(propan-2-yl)propan-2-amine (32 mg, 0.24 mmol). The reaction was stirred at 60° C. for 5 hr, then concentrated and purified by preparative TLC to give the desired product. LC-MS (IE, m/z): 377 [M+1]+. (0.73 μm)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=[C:12]([C:18]([F:21])([F:20])[F:19])[N:11]=2)[CH:6]=[CH:7][C:8]=1[F:9].[F:22][C:23]1[CH:24]=[C:25]([CH:35]([CH3:39])[C:36](O)=[O:37])[CH:26]=[CH:27][C:28]=1[CH2:29][NH:30][S:31]([CH3:34])(=[O:33])=[O:32].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>O1CCCC1>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[C:15]([CH2:16][NH:17][C:36](=[O:37])[CH:35]([C:25]3[CH:26]=[CH:27][C:28]([CH2:29][NH:30][S:31]([CH3:34])(=[O:32])=[O:33])=[C:23]([F:22])[CH:24]=3)[CH3:39])=[CH:14][CH:13]=[C:12]([C:18]([F:20])([F:21])[F:19])[N:11]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: CC(C(=O)O)c1ccc(CNS(C)(=O)=O)c(F)c1
Reactant: NCc1ccc(C(F)(F)F)nc1-c1ccc(F)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)NCc1ccc(C(F)(F)F)nc1-c1ccc(F)c(Cl)c1)c1ccc(CNS(C)(=O)=O)c(F)c1
Reaction time: 48 h

Procedure:
To a stirred solution of (2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)methanamine hydrochloride (1.104 g, 3.632 mmol) and 2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanoic acid (1 g, 3.632 mmol) in tetrahydrofuran (28 mL) was added 1-hydroxybenzotriazolhydrate (0.49 mL, 3.632 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.166 g, 3.632 mmol) and N-ethyldiisopropylamine (1.852 mL, 10.896 mmol) and the reaction mixture was allowed to stir for 48 h. The reaction mixture was concentrated under reduced pressure and the solid obtained was purified by column chromatography (eluent:ethyl acetate/cyclohexane 2:1) to afford a white solid (example 16) (605 mg, 30%).
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][O:7][C:8](=[O:23])[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[N:17]=[C:18]([CH:21]=[O:22])[S:19][CH:20]=2)[CH:14]=1.[CH3:28][Mg]Br>C1COCC1.[NH4+].[Cl-]>[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][O:7][C:8](=[O:23])[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[N:17]=[C:18]([CH:21]([OH:22])[CH3:28])[S:19][CH:20]=2)[CH:14]=1
Reactant: O=Cc1nc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)cs1
Reactant: C[Mg]Br
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1nc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)cs1
Temperature: -78 °C
Reaction time: 4.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [1-(2-formyl-thiazol-4-ylmethyl)-1H-pyrazol-4-yl]-carbamic acid 2-chloro-benzyl ester (155 mg, 0.41 mmol) in THF (4.0 mL) was treated at −78° C. with methylmagnesium bromide (0.41 mL of a 1M solution in THF, 0.41 mmol). The reaction mixture was stirred at −78° C. for 4.5 h then poured in sat. aq. NH4Cl (25 mL) and extracted with EA (2×25 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (90:10 CH2Cl2-MeOH) gave the title compound as a yellow oil. TLC: rf (90:10 CH2Cl2-MeOH)=0.28. LC-MS-conditions 02: tR=0.88 min; [M+H]+=393.11.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH2:3][CH2:2]1.C([Li])CCC.[Br:16]C(F)(F)C(Br)(F)F>O1CCCC1>[Br:16][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[O:4][CH2:3][CH2:2][O:1][C:10]=12
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: c1cnc2c(c1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1ccnc2c1OCCO2
Temperature: 25 °C

Procedure:
A solution of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (prepared by the method of H. Neunhoffer et al, Chem., Ber., 1990, 123 (12), 2453) (1.37 g, 10 mmol) in tetrahydrofuran (20 ml) under argon at −78° C. was treated over 15 minutes with a solution of n-butyl lithium (20 mmol) in tetrahydrofuran (8 ml). After 30 minutes a solution of 1,2-dibromo-1,1,2,2-tetrafluoro-ethane (2.6 g, 10 mmol) in tetrahydrofuran (10 ml) was added dropwise over 5 minutes. After a further 30 minutes the cooling bath was removed and saturated aqueous ammonium chloride (20 ml) and ether (20 ml) were added. The mixture was allowed to warm to room temperature then partitioned between ether/water. The organic extract was washed with half-saturated brine, dried and evaporated. The residue was chromatographed on silica eluting with a 0-30% gradient of ethyl acetate in dichloromethane affording a yellow solid (1.1 g, 51%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)[CH3:19]
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)Cc1cccc(O)c1
Temperature: 25 °C

