Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[S:10][C:9]([C:11]([OH:13])=O)=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].C(Cl)(C([Cl:18])=O)=O>ClCCl.CN(C=O)C>[C:1]([C:6]1[S:10][C:9]([C:11]([Cl:18])=[O:13])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1ccc(C(=O)O)s1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C(=O)Cl)s1
Reaction time: 8 h

Procedure:
To a suspension of acid 35 (0.64 g, 3.2 mmol) in dichloromethane (20 mL) under argon at room temperature was added a 2.0M solution of (COCl)2 in dichloromethane (2.4 mL, 4.8 mmol) and two drops of DMF, and stirred overnight. Excess (COCl)2 and dichloromethane were removed at reduced pressure, and the viscous, light, yellow product was dried overnight to afford the desired benzoyl chloride 36 as a yellow solid. The structure of the product was also confirmed using IR and 1H NMR spectroscopy.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:37]1[N:38]=[C:39]([NH:45][C:46]2[CH:47]=[C:48]3[C:53](=[CH:54][CH:55]=2)[CH2:52][N:51]([CH3:56])[CH2:50][CH2:49]3)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1>>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:37]1[N:38]=[C:39]([NH:45][C:46]2[CH:47]=[C:48]3[C:53](=[CH:54][CH:55]=2)[CH2:52][N:51]([CH3:56])[CH2:50][CH2:49]3)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: CN1CCc2cc(Nc3nc(Br)cn(C)c3=O)ccc2C1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc4c(c3)CCN(C)C4)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 58 %

Procedure:
Following Example 148b, 290 mg of 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d and 209 mg 5-bromo-1-methyl-3-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrazin-2(1H)-one 221b were reacted to give 283a as a yellow solid (217 mg, 58%). MS: [M+H]+ 699
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:31])=[C:6]([C@@:8]2([NH:19][C:20]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[S:21])[C@H:13]([CH2:14]O)[CH2:12][C@H:11]([CH:16]3[CH2:18][CH2:17]3)[O:10][CH2:9]2)[CH:7]=1.[N:32]1C=CC=C[CH:33]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[C:33]([C:2]1[CH:3]=[CH:4][C:5]([F:31])=[C:6]([C@:8]23[CH2:9][O:10][C@@H:11]([CH:16]4[CH2:18][CH2:17]4)[CH2:12][C@H:13]2[CH2:14][S:21][C:20]([NH:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:19]3)[CH:7]=1)#[N:32]
Reactant: O=C(NC(=S)N[C@@]1(c2cc(Br)ccc2F)CO[C@@H](C2CC2)C[C@H]1CO)c1ccccc1
Reactant: c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(F)c([C@]23CO[C@@H](C4CC4)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)c1
Temperature: 0 °C

