Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]2[C:31]3[CH2:38][C:37](=[O:39])[NH:36][C:32]=3[N:33]=[CH:34][N:35]=2)[CH:25]=[CH:26][C:27]=1[F:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]2[C:31]3[C:38](=[CH:16][C:13]4[NH:12][C:9]5[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][N:3]([CH2:19][CH3:20])[CH2:1][CH3:2])[C:7](=[O:18])[C:8]=5[C:14]=4[CH3:15])[C:37](=[O:39])[NH:36][C:32]=3[N:33]=[CH:34][N:35]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ncnc(Nc5ccc(F)c(Cl)c5)c43)c(C)c2C1=O
Yield: 39.4 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]-pyrimidin-6-one as starting materials to give 4-(3-chloro-4-fluoro-phenylamino)-5-[5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-ylmethylene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (53 mg, 39.4%) as a yellow solid.
Reaction SMILES: CN([CH:4]=[O:5])C.O[C:7]1[CH:22]=[CH:21][C:10]([C:11](=[O:20])[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.[H-].[Na+].ClC[CH2:27][CH2:28][OH:29]>O>[OH:29][CH2:28][CH2:27][CH2:4][O:5][C:17]1[CH:18]=[CH:19][C:14]([CH:13]=[CH:12][C:11]([C:10]2[CH:21]=[CH:22][CH:7]=[CH:8][CH:9]=2)=[O:20])=[CH:15][CH:16]=1
Reactant: O=C(C=Cc1ccccc1)c1ccc(O)cc1
Reactant: CN(C)C=O
Reactant: OCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=C(C=Cc1ccc(OCCCO)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A refined 4′-(3-hydroxypropyloxy)-chalcone (9.71 g, 34.4 mmol) was obtained with a yield of 51.4% by adding 90 ml of dry DMF to 4′-hydroxychalcone (15.0 g, 67 mmol) in an air current of argon, and adding sodium hydride (60%, 2.68 g, 67 mmol) through dropping in a reaction flask of 200 ml in ice cooling for 30 minutes; later, after heating to a room temperature and stirring for 5 hours, adding 3-chloro-1-propanol (6.33 g, 67 mmol) through dropping at the same temperature for 10 minutes; furthermore, heating to 80° C., and reacting for 7 hours; next, after injecting the solution into water with ice and extracting the product with ethyl acetate, washing with water, and drying through dehydration with magnesium sulfate, and removing the solvent; after refining (mobile phase, hexane:ethyl acetate=4:1) the gained coarse crystal with silica gel column, recrystallizing with ethyl acetate.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH:6]([CH2:11][P:12]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][CH:8]([CH3:10])[CH3:9])C.[OH-].[Na+]>CCO>[CH2:18]([O:17][P:12]([CH2:11][CH:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:5][C:4]([OH:20])=[O:3])([O:14][CH2:15][CH3:16])=[O:13])[CH3:19]
Reactant: CCOC(=O)CC(CC(C)C)CP(=O)(OCC)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOP(=O)(CC(CC(=O)O)CC(C)C)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
3-(Diethoxy-phosphorylmethyl)-5-methyl-hexanoic acid ethyl ester (1.0 g, 3.2 mmol) and NaOH (1.8 mL, 2.0 M) are combined in 10 mL of EtOH at 0° C. After 15 minutes, the reaction mixture is warmed to room temperature and stirred overnight. The EtOH is evaporated, and 50 mL of 2.0 M NaOH is added. The solution is extracted with Et2O (2×50 mL), and then acidified to pH=1 with concentrated HCl. The acidic solution is extracted with EtOAc (3×50 mL), and the combined extracts are dried over MgSO4 and evaporated to give 0.65 g (72% yield) of 3-(diethoxy-phosphorylmethyl)-5-methyl-hexanoic acid as an oil. NMR (H1, 400 MHz, CDCl3) δ 0.9 (6H, d); δ 1.3 (8H, m); δ 1.6 (1H, m); δ 1.8 (2H, m); δ 2.3 (1H, m); δ 2.5 (2H, m); δ 4.1 (4H, m).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C=O)C>[O:4]1[CH2:5][CH2:6][N:1]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.4 %

Procedure:
To a solution of morpholine (1.4 g, 16.3 mmol, 1.0 eq) in DMF were added K2CO3 (5.63 g, 40.7 mmol, 2.5 eq.) and ethyl 2-bromoacetate (4.07 g, 24.4 mmol, 1.5 eq.). The mixture was stirred at RT for 16 h and quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to afford the product in 71.4% yield (2 g). LC-MS (ESI): Calculated mass: 173.2; Observed mass: 174.0 [M+H]+ (rt: 0.20 min).