Procedure:
A solution of 3-hydroxyphenylacetic acid (15.5 g) in ethanol (200 mL) was added sulfuric acid (1 mL) and refluxed for 2.5 hours. The reaction mixture was cooled to room temperature. The mixture was added water and extracted with EtOAc. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. (18.2 g, 99.0%, pale brown oil)
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][SH:8])[NH2:6].[C:10]([O:14][C:15]([NH:17][C@H:18]([C:21](O)=[O:22])[CH2:19][OH:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].CN1CCOCC1>C(#N)C>[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][SH:8])[NH:6][C:19](=[O:20])[C@H:18]([CH2:21][OH:22])[NH:17][C:15]([O:14][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:16]
Reactant: COC(=O)[C@@H](N)CS
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CS)NC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A suspension of 17.2 g of L-cysteine methyl ester hydrochloride and 20.5 g of N-(t-butoxycarbonyl)-L-serine in 300 ml of acetonitrile was treated at 0° C. with 10.1 g of 4-methylmorpholine. To the stirred solution was added dropwise at 10° C. within 30 minutes a solution of 20.6 g N,N-dicyclohexylcarbodiimide in 300 ml of acetonitrile. After stirring the reaction mixture for 3 hours at 0° C. the precipitate formed was filtered off, and the filtrate was evaporated in vacuo. The oily residue was dissolved in 200 ml of ethyl acetate and the solution washed consecutively with 0.5N hydrochloric acid, water, 5% aqueous sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The crude product was chromatographed on silica gel using ethyl acetate/n-hexane as eluent, and the so purified product was crystallized from diethyl ether/n-hexane to give N-[N-(t-butoxycarbonyl)-L-seryl]-L-cysteine methyl ester as white crystals with mp 72°-74° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]2[CH2:14][CH2:15][C:16]([F:18])([F:17])[C@@H:9]12)C1C=CC=CC=1.[ClH:19]>CO>[ClH:19].[F:18][C:16]1([F:17])[C@@H:9]2[C@H:10]([O:11][CH2:12][CH2:13][NH:8]2)[CH2:14][CH2:15]1
Reactant: FC1(F)CC[C@H]2OCCN(Cc3ccccc3)[C@@H]21
Agent: Cl
Solvent: CO
Product: FC1(F)CC[C@H]2OCCN[C@@H]21
Reaction time: 1 h

Procedure:
Trans-4-benzyl-5,5-difluorooctahydrocyclopenta[b][1,4]oxazine (350 mg, 1.38 mmol) was dissolved in MeOH (10 mL). 3M HCl in MeOH (1.5 mL) was added and the solution was stirred for 1 hour. The solvent was evaporated and further azeotroped using toluene. The residue was then dissolved in MeOH (10 mL), and 20% Pd(OH)2/C (20% by wt, 50 mg) added. Hydrogen was purged through the reaction for 10 minutes and stirring was continued at room temperature under 1 atm of hydrogen for 16 hours. The reaction was filtered through celite, and the filtrate was concentrated to afford trans-5,5-difluorooctahydrocyclopenta[b][1,4]oxazine hydrochloride. 1H NMR (400 MHz, CD3OD) δ 4.16 (dd, J=13.6, 4.0 Hz, 1H), 3.78-3.92 (m, 2H), 3.65 (m, 1H), 3.43 (dd, J=13.2, 2.4 Hz, 1H), 3.28-3.31 (m, 2H), 2.15-2.55 (m, 2H), 1.89 (m, 1H). MS ESI calc'd. for C7H11F2NO [M+H]+ 164. found 164.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]([NH:9][S:10]([CH:13]([CH3:25])[CH2:14][CH2:15][CH:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[CH3:17])(=[O:12])=[O:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][Cl:35]>CC(C)=O>[C:1]([O:5][CH2:6][C:7]([NH:9][S:10]([CH:13]([CH3:25])[CH2:14][CH2:15][CH:16]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:33][CH2:34][Cl:35])=[CH:22][CH:23]=1)[CH3:17])(=[O:12])=[O:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(CCC(C)S(=O)(=O)NC(=O)COC(C)(C)C)c1ccc(O)cc1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(CCC(C)S(=O)(=O)NC(=O)COC(C)(C)C)c1ccc(OCCCl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.9 %