Procedure:
A solution of N-{[(3S,4R,6R)-3-(5-bromo-2-fluorophenyl)-6-cyclopropyl-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide (C57) (127 mg, 0.28 mmol) and pyridine (81 μL, 1.01 mmol) in dichloromethane (12 mL) was cooled to -50° C. Trifluoromethanesulfonic anhydride (94 μL, 0.56 mmol) was added drop-wise to the solution and the mixture was gradually warmed to 0° C. over 90 minutes. The reaction mixture was diluted with dichloromethane (20 mL), washed with water (2×30 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) afforded the product as a solid. Yield: 83 mg, 68%. LCMS m/z 436.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH:35][NH:36][C:37](=O)[CH2:38][O:39][CH3:40])=[N:10][N:11]([CH2:23][C:24]3[C:25]([CH3:34])=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=3)[C:12](=[O:22])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([C:37]([CH2:38][O:39][CH3:40])=[N:36][N:35]=3)[N:11]([CH2:23][C:24]3[C:25]([CH3:34])=[N:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[C:12](=[O:22])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: COCC(=O)NNc1nn(Cc2ccc(C(F)(F)F)nc2C)c(=O)c(-c2ccc(C#N)cc2)c1-c1ccc(Cl)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COCc1nnc2c(-c3ccc(Cl)cc3)c(-c3ccc(C#N)cc3)c(=O)n(Cc3ccc(C(F)(F)F)nc3C)n12
Temperature: 120 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl) -2-methoxyacetohydrazide (780 mg, 1.338 mmol) was dissolved in toluene (25 ml) and was heated at 120° C. for 15 min. After this time, POCl3(5 ml) was added and the reaction was stirred at 120° C. for an additional 2 hr. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (50 ml) and washed with saturated NaHCO3(20 ml), water (20 ml) and saturated NaCl (20 ml). The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified using an ISCO automated system (80 g silica gel, 20%-80% EtOAc/Hex) to give the product 4-(8-(4-chlorophenyl)-3-(methoxymethyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile (550 mg) as an off-white solid (73% yield). HPLC retention time 3.085 min (Method A); LCMS (M+H)=565.0. 1HNMR (CD3CN, 500 Hz) 7.67(1H, d, J=7.7Hz), 7.63(2H, d, J=8.8 Hz), 7.58(1H, d, J=7.75), 7.35-7.37(6H, m), 5.81(2H, s), 4.40(2H, s), 3.24(3H, s), 2.65(3H, s); 13CNMR (CD3CN, 500 Hz) 160.24, 157.25, 146.50(m), 146.00, 144.71, 139.15, 137.77, 135.93, 134.84, 134.25, 132.92, 132.64, 131.38, 129.26, 122.90(m), 119.25, 112.66, 65.06, 58.28, 50.01, 22.19.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1.[Br:18]([O-])(=O)=O.[K+].[OH-].[Na+]>>[Br:18][C:9]1[CH:8]=[C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:5][C:4]=1[O:3][C:2]([F:1])([F:16])[F:17]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: FC(F)(F)Oc1ccc(-c2cccnc2)cc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)Oc1ccc(-c2cccnc2)cc1Br
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 71.6 %

