Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]3[O:17][CH2:16][CH2:15][NH:14][CH2:13]3)[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[C:21]([NH2:26])[N:20]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:18][C:19]1[CH:24]=[C:23]([N:14]2[CH2:15][CH2:16][O:17][CH:12]([C:9]3[NH:10][CH:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=3)[CH2:13]2)[N:22]=[C:21]([NH2:26])[N:20]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: c1ccc(-c2c[nH]c(C3CNCCO3)n2)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Cl)cc(N2CCOC(c3nc(-c4ccccc4)c[nH]3)C2)n1
Yield: 115.1 %

Procedure:
A solution of 2-(4-phenyl-1H-imidazol-2-yl)morpholine (550 mg, 2.07 mmol), 4,6-dichloro-2-pyrimidinamine (339 mg, 2.07 mmol) and Hunig's base (0.901 mL, 5.17 mmol) in ethanol (80 mL) was heated at 85° C. for 5 hours. The mixture was concentrated to afford the crude title compound (850 mg) as a brown oil. LC-MS (ES) m/z=357 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.Cl[CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH2:14][CH2:13]1.C(N(CC)CC)C.Cl>CN(C=O)C>[F:27][C:24]([F:25])([F:26])[C:20]1[CH:19]=[C:18]([N:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][S:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][N:3]=3)[CH2:17][CH2:16]2)[CH:23]=[CH:22][CH:21]=1
Reactant: Sc1ccncn1
Reactant: FC(F)(F)c1cccc(N2CCN(CCCCl)CC2)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cccc(N2CCN(CCCSc3ccncn3)CC2)c1
Yield: 58.5 %

Procedure:
1.5 g (13.4 mmol) of 4-mercaptopyrimidine, 4.3 g (14 mmol) of 1-(3-chloropropyl)-4-(3-trifluoromethylphenyl) piperazine and 1.5 g (15 mmol) of triethylamine in 5 ml of DMF were stirred at 100° C. for 1 hour. The mixture was then poured into 5% strength hydrochloric acid and extracted with MTB ether. The aqueous phase was made alkaline with sodium hydroxide solution and then extracted with ethyl acetate, and the organic phase was dried over MgSO4 and concentrated. The residue was purified by chromatography (mobile phase: CH2Cl2/CH3OH═98/2). 3.0 g of product were obtained as a yellowish oil (=59% yield).
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([C:10]([O:12]CC)=O)[C:5]([O:7]CC)=O.Br.[O:16]1[CH2:21][CH2:20][N:19]([C:22]([NH2:24])=[NH:23])[CH2:18][CH2:17]1>CCO>[F:3][C:4]1[C:5]([OH:7])=[N:23][C:22]([N:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)=[N:24][C:10]=1[OH:12]
Reactant: CCOC(=O)C(F)C(=O)OCC
Reactant: N=C(N)N1CCOCC1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Oc1nc(N2CCOCC2)nc(O)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.6 %

Procedure:
Sodium hydride (60% in oil, 3.9 g, 96.5 mmol) was washed with hexanes in a round bottom flask under argon and cooled with an ice water bath. EtOH (100 mL) was slowly added. The resulting mixture was warmed to RT and stirred for 30 minutes. To the base mixture, diethyl 2-fluoromalonate (5.7 g, 32.2 mmol) was added, followed by morpholinoformamidine hydrobromide (6.8 g, 32.2 mmol). The mixture was heated to 90-95° C. with stirring under argon. After 12 hours, the reaction was cooled to room temperature and the EtOH was removed in vacuo. The resulting white solid was dissolved in water (25 mL) and acidified with conc. HCl to pH=3-4. A white precipitate formed which was collected on a Büchner filter, washed with water (2×50 mL), air dried on the filter, and dried in vacuo to give 5-fluoro-2-morpholinopyrimidine-4,6-diol (0.87 g, 12%). LC/MS (m/z): 216.0 (MH+), Rt 0.63 minutes.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[S:9]([NH:12][O:13][CH3:14])(=[O:11])=[O:10].[N+:15]([C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1Cl)([O-:17])=[O:16].[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[S:9]([N:12]([C:19]1[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=1[N+:15]([O-:17])=[O:16])[O:13][CH3:14])(=[O:10])=[O:11]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CONS(=O)(=O)c1c(C)nn(C)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])S(=O)(=O)c1c(C)nn(C)c1Cl
Temperature: 25 °C
Yield: 80.1 %