Reaction SMILES: [N:1]1([CH2:14][C@@H:15]([NH2:17])[CH3:16])[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[CH:3]=[CH:2]1)[N:10]=[CH:9][CH:8]=[CH:7]3.[CH2:18]1[O:28][C:27]2[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=2[O:19]1.[BH4-].C(=O)C1C=CC=CC=1.N.[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]/[C:42]([OH:44])=[O:43]>CC(O)C.CO>[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]/[C:42]([OH:44])=[O:43].[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]/[C:42]([OH:44])=[O:43].[N:1]1([CH2:14][C@@H:15]([NH:17][CH2:23][C:22]2[CH:25]=[CH:26][C:27]3[O:28][CH2:18][O:19][C:20]=3[CH:21]=2)[CH3:16])[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[CH:3]=[CH:2]1)[N:10]=[CH:9][CH:8]=[CH:7]3
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: C[C@H](N)Cn1ccc2ccc3ncccc3c21
Agent: N
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Solvent: CO
Solvent: CC(C)O
Solvent: O=Cc1ccccc1
Product: C[C@@H](Cn1ccc2ccc3ncccc3c21)NCc1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
A mixture of (S)-1-(1H-pyrrolo[2,3-f]quinolin-1-yl)-2-propylamine (0.025 g, 0.11 mmol), 3,4-methylenedioxybenzaldehyde (0.033 g, 0.22 mmol) and methanol (1 mL) was shaken for 3 h. To the mixture was added Amberlite IRA-400 borohydride resin (2.5 mmol/g —BH4, 0.12 g, 0.3 mmol) and the mixture was shaken for 18 h. To the mixture was added PS-benzaldehyde (2.5 mmol/g —CHO, 0.12 g, 0.3 mmol) and the mixture was shaken for 18 h and filtered. The filter-cake was washed with dichloromethane (2×1 mL) and methanol (2×1 mL) and the filtrate was concentrated in vacuo. The concentrate was dissolved in dichloromethane (2 mL) and Amberlyst-15 (0.5 g) was added. The mixture was shaken for 1 h and filtered. The filter-cake was washed with dichloromethane (2×1 mL) and methanol (2×1 mL), suspended in methanolic ammonia solution (2 M, 1 ML, 2 mmol), shaken for 1 h, and filtered. The filter-cake was washed (dichloromethane) and the filtrate was concentrated in vacuo, treated with a solution of fumaric acid (0.030 g, 0.26 mmol) in 2-propanol (2 mL), cooled to 0° C., shaken for 1 h and filtered. The filter-cake was dried to give the product as a beige solid (0.052 g, 79%): mp 171-175° C. (dec); NMR ΔH (400 MHz, DMSO-d6) 0.99 (3H, d, J 6.5 Hz) 3.15 (1H, m) 3.58 (1H, d, J 14 Hz) 3.73 (1H, d, J 14 Hz) 4.46 (1H, dd, J 8.5, 14.5 Hz) 4.76 (1H, dd, J 6, 14.5 Hz) 5.96 (2H, s) 6.66 (1H, d, J 7.5 Hz) 6.73 (1H, d, J 7.5 Hz) 6.87 (1H, s) 7.47 (1H, dd, J 4.5, 8.5 Hz) 7.50 (1H, d, J 3 Hz) 7.64 (1H, d, J 9 Hz) 7.94 (1H, d, J 9 Hz) 8.64 (1H, d, J 8.5 Hz) 8.77 (1H, d, J 4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH:16]=[C:15]([C:17]2[N:22]=[N:21][C:20]([N:23]3[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH:14]=[N:13]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:26]2[CH2:27][CH2:28][N:23]([C:20]3[N:21]=[N:22][C:17]([C:15]4[CH:14]=[N:13][N:12]([CH3:11])[CH:16]=4)=[CH:18][CH:19]=3)[CH2:24][CH2:25]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: Cn1cc(-c2ccc(N3CCC(=O)CC3)nn2)cn1
Product: Cn1cc(-c2ccc(N3CCC(N4CCc5ccc(Cl)cc54)CC3)nn2)cn1

Procedure:
The title compound was prepared following the procedure as described in Example 5, STEP 4, reacting 6-chloroindoline and 1-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-one.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22].C1C(=O)N([Br:30])C(=O)C1>CN(C=O)C>[F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:30])=[CH:18][C:17]=1[Cl:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc2snnc2c(F)c1Nc1ccccc1Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc2snnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