Procedure:
3-(4-Trifluoromethoxyphenyl)pyridine (Description 61) (1.26 g, 5.27 mmol) was suspended in aqueous sulfic acid (50%, 16 ml) and cooled to 0° C. Potassium bromate (0.88 g, 5.27 mmol) was added in portions over 2 hours and the mixture was stirred at room temperature for 40 min. The mixture was poured into ice/water and basified with aqueous sodium hydroxide (4M). The mixture was extracted with ethyl acetate (3×100 ml) and the combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/ether (60:40) to give the title compound as an oil (1.2 g, 74%). 1H NMR (360 MHz, CDCl3) δ 8.82 (1H, s), 8.62 (1H, d), 7.84 (2H, m), 7.54 (1H, dd, J=8.5, 2.2 Hz), 7.41 (2H, m). m/z (ES+) 318, 320 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([O:14]C(C)(C)C)=O)[CH2:7][CH2:6]1)=[O:4].C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:59]1([CH2:62][NH:63][CH2:64][C:65]2[NH:66][C:67](=[O:75])[CH:68]3[CH2:74][O:73][CH2:72][CH2:71][CH:69]3[N:70]=2)[CH2:61][CH2:60]1>ClCCl.CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:6][CH2:7][N:8]([CH2:11][C:12](=[O:14])[N:63]([CH2:62][CH:59]2[CH2:61][CH2:60]2)[CH2:64][C:65]2[NH:66][C:67](=[O:75])[CH:68]3[CH2:74][O:73][CH2:72][CH2:71][CH:69]3[N:70]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1CCN(CC(=O)OC(C)(C)C)CC1
Reactant: O=C1NC(CNCC2CC2)=NC2CCOCC12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(CC(=O)N(CC2=NC3CCOCC3C(=O)N2)CC2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
To a solution of 1-tert-butoxycarbonylmethyl-piperidine-4-carboxylic acid methyl ester (0.65 g, 2.53 mmol, 1 eq.) in 2.5 mL of dichloromethane was added TFA (2.53 mL, 32.8 mmol, 13 eq.). The resulting mixture was stirred at room temperature overnight. After 18 h, the reaction mixture was concentrated and dried under high vacuum. To this oil (0.52 g, 2.22 mmol, 1 eq.) was added DIEA (1.16 mL, 6.66 mmol, 3 eq.) in 5 mL of DMF, followed by HATU (1.69 g, 4.44 mmol, 2 eq.). The resulting mixture was stirred at room temperature for 30 min. 2-[(Cyclopropylmethyl-amino)-methyl]-3,4a,5,7,8,8a-hexahydro-pyrano[4,3-d]pyrimidin-4-one (0.7 g, 2.22 mmol, 1 eq.) in 5 mL of DMF was added and the resulting mixture was stirred at room temperature overnight. After 18 h, the reaction mixture was quenched with H2O (25 mL) and extracted with dichloromethane (3×50 mL). The combined organic layer was concentrated and purified via preparative HPLC (20-100% CH3CN/H2O over 10 min with 0.1% TFA, sun fire C18 OBD 50×50 mm column with flow rate of 60 mL/min) to give the title compound as a white solid (0.69 g). Exact mass calculated for C21H33N4O5 421.2. MS (ESI) m/z 421.6 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][CH3:12])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23].O>C(Cl)Cl>[CH2:11]([NH:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([NH:1][C:22](=[O:23])[CH2:21][O:20][CH3:19])[C:3]=1[C:4]#[N:5])[CH3:12]
Reactant: COCC(=O)Cl
Reactant: CCNc1cccc(N)c1C#N
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCNc1cccc(NC(=O)COC)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(ethylamino)benzonitrile (3.4 g) in methylene chloride (50 ml) is added pyridine (2.4 ml), and thereto is added dropwise methoxyacetyl chloride (2.8 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, water is added thereto, and the mixture is extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting crude crystals are recrystallized from ethyl acetate-hexane to give the title compound (3.2 g) having the following physical properties.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][NH:9][CH2:8][CH2:7]2.[BrH:14]>>[BrH:14].[CH2:10]1[C:11]2[C:6](=[CH:5][C:4]([OH:3])=[CH:13][CH:12]=2)[CH2:7][CH2:8][NH:9]1
Reactant: COc1ccc2c(c1)CCNC2
Agent: Br
Agent: Cl
Product: Oc1ccc2c(c1)CCNC2
Temperature: 100 °C

Procedure:
6-Methoxy-1,2,3,4-tetrahydro-isoquinoline hydrochloride, prepared as in WO 2004/26305, (18.9 g, 94 mmol) in 48% aqueous hydrobromic acid was heated at 100° C. for 12 h and then cooled to 0° C. The solid was filtered off, washed with t-butyl methyl ether and dried.
Reaction SMILES: [C:1](OC(=NC1CCCCC1)NC1CCCCC1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[C:26]([CH2:28][C:29]([OH:31])=[O:30])[CH:25]=[CH:24][N:23]=1>C(Cl)Cl>[Cl:21][C:22]1[CH:27]=[C:26]([CH2:28][C:29]([O:31][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:30])[CH:25]=[CH:24][N:23]=1
Reactant: O=C(O)Cc1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=NC1CCCCC1)NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cc1ccnc(Cl)c1
Reaction time: 24 h
Yield: 75.7 %

Procedure:
Compound 2-tert-butyl-1,3-dicyclohexylisourea (650 mg, 2.30 mmol) was added to a solution of 2-(2-chloropyridin-4-yl)acetic acid (200 mg, 1.16 mmol) in DCM (5 ml) at room temperature. The reaction mixture was stirred for 24 h, filtered, washed with DCM (5 ml) and saturated sodium bicarbonate solution (10 ml). The solvent was evaporated in vacuum to afford 200 mg (77%) of tert-butyl 2-(2-chloropyridin-4-yl)acetate as a colorless liquid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:12](CC)CC)C>C(#N)C>[C:1]([NH2:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccccc1
Solvent: CC#N
Product: NC(=O)c1ccccc1
Reaction time: 3 h