Procedure:
To a solution of 5-chloro-1,3-dimethyl-N-methoxy-4-pyrazolesulfonamide (0.48 g (2.00 mmol)) and 2,4-dinitrochlorobenzene (0.49 g (2.42 mmol)) in DMF (3.0 ml), sodium hydride (60%, 0.09 g (2.25 mmol)) was added dropwise under cooling with ice and with stirring and the mixture was stirred under cooling with ice for one hour and at room temperature for one hour. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with chloroform-hexane (10:1) as eluent to give 0.65 g (87%) of the title compound as pale yellow crystals.
Reaction SMILES: [CH3:1][CH:2]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH:7]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:5][C:4](=[O:18])[NH:3]1.[NH2-].[Na+].N.[CH3:22]I>CN(C)P(=O)(N(C)C)N(C)C.O>[CH3:22][N:3]1[CH:2]([CH3:1])[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH:7]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:5][C:4]1=[O:18]
Reactant: CI
Reactant: CC1NC(=O)OC12CCCCC2c1ccccc1
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CC1N(C)C(=O)OC12CCCCC2c1ccccc1
Reaction time: 1 h

Procedure:
4-Methyl-6-phenyl-1-oxa-3-azaspiro [4.5] decan-2-one (Example XXIII) (23.6 g) in hexamethylphosphoric triamide (HMPT) is added dropwise to 5 g sodium amide in 35 ml HMPT. The mixture is stirred until NH3 evolution is essentially finished and 11 ml methyl iodide added at about 40° over a 1/2 hour period. The mixture is stirred 1 hour, added to 700 ml water and extracted with ethyl acetate. The extract is washed with water, dried and concentrated to give 25 g crude product. A sample of the crude product, recrystallized from cyclohexane, gave the crystalline product, m. 85°-6°.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]3[C:18]=2[CH2:19][N:20]([CH3:27])[C:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:5][CH:4]=1>C(O)(=O)C.Cl.C(O)(C)C.[Rh]>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][N:12]3[C:18]=2[CH2:19][N:20]([CH3:27])[C:21](=[O:26])[CH2:22][CH:23]([CH3:24])[CH3:25])=[CH:5][CH:4]=1
Reactant: Cc1ccc2nc(-c3ccc(Cl)cc3)c(CN(C)C(=O)CC(C)C)n2c1
Agent: [Rh]
Agent: Cl
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(C)CC(=O)N(C)Cc1c(-c2ccc(Cl)cc2)nc2n1CC(C)CC2
Yield: 93.3 %

Procedure:
3 g (8.1 mmol) of N-[{2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl}methyl]-N,3-dimethylbutanamide hydrochloride is dissolved in 200 ml of acetic acid, 0.7 g of rhodium on alumina (5% rhodium) is added and the mixture is hydrogenated under a pressure of approximately 0.35 MPa (50 PSI) until absorption is complete. The catalyst is removed by filtration and the solvent evaporated off under reduced pressure. The residue is taken up with dichloromethane and the solution washed with bicarbonate water. The organic phase is separated after settling and dried over magnesium sulphate. After filtration and evaporation of the solvent, a solid residue is taken up with ether and purified by chromatography on a silica column. The hydrochloride is prepared therefrom in 0.1N hydrogen chloride in isopropyl alcohol. 1.55 g of the expected product is obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[F:23][C:24]([F:36])([F:35])[C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27](=O)[CH2:28]Br>O>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:6]1[C:5]([C:3]([OH:2])=[O:4])=[CH:10][C:9]([C:11]2[S:13][CH:28]=[C:27]([C:26]3[CH:31]=[CH:32][CH:33]=[CH:34][C:25]=3[C:24]([F:23])([F:35])[F:36])[N:12]=2)=[CH:8][CH:7]=1)([O-:22])=[O:21]
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1ccccc1C(F)(F)F
Solvent: O
Product: O=C(O)c1cc(-c2nc(-c3ccccc3C(F)(F)F)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 19 %

Procedure:
2′-Nitro-4-[4-(2-trifluoromethyl-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (56 mg, 19%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-(trifluoromethyl)phenacyl bromide (available from Maybridge) using the procedure described for the preparation of Example 18 except that the entire 4 mL of water was added at the beginning of the hydrolysis step rather than being added in two portions. 1H NMR (300 MHz, DMSO-d6) δ 13.06 (br s, 1H), 8.52 (d, J=1.6 Hz, 1H), 8.20 (dd, J=8.2, 1.7 Hz, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.96 (s, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.64-7.80 (m, 4H), 7.40-7.46 (m, 2H).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:15][CH:16]1[CH2:18][CH2:17]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH:16]1([CH2:15][N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CC2CC2)CC1
Reaction time: 12 h
Yield: 62.4 %