To a solution of methyl 4-fluoro-5-((2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate (1.82 g, 5.39 mmol) in DMF (10 mL) was added NBS (1.0 g, 5.65 mmol). After stirring for 4 h at ambient temperature, the reaction was quenched by saturated NH4Cl (aq.). The solution was extracted with ethyl acetate (30 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL) successively, dried over Na2SO4 and concentrated in vacuo to give the desired product (yellow solid, 2.02 g, 90.1% yield). 1H NMR (400 MHz, CDCl3): δ 8.84 (s, 1H), 8.60 (d, 1H), 7.59 (d, 1H), 7.29 (m, 1H), 6.77 (m, 1H), 4.04 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].N1C=CC=CC=1.[C:22](Cl)(=[O:24])[CH3:23]>ClCCl.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>[C:22]([NH:1][CH2:2][C@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=[O:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCOC[C@@H]1CN
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1COCCN1C(=O)OC(C)(C)C

Procedure:
To a solution of (S)-tert-butyl 3-(aminomethyl)morpholine-4-carboxylate (commercially available, 0.62 g, 2.87 mmol) in dichloromethane (28.0 ml) were added sequentially pyridine (0.5 ml, 5.73 mmol) and acetyl chloride (0.25 ml, 3.44 mmol). After 30 min the reaction was diluted with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The resulting mixture was extracted with ethyl acetate (×3), and the combined organic layers were then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting light yellow oil was purified by flash column chromatography (ISCO, SiO2, 0-10% methanol in ethyl acetate over 10 min) to afford (S)-tert-butyl 3-(acetamidomethyl)morpholine-4-carboxylate (0.741 g, yield: almost quantitative, INTERMEDIATE 86A STEP 1).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[F:7][C:8]([F:13])([F:12])[C:9]([OH:11])=[O:10]>O>[O-:11][C:9]([C:8]([F:13])([F:12])[F:7])=[O:10].[NH2:1][C:2]1[NH:3][NH+:4]=[CH:5][N:6]=1
Reactant: Nc1nc[nH]n1
Reactant: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1nc[nH+][nH]1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Amino-1,2,4-triazole (1.27 g, 15.14 mmol) was dissolved in 5 ml of distilled water. Trifluoroacetic acid (1.12 ml, 15.14 mmol) was added via syringe at room temperature and the reaction was stirred at room temperature for 1 hour. The water was removed in vacuo with heating to approximately 90° C. for 4 hours.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:14])[CH2:10]S(C)=O.[C:15]([C:17]1[CH:26]=[CH:25][C:20]([CH:21]=[CH:22][CH:23]=O)=[CH:19][CH:18]=1)#[N:16].COC1C2OC(C=CC3C=CC(C#N)=CC=3)=CC(=O)C=2C=CC=1>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]2[O:1][C:23]([CH:22]=[CH:21][C:20]3[CH:19]=[CH:18][C:17]([C:15]#[N:16])=[CH:26][CH:25]=3)=[CH:10][C:9](=[O:14])[C:3]=2[CH:4]=1
Reactant: Cc1ccc(O)c(C(=O)CS(C)=O)c1
Reactant: N#Cc1ccc(C=CC=O)cc1
Agent: COc1cccc2c(=O)cc(C=Cc3ccc(C#N)cc3)oc12
Product: Cc1ccc2oc(C=Cc3ccc(C#N)cc3)cc(=O)c2c1

Procedure:
This was prepared by reacting 6.36 g of 2'-hydroxy-5'-methyl-2-(methylsulfinyl)acetophenone with 6.36 g of p-cyanocinnamaldehyde in analogous fashion to 4-[2-(8-methoxy-4-oxo-4H-1-benzopyran-2-yl)ethenyl]benzonitrile. The material was recrystallized from toluene, mp 249°-51°; yield 3.5g (41%) λ max mμ (ε) 219 (19,300); 278 (13,500), 339 (41,000); ν max 825 (m), 980 (m), 1235 (m), 1580 (m), 1630 (m), 1670 (s), 2240 (m) cm-1.