Procedure:
To 3,3′-(3-amino-2,6-pyridinediylbistoxy)]bis(benzonitrile) (1.0g, 2.9 mmol) dissolved in acetonitrile (50 mL) was added benzoyl chloride (0.50 g, 3.5 mmol) and triethylamine (0.45 g, 0.60 mmol). After stirring for 3 hours, the reaction was partitioned between ether and water. The organic layer was separated, washed with water, saturated aqueous sodium bicarbonate, and brine, dried (MgSO4), and the solvent was removed in vacuo. Chromatography on silica gel with ethyl acetate/hexane (1/3) as eluent gave N-[2,6-bist3-cyanophenoxy)-pyridin-3-yl]benzamide; NMR (CDCl3) 8.95 (d,1), 8.25 (s,1), 7.9 (d,1), 7.2-7.7 (m,12), 6.8 (d,1) ppm.
Reaction SMILES: N1C=CN=C1.[NH2:6][C:7]([CH:9]1[CH2:13][CH:12]([F:14])[CH2:11][N:10]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O.P(Cl)(Cl)(Cl)=O.[Cl-].[Na+]>C(OC(=O)C)C.N1C=CC=CC=1>[C:7]([C@@H:9]1[CH2:13][C@H:12]([F:14])[CH2:11][N:10]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])#[N:6]
Reactant: CC(C)(C)OC(=O)N1CC(F)CC1C(N)=O
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C#N
Temperature: 2.5 °C

Procedure:
In a 5.0 L 4-necked RB flask, fitted with a mechanical stirrer and reflux condenser, pyridine (1000 ml) and imidazole (58.6 gm, 0.86 mol) were added at 25-35° C. while stirring. The reaction mixture was cooled to 0-5° C. while stirring for 30 min, tert-butyl 2-(aminocarbonyl)-4-fluoropyrrolidine-1-carboxylate (100 gm, 0.43 mol) and phosphorous oxychloride (165.7 gm, 1.07 mol) were added slowly at 0-5° C. while stirring. After addition, the reaction mixture was maintained for 1 hr. The progress of the reaction was monitored by TLC. After ascertaining completion of the reaction by TLC, the reaction mixture was poured into an ice cold water (5 L), sodium chloride and ethylacetate (800 ml) mixture. The aqueous layer was washed with an ethyl acetate (800 ml), dilute HCl (4 100), sodium bicarbonate and saturated brine solution. The ethylacetate layer was distilled below 55° C. under vacuum and hexane (500 ml) was added to the resulting mass. Trace ethylacetate was distilled off. The resulting mass was taken as such to the next stage.
Reaction SMILES: [CH2:1]([S:17](Cl)(=[O:19])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O.NN>CO>[CH2:1]([S:17]([OH:19])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Cl
Agent: NN
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCCCS(=O)O