Procedure:
Tert-butyl piperazine-1-carboxylate 7a (6.14 g, 33 mmol), bromomethyl-cyclopropane (4.05 g, 30 mmol) and triethylamine (6.06 g, 60 mmol) were dissolved in 70 mL of dichloromethane. The reaction solution was stirred for 12 hours. The resulting solution was added with 50 mL of aqeuous saturated sodium bicarbonate solution and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound tert-butyl 4-(cyclopropylmethyl)piperazine-1-carboxylate 31a (4.50 g, yield: 62.5%) as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65](=[O:76])[C:66]1[CH:71]=[CH:70][C:69]([NH2:72])=[C:68]([O:73][CH2:74][CH3:75])[CH:67]=1>>[CH3:63][O:64][C:65](=[O:76])[C:66]1[CH:71]=[CH:70][C:69]([NH:72][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:35])([CH3:37])[CH3:36])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[C:68]([O:73][CH2:74][CH3:75])[CH:67]=1
Reactant: CCOc1cc(C(=O)OC)ccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C(=O)OC)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.4 g, 0.69 mmol), was reacted with diisopropylethylamine (0.46 g, 3.6 mmol), diphenylphosphinic chloride (0.34 g, 1.4 mmol), then reacted with 4-amino-3-ethoxy-benzoic acid methyl ester (0.21 g, 1.1 mmol) to give rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-ethoxy-benzoic acid methyl ester as a white solid (Yield, 0.13 g, 29%).
Reaction SMILES: COC[O:4][C:5]1[C:6]([C:19]2[CH:20]=[C:21]([C:25](=[CH2:29])[C:26]([OH:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1.CO.[CH2:32]1COCC1.S(=O)(=O)(O)O>O>[OH:4][C:5]1[C:6]([C:19]2[CH:20]=[C:21]([C:25](=[CH2:29])[C:26]([O:28][CH3:32])=[O:27])[CH:22]=[CH:23][CH:24]=2)=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:15])([CH3:16])[C:13]=2[CH:14]=1
Reactant: C=C(C(=O)O)c1cccc(-c2cc3c(cc2OCOC)C(C)(C)CCC3(C)C)c1
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: C=C(C(=O)OC)c1cccc(-c2cc3c(cc2O)C(C)(C)CCC3(C)C)c1
Temperature: 25 °C

Procedure:
2 g (5 mmol) of 3-(3-methoxymethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)phenylacrylic acid, 10 ml of methanol and 10 ml of THF are introduced into a round-bottomed flask. 2.8 ml of concentrated sulphuric acid are added and the mixture is stirred at room temperature for &é hours. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, washed with water, dried over magnesium sulphate and evaporated. 1.80 g (98%) of the expected methyl ester are collected, with a melting point of 182-3° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[O:8])[CH:2]=1.S(=O)(=O)(O)O.[N+:21]([O-])([OH:23])=[O:22].[OH-].[NH4+]>>[Cl:15][C:10]1[CH:11]=[CH:12][C:13]([N+:21]([O-:23])=[O:22])=[CH:14][C:9]=1[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:8]
Reactant: O=C(c1cccnc1)c1ccccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: O=C(c1cccnc1)c1cc([N+](=O)[O-])ccc1Cl
Yield: 94.2 %