Procedure:
To a stirred mixture of N-tertbutoxyacetyl-2-(4-hydroxyphenyl)propyl-2-propanesulfonamide (4.0 g, 11.2 mmol) in acetone (40 mL) was added potassium carbonate (4.64 g, 33.6 mmol) under nitrogen. The resulting mixture was stirred 30 minutes at ambient temperature. Next, 1-bromo-2-chloroethane (1.12 ml, 13.4 mmol) was added and the resulting mixture was heated to reflux while stirring for 48 h. The resulting mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with water (2×50 mL) and brine (1×50 mL), dried over magnesium sulfate, and filtered. Evaporation of the filtrate in vacuo followed by chromatography on silica gel eluting with ethyl acetate-hexane gave 1.5 g (32%) of the pure title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>>[N:8]1([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: ClCCCCCCn1ccc2ccccc21
Reactant: CCC(=O)Nc1ccc(C2CCNCC2)cc1
Product: CCC(=O)Nc1ccc(C2CCN(CCCCCCn3ccc4ccccc43)CC2)cc1

Procedure:
Prepared by Procedure AH and Scheme P using 1-(6-chlorohexyl)-1H-indole and N-[4-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 432.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:18][N:19]([CH2:21][C:22]#[CH:23])[CH3:20]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCN(CC)CC>[CH3:18][N:19]([CH3:20])[CH2:21][C:22]#[C:23][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCN(C)C
Reactant: COc1ccc(C(=O)c2ccc(Cl)nc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)c2ccc(C#CCN(C)C)nc2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 80.2 %

Procedure:
A 25 ml Schlenk flask was charged with (6-chloropyridin-3-yl)(4-methoxy-phenyl)methanone (124 mg, 0.5 mmol), Pd(PPh3)2Cl2 (18 mg, 0.0 25 mmol), CuI (10 mg, 0.05 mmol), Et3N (10 mL), and N,N-dimethylpropargylamine (83 mg, 1.0 mmol). The flask was flushed with argon three times and the mixture was stirred at 80° C. for 24 h. The solvent was evaporated under vacuum and the residue was purified by column chromatography to give the product (118 mg, 80% yield).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:23]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=2)[N:22]=[C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=3)[CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.1 %

Procedure:
To a cooled and stirred solution of 3′-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (example 155) (0.38 g, 0.65 mmol) in dichloromethane (5 mL) was added TFA (5 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as a white solid (0.31 g, 90%). MS (ISN) 522.3 [(M−H)−]; mp 267° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1.C1C=CC=CC=1.Cl>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[S:30]
Reactant: COc1cc(C(=O)N2CCNCC2)cc(OC)c1OC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(C(=S)N2CCNCC2)cc(OC)c1OC
Yield: 61.5 %

