Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:34])=[C:17]([C:19]3[S:23][C:22]([S:24][CH3:25])=[C:21]([C:26]#[N:27])[C:20]=3[C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH:18]=2)[CH:9]=[CH:10][CH:11]=1.CCN(CC)CC.[CH3:42][S:43](Cl)(=[O:45])=[O:44].O>C(Cl)Cl>[C:26]([C:21]1[C:20]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[C:19]([C:17]2[CH:18]=[C:13]([NH:12][C:8]3[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=3)[O:5][CH2:4][CH2:3][CH2:2][O:1][S:43]([CH3:42])(=[O:45])=[O:44])[CH:14]=[CH:15][C:16]=2[CH3:34])[S:23][C:22]=1[S:24][CH3:25])#[N:27]
Reactant: CSc1sc(-c2cc(Nc3cccc(OCCCO)c3)ccc2C)c(-c2cccnc2)c1C#N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CSc1sc(-c2cc(Nc3cccc(OCCCOS(C)(=O)=O)c3)ccc2C)c(-c2cccnc2)c1C#N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-{5-[3-(3-hydroxy-propoxy)-phenylamino]-2-methyl-phenyl}-2-methylsulfanyl-4-pyridin-3-yl-thiophene-3-carbonitrile (370 mg, 0.76 mmol) in DCM (10 mL) was added Et3N (155 mg, 0.15 mmol) followed by MsCl (130 mg, 1.15 mmol). The resulting mixture was stirred at ambient temperature for 10 min under nitrogen then poured into 20 ml water and extracted with DCM (20 ml×3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The desired product was obtained (391 mg, 91%) and confirmed by LC/MS (Calculated: 565.12; observed: 565.1+1, ES+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:17])[C:15]2[C:14](=[O:18])[N:13]([CH2:19][CH2:20][CH3:21])[C:12](=[O:22])[N:11]([CH2:23][CH2:24][CH3:25])[C:10]=2[N:9]=1.Cl[S:32]([OH:35])(=[O:34])=[O:33]>S(Cl)(Cl)=O>[CH3:30][O:29][C:28]1[CH:27]=[C:26]([S:32]([OH:35])(=[O:34])=[O:33])[C:5](=[CH:4][C:3]=1[O:2][CH3:1])/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:17])[C:15]2[C:14](=[O:18])[N:13]([CH2:19][CH2:20][CH3:21])[C:12](=[O:22])[N:11]([CH2:23][CH2:24][CH3:25])[C:10]=2[N:9]=1
Reactant: O=S(=O)(O)Cl
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3ccc(OC)c(OC)c3)n2C)n(CCC)c1=O
Solvent: O=S(Cl)Cl
Product: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)O)n2C)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
(E)-8-(3,4-Dimethoxystyryl)-7-methyl-1,3-dipropylxanthine (WO92/06976) (2.41 g, 5.84 mmol) was dissolved in thionyl chloride (11 ml), and chlorosulfonic acid (1.17 ml, 17.53 mmol) was added dropwise thereto at 0° C. The resulting solution was stirred at room temperature for 30 minutes and then poured into ice-water cautiously. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to give 2.77 g (yield 93%) of Compound 1 as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[S:25])=[CH:19][CH:18]=1.CCOCC>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:7]1[C:2]([NH:1][C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)=[S:25])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: S=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1ccccc1

Procedure:
A stirring mixture of 2-amino-3-benzyloxy pyridine (5.37 g, 0.0268 mol) and 4-chlorophenylisothiocyanate (5 g, 0.0295 mol) in toluene (20 ml) was heated under reflux for 2 h. After allowing to cool, the solution was treated with ether, and the resulting solid filtered off, washed and dried. Yield 8.33 g (84%), m.p. 140°-143 ° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[C:13]([C:4]1[CH:5]=[C:6]([NH:9][C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][C:3]=1[OH:2])(=[O:15])[CH3:14]
Reactant: COc1ccc(NC(C)=O)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)Nc1ccc(O)c(C(C)=O)c1
Yield: 86.3 %