Procedure:
200 g of cetyl sulphonic acid chloride are introduced at room temperature into 87 ml of hydrazine hydrate in 600 ml of methanol. The sulphonic acid hydrazide precipitates and may be separated by suction filtration. The residue is then introduced into a solution of 48 g of NaOH in 1,500 ml of water and 1,000 ml of methanol and slowly heated to boiling with stirring. The solvent is slowly distilled off and the temperature is maintained at 90° to 95° C. for about 4 hours. The sodium salt of cetyl sulphinic acid is separated by suction filtration after cooling. The compound is dried.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:17][CH2:16][N:15]3[C@H:10]([CH2:11][O:12][C:13]([CH3:19])([CH3:18])[CH2:14]3)[CH2:9]2)=[CH:6][C:5]([C:20]#[N:21])=[CH:4][C:3]=1[NH:22]C(=O)OC(C)(C)C.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(Cl)Cl>[NH2:22][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([N:8]2[CH2:17][CH2:16][N:15]3[C@H:10]([CH2:11][O:12][C:13]([CH3:19])([CH3:18])[CH2:14]3)[CH2:9]2)[C:2]=1[Cl:1])[C:20]#[N:21]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN3CC(C)(C)OC[C@@H]3C2)c1Cl
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC1(C)CN2CCN(c3cc(C#N)cc(N)c3Cl)C[C@H]2CO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
(S)-tert-butyl (2-chloro-5-cyano-3-(3,3-dimethylhexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)phenyl)carbamate (87 mg, 0.207 mmol) was taken up in DCM (2 mL) and cooled to 0° C. 2,6-Lutidine (0.072 mL, 0.620 mmol) was added, followed by dropwise addition of trimethylsilyl trifluoromethanesulfonate (0.112 mL, 0.620 mmol). The reaction was stirred at 0° C. for 30 min, then warmed to room temperature and stirred for 30 min. The solvent was removed in vacuo and the material was purified by flash column chromatography, eluting with 0-2% (2N NH3/MeOH)/DCM. (S)-3-amino-4-chloro-5-(3,3-dimethylhexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)benzonitrile (22 mg) was obtained as a yellow glass.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[C:9](Cl)(=[O:11])[CH3:10].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:11])[CH3:10]
Reactant: Nc1ccccc1Br
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1Br
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of 2-bromophenylamine (1.0 equiv.) in DCM (0.2 M) was added acetyl chloride (1.5 M) at 0° C. The resulting mixture was stirred at this temperature overnight. 1 N hydrochloric acid (0.4 equiv.) was added to quench the reaction. The mixture was extracted with DCM and sodium bicarbonate and the combined organic layers were washed with brine, dried over sodium sulfate, concentrated and triturated from 16% ethyl acetate in petroleum ether to give the desired product (73% yield) as a white power. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 8.33-8.31 (m, 1H), 7.61 (br, 1H), 7.54-7.52 (m, 1H), 7.33-7.26 (m, 1H), 6.99-6.95 (m, 1H), 2.24 (s, 3H); MS (ESI) m/z 203.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][N:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:10]([O-:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1([C@@H]([NH3+])C)C=CC=CC=1.S(=O)(=O)(O)O>C(O)(C)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][N:14]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN(c1ccccc1)c1ccccn1)C(=O)[O-]
Agent: C[C@H]([NH3+])c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H](CN(c1ccccc1)c1ccccn1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
A suspension of (S)-1-phenylethyl-ammonium (S)-2-tert-butoxycarbonylamino-3-(phenyl-pyridin-2-ylamino)-propanoate (2.25 g, 4.69 mmol, 99.5% de) in aqueous isopropanol (50% strength, 6 ml) is admixed with 1N sulfuric acid (6 ml, 5.85 mmol) and stirred for 2 h at RT. The solid is filtered off with suction and dried to give (S)-2-tert-butoxycarbonylamino-3-(phenyl-pyridin-2-ylamino)-propanoic acid (1.35 g, 81%, >99.9% ee) as a colorless solid.
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:8]([N:10]([CH2:19][CH3:20])[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)[CH3:9]>>[CH2:8]([N:10]([CH2:19][CH3:20])[C:11]1[CH:18]=[CH:17][C:14]([CH:15]([NH:7][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])[NH:7][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])=[CH:13][CH:12]=1)[CH3:9]
Reactant: CCN(CC)c1ccc(C=O)cc1
Reactant: CCCCC(N)=O
Product: CCCCC(=O)NC(NC(=O)CCCC)c1ccc(N(CC)CC)cc1
Yield: 69 %

Procedure:
Compound 52 was prepared from pentanamide and 4-(diethylamino)benzaldehyde using method 1. Yield: 69%. 1H NMR (400 MHz, CD3OD) δ 7.18 (d, J=8.8 Hz, 2H), 6.71 (d, J=8.8 Hz, 2H), 6.58 (t, J=8.4 Hz, 1H), 3.33-3.41 (m, 4H), 2.25 (t, J=7.2 Hz, 4H), 1.58-1.66 (m, 4H), 1.33-1.43 (m, 4H), 1.14 (t, J=7.2 Hz, 6H), 0.95 (t, J=2.8 Hz, 6H). LC-MS (ESI): m/z 362.2 (M+H)+. HRMS (ESI) for C21H36N3O2 (MH+): calcd, 362.2802. found 362.2792.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH2:31][CH:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]([C:38]2[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=2)[N:28]=1.N1CCCCC1>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH2:31][CH:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]([C:38]2[CH:39]=[CH:40][C:41]([CH:42]=[CH:1][C:2]3[O:3][C:4]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=3)=[CH:44][CH:45]=2)[N:28]=1
Reactant: COc1ccccc1C1=NN(c2ccc(C=O)cc2)C(c2ccccc2)C1
Reactant: CC1=CC(=C(C#N)C#N)C=C(c2ccccc2)O1
Solvent: C1CCNCC1
Product: COc1ccccc1C1=NN(c2ccc(C=CC3=CC(=C(C#N)C#N)C=C(c4ccccc4)O3)cc2)C(c2ccccc2)C1
Temperature: 75 °C