Procedure:
To a mixture of o-chlorophenyl 3-pyridyl ketone (10.0 g, 0.460 mol) and concentrated sulfuric acid at 0° C. is added dropwise a mixture of 90% nitric acid (2.40 ml) and concentrated sulfuric acid (6.0 ml). The resultant mixture is stirred one hour at 0° C., poured onto ice and neutralized with 30% ammonium hydroxide. Filtration and drying affords the title compound as a solid (11.4 g, 94.2%) which is identified by mass spectral analysis.
Reaction SMILES: [C:1]([O:10]N1C(=O)CCC1=O)([O:3][CH2:4][CH2:5][Si:6]([CH3:9])([CH3:8])[CH3:7])=O.[Si:18]([O:25][CH:26]1[CH2:31][CH2:30][CH:29]([CH2:32][C@H:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:34][NH:35][CH3:36])[CH2:28][CH2:27]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>O.C(Cl)Cl>[Si:18]([O:25][CH:26]1[CH2:27][CH2:28][CH:29]([CH2:32][C@H:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:34][N:35]([CH3:36])[C:1]([O:3][CH2:4][CH2:5][Si:6]([CH3:7])([CH3:8])[CH3:9])=[O:10])[CH2:30][CH2:31]1)([C:21]([CH3:23])([CH3:24])[CH3:22])([CH3:20])[CH3:19]
Reactant: CNC[C@H](CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CN(C[C@H](CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
Solid Teoc-OSu (1.35 g, 5.25 mmol) was added to a two-phase solution of (S)-tert-butyl 1-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-3-(methylamino)propan-2-ylcarbamate (2.0 g, 5.0 mmol), K2CO3 (0.75 g, 9.0 mmol) in H2O (6 ml) and CH2Cl2 (12 mL). The mixture was vigorously stirred for 2 h at rt. The product was extracted with CH2Cl2. The combined organic layers were washed with sat'd aq NaHCO3 and brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography to provide (S)-tert-butyl 1-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamate (1.9 g, 3.49 mmol, 70% yield). 1H NMR (400 MHz, CD3OD): 0.05 (s, 15H), 0.87 (s, 9H), 1.40 (s, 9H), 1.69 (s, 3H), 2.96 (m, 3H), 3.40-3.52 (m, 1H), 3.81-3.92 (m, 1H), 4.12-4.29 (m, 2H). MS (E/Z): 545 (M+H+)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16](I)=[CH:17][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[CH:17][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1cnc2c(c1)N(Cc1ccccc1)CCN2
Reactant: OB(O)c1cccnc1
Product: c1ccc(CN2CCNc3ncc(-c4cccnc4)cc32)cc1
Yield: 23 %

Procedure:
1-Benzyl-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (30 mg) was reacted with pyridine 3-boronic acid as in General Procedure 4A to give the title compound as a light yellow film (23% yield). M.p. (film), LCMS: m/z=303.40 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.41-3.44 m, 2H), 3.60-3.63 (m, 2H), 4.49 (s, 2H), 6.80 (s, 1H), 5.40 (bs, 1H), 6.80 (s, 1H), 7.27-7.42 (m, 5H), 7.64 (s, 1H), 7.65 (d, J=7.8 Hz, 1H), 8.48 (d, J=4.8 Hz, 1H), 8.63 (s, 1H).
Reaction SMILES: C(OC([N:8]1[C@H:12]([CH2:13][CH2:14][S:15][CH2:16][CH3:17])[CH:11]([C:18]([OH:20])=[O:19])[O:10]C1(C)C)=O)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].[C:29]([O:35][CH2:36]Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C.C(OCC)(=O)C>[NH2:8][C@H:12]([CH2:13][CH2:14][S:15][CH2:16][CH3:17])[CH:11]([OH:10])[C:18]([O:20][CH2:36][O:35][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:19]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCSCC[C@@H]1C(C(=O)O)OC(C)(C)N1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCSCC[C@@H](N)C(O)C(=O)OCOC(=O)C(C)(C)C
Reaction time: 1 h

Procedure:
A solution of Example 22B (0.102 g, 0.31 mmol), cesium carbonate (0.111 g, 0.34 mmol), and chloromethyl pivalate (0.055 mL, 0.38 mmol) in DMF (3 mL) at room temperature was stirred for 24 hours, diluted with ethyl acetate, washed sequentially with water, aqueous NaHCO3, pH 7 buffer, and brine, dried (MgSO4), filtered, and concentrated. The residue was dissolved in 4M HCl in dioxane (2 mL), stirred for 1 hour, treated with water (1 mL), stirred for 1 hour, concentrated, and purified by reverse phase HPLC with acetonitrile/water to provide the desired product. MS (ESI) m/e 308 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 7.87–7.80 (br s, 2H), 6.53 (m, 0.7H), 6.33 (d, 0.3H), 4.40 (m, 0.3H), 4.24 (m, 0.7H), 4.28 (s, 0.6H), 4.26 (s, 1.4H), 3.53 (m, 1H), 2.63 (m, 2H), 2.48 (m, 2H), 1.90–1.75 (m, 2H), 1.22–1.16 (m, 12H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:21]1[C:30]2[C:25](=[CH:26][C:27]([CH2:31][NH2:32])=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:32][CH2:31][C:27]4[CH:26]=[C:25]5[C:30](=[CH:29][CH:28]=4)[N:21]=[CH:22][CH:23]=[N:24]5)[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: NCc1ccc2nccnc2c1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(NCc4ccc5nccnc5c4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (100 mg, 0.35 mmol) and quinoxalin-6-ylmethanamine (150 mg, 0.94 mmol) in acetonitrile (1 mL) and N,N-diisopropylethylamine (500 μL, 3 mmol) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (30-60% acetonitrile-water [10 mM DEA]) to afford a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][S:13][CH2:14][CH:15]([C:22](=[O:29])[C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:16][C:17]([O:19]CC)=[O:18])=[O:9])=[CH:4][CH:3]=1.[OH-].[Li+]>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][CH2:12][S:13][CH2:14][CH:15]([C:22](=[O:29])[C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:16][C:17]([OH:19])=[O:18])=[O:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(CSCCNC(=O)c1ccc(F)cc1)C(=O)c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CC(CSCCNC(=O)c1ccc(F)cc1)C(=O)c1cccnc1
Yield: 97.5 %