Procedure:
A mixture of 1-(3,4,5-trimethoxybenzoyl)piperazine (2.0 g), a Lawesson reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphethane-2,4-disulfide] (2.9 g) and benzene (20 ml) is heated for 30 minutes under reflux. 1N HCl (100 ml) and ethyl acetate are added to the reaction mixture. The mixture is shaken. The aqueous layer is separated, and treated with an aqueous solution of sodium hydroxide to make the system alkalline, followed by extraction with methylene chloride. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue is recrystallized from methylene chloride to give 1-(3,4,5-trimethoxythiobenzoyl)piperazine as pale yellow crystals (1.3 g), m.p. 116°-118° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:24][C:25]([OH:27])=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:3]=12.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:24][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:3]=12
Reactant: C1COCCN1
Reactant: O=C(O)Cn1nc(-c2ccc(F)cc2)c2c(Cl)c(-c3ccccc3)nnc21
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: ClCCl
Product: O=C(Cn1nc(-c2ccc(F)cc2)c2c(Cl)c(-c3ccccc3)nnc21)N1CCOCC1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a suspension of 2-(4-chloro-3-(4-fluorophenyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (150 mg, 0.39 mmol) in CH2Cl2 (3 mL) were added morpholine (34 mg, 0.39 mmol), diisopropylethylamine (DIPEA) (200 μL, 1.2 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (180 mg, 0.47 mmol). The solution obtained was stirred at room temperature for 75 min before being purified using chromatography (silica gel, gradient 20 to 100% ethyl acetate/isohexane) followed by preparative HPLC yielding Compound 75 as a clear glass solid (11.5 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[N:8]=[C:9]([C:14]3[N:22]=[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][N:16]4[N:15]=3)[C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>C(Cl)Cl>[N:22]1[C:14]([C:9]2[C:10]([NH2:13])=[N:11][CH:12]=[C:7]([C:4]3[CH2:3][CH2:2][N:1]([S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[CH2:6][CH:5]=3)[N:8]=2)=[N:15][N:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=12
Reactant: Nc1ncc(C2=CCNCC2)nc1-c1nc2ccccn2n1
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CC=C(c2cnc(N)c(-c3nc4ccccn4n3)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(1,2,3,6-tetrahydropyridin-4-yl)-3-([1,2,4]triazolo[1,5-a]pyridin-2-yl)pyrazin-2-amine (82 mg, 0.1291 mmol) was dissolved in DCM (4 mL) and treated with triethylamine (78.38 mg, 108.0 μL, 0.7746 mmol) followed by ethanesulfonyl chloride (18.26 mg, 13.46 μL, 0.1420 mmol). The reaction mixture was allowed to stir at ambient temperature for 1 hour when analysis showed SM remaining. The mixture was treated with further ethanesulfonyl chloride (16.60 mg, 12.23 μL, 0.1291 mmol) and stirred for a further hour. The reaction was diluted with DCM, washed with water and the aqueous layer extracted further with dichloromethane (2×). The combined organics were washed with saturated aqueous NaHCO3, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography (ISCO Companion™, 12 g column, 0-2.5% MeOH/DCM) to afford the title compound which was freeze-dried to give a yellow solid (9 mg, 17% Yield). 1H NMR (400.0 MHz, DMSO) d 1.24 (t, J=7.4 Hz, 3H), 2.71 (br s, 2H), 3.14 (q, J=7.3 Hz, 2H), 3.48 (t, J=5.7 Hz, 2H), 3.98 (d, J=2.9 Hz, 2H), 6.62 (br s, 1H), 7.30-7.33 (m, 1H), 7.72 (br s, 2H), 7.75-7.79 (m, 1H), 7.98 (d, J=8.8 Hz, 1H), 8.40 (s, 1H) and 9.11 (d, J=6.7 Hz, 1H) ppm; MS (ES+) 386.0
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][C:27]=1[CH3:34])=[O:25].O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][C:27]=2[CH3:34])=[O:25])[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Cc1cc(CO)ccc1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-benzyloxy-1H-pyridin-2-one (728 mg, 3.62 mmol) in DMSO (4.00 mL) is added cesium carbonate (2.95 g, 9.05 mmol) and the mixture is stirred 15 min at room temperature. 2-Bromo-1-(4-hydroxymethyl-2-methyl-phenyl)-ethanone (preparation 1b, 880 mg, 3.62 mmol) is added in portions and the mixture and is stirred 2 h at room temperature. After addition of water, the precipitate is collected, washed with water and dried.
Reaction SMILES: [NH2:1][C@H:2]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:29][CH:28]=1)[C:3]([NH:5][C@@H:6]([C@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:18])[CH2:16][CH3:17])[N:14]=1)=[O:8])=[O:4].C(N(C(C)C)CC)(C)C.[O:51]=[C:52](Cl)OC(Cl)(Cl)Cl>O1CCCC1>[N:36]1([CH2:35][CH2:34][O:33][C:30]2[CH:31]=[CH:32][C:27]([CH:2]3[C:3](=[O:4])[N:5]([C@@H:6]([C@H:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH3:20])[C:7]([NH:9][C:10]4[S:11][CH:12]=[C:13]([C:15](=[O:18])[CH2:16][CH3:17])[N:14]=4)=[O:8])[C:52](=[O:51])[NH:1]3)=[CH:28][CH:29]=2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: CCC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](N)c2ccc(OCCN3CCOCC3)cc2)[C@@H](C)c2ccccc2)n1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)NC(c3ccc(OCCN4CCOCC4)cc3)C2=O)n1
Reaction time: 0.33 h

Procedure:
Crude (2S,3S)-2-{(R)-2-amino-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetylamino}-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide (≈0.19 mmol) was dissolved in tetrahydrofuran (10 mL) that contained diisopropylethylamine (160 μL, 122 mg, 0.94 mmol) and was transferred via cannula to a solution of diphosgene (16 μL, 26 mg, 0.13 mmol) in tetrahydrofuran (15 mL) at 0° C. The reaction mixture was stirred for 20 minutes and then partitioned between ethyl acetate and water. The organic layer was separated and dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel gradient eluted with 0-100% ethyl acetate in hexanes and the isolated material further purified by preparative thin layer chromatography using silica gel eluted with ethyl acetate. Precipitation of the isolated product from dichloromethane with an excess of hexanes gave (2S,3S)-2-{4-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide as an off white solid (32 mg, 29%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]([CH2:24][CH2:25][C:26]#[N:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C[O-].[Na+]>CS(C)=O>[NH:17]([CH:24]=[C:25]([CH2:13][C:12]1[CH:15]=[CH:16][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)[C:26]#[N:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#CCCNc1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CC(=CNc1ccccc1)Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
p-Benzyloxybenzaldehyde (25 g.), β-anilinopropionitrile (22 g.), and dimethylsulphoxide (25 ml.) were heated together to 95° C, and a slurry of sodium methoxide (1 g.) in dimethylsulphoxide (20 ml.) was carefully added such that the temperature rose to 105° C. The mixture was heated to 125°-130° and held at that temperature for 11/2 hr. The reaction mixture was poured into ice-water (500 ml.), and the resulting solid was collected and washed by decantation. The crude product was slurried in cold ethanol to give β-anilino-α-(p-benzyloxybenzyl) acrylonitrile. Wt. = 27 g.