Procedure:
As shown in the following reaction 5, 0.197 g (0.84 mmol) of 2-(2-methyl-6-phenyl-pyran-4-ylidene)-malononitrile and 0.30 g (0.84 mmol) of 4-[3-(2-methoxy-phenyl)-5-phenyl-4,5-dihydro-pyrazol-1-yl]-benzaldehyde were added into 20 ml of alcohol (ethanol), and 0.10 g (1.2 mmol) of piperidine was added thereto. The reaction solution was heated at 75° C. for 10 hours.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([O:17][C@@H:18]([C:22]([O:35][CH3:36])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]([OH:21])=[O:20])[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:43]([O:46][C@@H:47]1[C@@H:52]([O:53][C:54](=[O:56])[CH3:55])[C@H:51]([O:57][C:58](=[O:60])[CH3:59])[C@@H:50]([C:61]([O:63][CH3:64])=[O:62])[O:49][C@@H:48]1Br)(=[O:45])[CH3:44]>C(#N)C>[C:43]([O:46][C@@H:47]1[C@@H:52]([O:53][C:54](=[O:56])[CH3:55])[C@H:51]([O:57][C:58](=[O:60])[CH3:59])[C@@H:50]([C:61]([O:63][CH3:64])=[O:62])[O:49][C@H:48]1[O:20][C:19](=[O:21])[C@@H:18]([O:17][C:12]1[N:11]=[C:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:15]=[C:14]([CH3:16])[N:13]=1)[C:22]([O:35][CH3:36])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)(=[O:45])[CH3:44]
Reactant: COC(=O)[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COC(c1ccccc1)(c1ccccc1)[C@H](Oc1nc(C)cc(COCc2ccccc2)n1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@H]1O[C@@H](OC(=O)[C@@H](Oc2nc(C)cc(COCc3ccccc3)n2)C(OC)(c2ccccc2)c2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
To a solution of the compound of Example 14 (0.997 g, 2.05 mmol) in acetonitrile (20 mL) is added potassium carbonate (0.284 g, 2.05 mmol) and the reaction mixture stirred for 0.5 hr. (2R,3R,4S,5S,6S)-2-Bromo-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.817 g, 2.05 mmol) is added to the reaction mixture and the reaction stirred for 12 hr. The reaction mixture is filtered and the filtrate concentrated under reduced pressure on a rotary evaporator to give a crude product. The crude product is purified by column chromatography on silica gel eluted with ethyl acetate-hexane (2:8) to yield the title compound (1.0 g, 60%). MS m/z 801.1 (M+.+1); 1H NMR (CDCl3, 200 MHz) δ 5.65 (C-6 pyran H, d, J5,6=8 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[C@@H:10]([CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:27][C:28]([NH:30][C:31]([CH3:37])([CH3:36])[CH2:32][C:33](O)=[O:34])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[CH2:1]([O:8][C:9](=[O:22])[C@H:10]([NH:11][C:33](=[O:34])[CH2:32][C:31]([NH:30][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])([CH3:37])[CH3:36])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Product: CC(C)(CC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Prepared from D-tryptophan benzyl ester (1 g; 3.40 mmol) and 3-t-butoxycarbonylamino-3-methylbutanoic acid (0.91 g; 4.19 mmol) by the procedure described in Example 6, Step C. The yield was 0.981 g (58%).