Procedure:
A solution of ethyl 3-({2-[(4-fluorophenyl)carbonylamino]ethylthio}methyl)-4-oxo-4-(3-pyridyl)butanoate (100 mg) and lithium hydroxide (1 eq) was stirred a temperature in ethanol-water (1:1, 2 mL) till the starting material disappeared. The solution was acidified and purified on preparative HPLC (C-18 prep column, 10% to 90% acetonitrile in water both containing 0.1% TFA) to give 91 mg of 3-({2-[(4-fluorophenyl)carbonylamino]ethylthio}methyl)-4-oxo-4-(3-pyridyl)butanoic acid. The acid (91 mg) was treated with ethyl chloroformate (1.1 eq) and triethylamine (1.1 eq) in tetrahydrofuran (2.5 mL) at room temperature for 10 minutes. Piperidine (1.1 eq) was added to the reaction mixture and stirred at room temperature overnight. The solution was concentrated and purified on preparative HPLC (C-18 prep column, 10% to 90% acetonitrile in water both containing 0.1% TFA) to give 66 mg of the title compound; ESMS (M+1)+458.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:6][N:5]=[C:4]([S:16][CH3:17])[N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1>C(Cl)(Cl)Cl>[CH3:13][C:12]([NH:11][S:8]([C:7]1[C:2]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)=[N:3][C:4]([S:16][CH3:17])=[N:5][CH:6]=1)(=[O:10])=[O:9])([CH3:15])[CH3:14]
Reactant: Cc1cccc(N)c1
Reactant: CSc1ncc(S(=O)(=O)NC(C)(C)C)c(Cl)n1
Solvent: ClC(Cl)Cl
Product: CSc1ncc(S(=O)(=O)NC(C)(C)C)c(Nc2cccc(C)c2)n1
Temperature: 25 °C
Yield: 96.7 %

Procedure:
4-Chloro-N-(1,1-dimethylethyl)-2-(methylthio)-5-pyrimidinesulfonamide (1.45 g, 4.91 mmol) was dissolved in chloroform (15 mL). m-Toluidine (1.08 mL, 10.07 mmol, 2.05x) was added, and the mixture was refluxed for 90 minutes. The reaction was cooled to ambient temperature, the chloroform removed under reduced pressure, and the residue crystallized from ethanol and water to yield 1.74 g (4.75 mmoles, 97%) of pale yellow needles, m.p. 177.5°-178° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[CH2:24]([O:26][C:27](=[O:34])/[CH:28]=[CH:29]\[CH2:30][CH:31]([CH3:33])[CH3:32])[CH3:25]>C(Cl)Cl>[CH2:24]([O:26][C:27]([C@H:28]1[C@@H:29]([CH2:30][CH:31]([CH3:32])[CH3:33])[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12]1)=[O:34])[CH3:25]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)/C=C\CC(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1CC(C)C
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 46.3 %

Procedure:
N-Benzyl-N-(methoxymethyl)trimethylsilylmethylamine (4.0 g, 16.8 mmol), followed by TFA (1.0 M solution in CH2Cl2, 1.0 mL, 1 mmol) were added to a solution of (Z)-5-methyl-hex-2-enoic acid ethyl ester 8 (3.0 g, 19.2 mmol) in methylene chloride (30 mL) maintained at −5° C. under nitrogen atmosphere. After 15 minutes, the bath was removed and stirring was continued overnight. The reaction mixture was washed with saturated NaHCO3 (10 mL), water (15 mL), brine (20 mL), and dried. The product was purified by chromatography on silica gel, and compound was eluted with 20% ethyl acetate in hexane to give (cis)-1-benzyl-4-isobutyl-pyrrolidine-3-carboxylic acid ethyl ester 9 as an oil (2.25 g, 41%).