Reaction SMILES: [C:1]([CH:3]=[C:4]([NH:13]C(=O)OCC)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])#[N:2].[NH:19]([C:21](=[O:25])C(O)=O)[NH2:20].O.[C:27](OCC)(=O)C>CN1C(=O)CCC1>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:4]1[N:13]=[C:21]([OH:25])[N:19]2[N:20]=[CH:27][N:2]=[C:1]2[CH:3]=1
Reactant: CCOC(C)=O
Reactant: NNC(=O)C(=O)O
Reactant: CCOC(=O)NC(=CC#N)c1ccc(Cl)cc1Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: Oc1nc(-c2ccc(Cl)cc2Cl)cc2ncnn12
Temperature: 160 °C
Reaction time: 4 h

Procedure:
500 mg (1.75 mmol) of ethyl [2-cyano-1-(2,4-dichlorophenyl)ethenyl]carbamate (Example 128A) and 182 mg (1.75 mmol) of hydrazino(oxo)acetic acid are dissolved in NMP (2 ml) under argon and stirred in a flask with a calcium chloride drying tube at an oil-bath temperature of 160° C. for 4 h. The reaction mixture is cooled to RT, mixed with water (20 ml) and stirred for 20 min. Ethyl acetate (150 ml) and water (100 ml) are added and the organic phase is separated off, dried with magnesium sulphate and concentrated. The residue is stirred with diethyl ether/dichloromethane, and the solid is filtered off and dried. 150 mg (31% of theory) of the product are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:18]2[N:19]=[C:20]3[CH2:24][CH2:23][CH2:22][N:21]3[C:17]2=[CH:16][CH:15]=1>N1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:18]2[N:19]=[C:20]3[CH2:24][CH2:23][CH2:22][N:21]3[C:17]2=[CH:16][CH:15]=1)(=[O:11])=[O:10]
Reactant: COC(=O)c1c(N)ccc2c1nc1n2CCC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1nc1n2CCC1
Yield: 45.6 %

Procedure:
2-Bromo-4-fluorobenzenesulfonyl chloride (0.410 g) was added to a solution of methyl 6-amino-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-5-carboxylate (Intermediate 55, 0.290 g) in pyridine (10 mL) and DCM (10 mL) and the resultant mixture was stirred at room temperature for 24 hours. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-15% to give a sandy coloured solid which was triturated with ether and filtered to give methyl 6-(2-bromo-4-fluorobenzenesulfonylamino)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-5-carboxylate (0.268 g).
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[CH2:44]([C@@H:51]1[CH2:55][O:54][C:53](=[O:56])[N:52]1[C:57]1[CH:58]=[C:59]([CH:63]=[CH:64][CH:65]=1)[C:60](O)=[O:61])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.[CH:66]12[CH2:72][CH:69]([CH2:70][CH2:71]1)[CH2:68][CH:67]2[NH:73][C:74](=[O:89])[C@H:75]([CH3:88])[CH2:76][C@H:77]([OH:87])[C@@H:78]([NH2:86])[CH2:79][C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1>>[CH2:79]([C@H:78]([NH:86][C:60](=[O:61])[C:59]1[CH:63]=[CH:64][CH:65]=[C:57]([N:52]2[C@H:51]([CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH2:55][O:54][C:53]2=[O:56])[CH:58]=1)[C@@H:77]([OH:87])[CH2:76][C@H:75]([C:74](=[O:89])[NH:73][CH:67]1[CH2:68][CH:69]2[CH2:72][CH:66]1[CH2:71][CH2:70]2)[CH3:88])[C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Reactant: O=C(O)c1cccc(N2C(=O)OC[C@H]2Cc2ccccc2)c1
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cccc(N2C(=O)OC[C@H]2Cc2ccccc2)c1)C(=O)NC1CC2CCC1C2

Procedure:
Prepared in an analogous manner to E6 from 3-((R)-4-benzyl-2-oxooxazolidin-3-yl)benzoic acid (D21) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:28])[C:9](=[O:27])[C:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH:3]=1.C(N(C(C)C)C(C)C)C.[C:45]([O:48][CH2:49][C:50](Cl)=[O:51])(=[O:47])[CH3:46]>ClCCl>[F:22][C:19]([F:20])([F:21])[C:17]1[CH:18]=[C:13]([C:10]([CH3:12])([CH3:11])[C:9]([N:8]([CH3:28])[C:5]2[C:4]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])=[CH:3][C:2]([NH:1][C:50]([CH2:49][O:48][C:45](=[O:47])[CH3:46])=[O:51])=[N:7][CH:6]=2)=[O:27])[CH:14]=[C:15]([C:23]([F:26])([F:24])[F:25])[CH:16]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1ccccc1-c1cc(N)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC(=O)Nc1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To a solution of 100 mg (0.20 mmol) N-(6-amino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 3 ml dichloromethane were added 27 mg (0.21 mmol) N-ethyldiisopropylamine and 30 mg (0.21 mmol) acetoxy acetyl chloride. After stirring overnight, the solvent was evaporated and the residue was purified by flash-chromatography to give 62 mg (52%) of the title compound as white solid.
Reaction SMILES: [CH3:1][C@@H:2]1[O:6][S:5](=[O:7])[N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.I([O-])(=O)(=O)=[O:16].[Na+]>C(#N)C.O.C(OCC)(=O)C>[CH3:1][C@@H:2]1[O:6][S:5](=[O:16])(=[O:7])[N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)O1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reaction time: 0.08 h
Yield: 98 %

Procedure:
To a solution of tert-butyl (5S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (5.7 g, 25.8 mmol) in acetonitrile (60 mL) and water (30 mL) is added sodium periodate (8.3 g, 38.7 mmol) in one portion. After 5 min, a few crystals of RuCl3 is added. The reaction is stirred for 3 h and the resulting thick slurry is diluted with water (100 mL) and ethyl acetate (20 mL) and is passed through a bed of Celite, rinsing with additional EtOAc. The filtrate is concentrated to remove the organic solvents and the resulting solid is isolated by filtration to afford the title compound (6.0 g, 97%).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[F:13][C:14]([F:22])([F:21])[CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(CC)C(C)C)(C)C.[CH3:32][N:33]([CH3:55])[C:34](=[O:54])[C:35]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:37][C:36]=1[CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>ClCCl.O>[CH3:32][N:33]([CH3:55])[C:34]([C:35]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:37][C:36]=1[CH2:47][N:48]1[CH2:53][CH2:52][N:51]([C:5]([O:20][CH:15]([C:16]([F:19])([F:18])[F:17])[C:14]([F:22])([F:21])[F:13])=[O:11])[CH2:50][CH2:49]1)=[O:54]
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: CN(C)C(=O)c1cc(-c2ccccc2)ccc1CN1CCNCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(C)C(=O)c1cc(-c2ccccc2)ccc1CN1CCN(C(=O)OC(C(F)(F)F)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
A 100 mL round-bottom flask was charged with triphosgene (55.0 mg, 0.190 mmol, 0.30 equiv) in dichloromethane (10 mL). 1,1,1,3,3,3-Hexafluoropropan-2-ol (104 mg, 0.620 mmol, 1.00 equiv) and N,N-diisopropylethylamine (152 mg, 1.18 mmol, 1.90 equiv) were added dropwise. The mixture was stirred for 30 min at room temperature. N,N-Dimethyl-5-phenyl-2-(piperazin-1-ylmethyl)benzamide (200 mg, 0.620 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with water (20 mL), extracted with dichloromethane (3×20 mL) and the organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product (240 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% Phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% CH3CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 93.2 mg (28% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-(dimethylcarbamoyl)-4-phenylphenyl]methyl]piperazine-1-carboxylate as light yellow oil. 1H NMR 300 MHz (CDCl3) δ 7.36-7.81 (m, 8H), 5.70-5.80 (m, 1H), 3.41-3.67 (m, 4H), 3.03-3.30 (m, 4H), 2.84-3.02 (m, 4H), 2.40-2.66 (m, 4H). LCMS (ESI, m/z): 518 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][C:6](=[O:10])[O:7]2)[C@H:3]1/[CH:11]=[CH:12]/[C@@H:13]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[OH:10][CH:6]1[CH2:5][C@H:4]2[C@H:8]([CH2:9][C@@H:2]([OH:1])[C@@H:3]2/[CH:11]=[CH:12]/[C@@H:13]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[O:7]1
Reactant: CCCCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1O)OC1CCCCO1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CCCCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(O)O[C@H]2C[C@H]1O)OC1CCCCO1

Procedure:
Alcohol (6) (2.00 g) was reduced in dry toluene (40 ml) using DIBAL-H at -70° C. The lactol (7) was obtained by a usual work up.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[BH3-]C#N.[Na+].[CH3:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[CH:27]=[C:26]([O:28][C:29]3[CH:34]=[CH:33][C:32]([CH:35]=[O:36])=[CH:31][C:30]=3[F:37])[C:20]3[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=3[CH:18]=2)=[O:16])=[N:10]1>CO>[CH3:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[CH:27]=[C:26]([O:28][C:29]3[CH:34]=[CH:33][C:32]([CH2:35][N:2]([CH3:3])[CH3:1])=[CH:31][C:30]=3[F:37])[C:20]3[CH2:21][C:22]([CH3:24])([CH3:25])[O:23][C:19]=3[CH:18]=2)=[O:16])=[N:10]1.[CH3:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[CH:27]=[C:26]([O:28][C:29]3[CH:34]=[CH:33][C:32]([CH2:35][OH:36])=[CH:31][C:30]=3[F:37])[C:20]3[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=3[CH:18]=2)=[O:16])=[N:10]1
Reactant: Cn1ccc(NC(=O)c2cc(Oc3ccc(C=O)cc3F)c3c(c2)OC(C)(C)C3)n1
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1ccc(Oc2cc(C(=O)Nc3ccn(C)n3)cc3c2CC(C)(C)O3)c(F)c1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(CO)cc3F)c3c(c2)OC(C)(C)C3)n1
Temperature: 50 °C
Yield: 24 %
Yield: 25 %

Procedure:
To dimethylamine (0.6 mL, 2.0 M, 1.0 mmol) in MeOH (5 mL) was added NaCNBH3 (31 mg, 0.49 mmol). The mixture was heated to 50° C. for 1 hr, and then 4-(2-fluoro-4-formyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide (39a) (100 mg, 0.24 mmol) was added. The reaction mixture was heated to 50° C. for 1 hr. Additional NaCNBH3 (31 mg, 0.49 mmol) and dimethylamine (0.3 mL, 2.0 M, 0.5 mmol) were added to the reaction mixture. The mixture was heated at 50° C. for 1 hr, then concentrated and purified by reverse phase chromatograph to give 4-(4-dimethylaminomethyl-2-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide (26 mg, 24% yield) and 4-(2-Fluoro-4-hydroxymethyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide (25 mg, 25% yield) as white solid.