Procedure:
To a stirring suspension of N-(4-methoxy-phenyl)-acetamide (5.253 g, 32 mmol) and acetyl chloride (6.6 ml, 93 mmol, 2.9 equ) in dichloromethane (55 ml) was added aluminium trichloride (14.55 g, 109 mmol, 3.4 equ) in portions over 90 minutes. The reaction was then heated to reflux for 4.5 hours and cooled overnight. The mixture was poured onto ice then extracted into dichloromethane (5×), dried (MgSO4) and concentrated in vacuo to give N-(3-acetyl-4-hydroxy-phenyl)-acetamide (5.336 g, 87%) as a pale green solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:15]=[C:16]([C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][CH:19]=1)#[CH:13].N>>[F:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]([C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][CH:19]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: C#Cc1cccc(C(C)=O)c1
Reactant: ON=C(Cl)c1cncc(F)c1
Agent: N
Product: CC(=O)c1cccc(-c2cc(-c3cncc(F)c3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of product of Example 28B (88 mg, 0.5 mmol) and 1-(3-ethynylphenyl)ethanone (GFS Chemicals, 72 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 2.69 (s, 3H), 7.54 (s, 1H), 7.71 (t, J=7.5 Hz, 1H), 8.08-8.24 (m, 3H), 8.51 (t, J=1.8 Hz, 1H), 8.62 (d, J=2.8 Hz, 1H), 8.99 (t, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 283 (M+H)+.
Reaction SMILES: [Mg].BrCCBr.C(Br)(C)C.C([Mg]Br)(C)C.[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[C:21]([CH2:23][CH2:24][C:25]#[CH:26])=[O:22].C1(S([CH:36]2[CH2:42][CH2:41][CH2:40][CH2:39][C@@H:38]([CH2:43][O:44][C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=3)[O:37]2)(=O)=O)C=CC=CC=1>C1COCC1.[Zn+2].[Br-].[Br-]>[F:51][C:48]1[CH:47]=[CH:46][C:45]([O:44][CH2:43][C@H:38]2[O:37][C@H:36]([C:26]#[C:25][CH2:24][CH2:23][C:21]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][O:15]3)=[O:22])[CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:50][CH:49]=1
Reactant: O=S(=O)(c1ccccc1)C1CCCC[C@@H](COc2ccc(F)cc2)O1
Reactant: C#CCCC(=O)C1CCCCO1
Agent: CC(C)[Mg]Br
Agent: [Br-]
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Solvent: CC(C)Br
Product: O=C(CCC#C[C@@H]1CCCC[C@@H](COc2ccc(F)cc2)O1)C1CCCCO1
Reaction time: 1 h

Procedure:
To a suspension of magnesium (0.58 g, 24.2 mmol) in dry THF (10 ml) was added catalytic 1,2-dibromoethane followed by dropwise addition of a soluton of isopropyl bromide (1.85 g, 15.1 mmol) in THF (5 ml). The reaction mixture was stirred for 1 hour and isopropylmagnesiumbromide was cannulated into a 50 ml two-necked flask. A solution of 4-tetrahydropyranoyl-1-butyne (1.86 g, 12.0 mmol) in THF (5 ml) was added and the mixture was stirred for 30 minutes followed by addition of freshly prepared ZnBr2 solution (1 M, 7.25 ml, 7.2 mmol) in THF at 0° C. After 45 minutes (2RS,7S)-2-(benzenesulfonyl)-7-(4-fluorophenoxymethyl)oxepane (2.2 g, 6.0 mmol) in THF (10 ml) was added and the mixture stirred for 30 hours. The reaction was quenched with saturated aqueous NH4Cl solution at 0° C. THF was removed under reduced preesure and the residue was portioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give (2S,7S)-7-(4-fluorophenoxymethyl)-2-(4-tetrahydropyranoyl-1-butynyl)oxepane. The crude product was dissolved in MeOH (25 ml) and 1% HCl in MeOH (5 ml) was added. The hydrolysis of the THP group was completed in 2 hours and neutralized with saturated Na2CO3 solution and concentrated. The crude product was purified by silica gel chromotography using EtOAc-hexane (1:8) to give (2S,7S)-7-(4-fluorophenoxymethyl)-2-(4-hydroxybutynyl)oxepane (1.32 g, 75%); [α]d−74 (c 3.63, CHCl3), 1H-NMR (CDCl3, 200 Hz): δ 1.4-2.0 (m, 7H), 2.12 (m, 1H), 2.3 (s, 1H), 2.46 (dt, 2H), 3.65 (t, J=3.6 Hz, 2H), 3.74-3.97 (m, 2H), 4.51 (q, 1H), 6.8-7.0 (m, 4H); HRMS (E1): calcd. for C17H21O3F (M+) 292.147756 found 292.147473. Also, (2S,7S)-7-(4-fluorophenoxymethyl)-2-(4-hydroxybutynyl)oxepane by similar procedure: [α]D+26.9 (c 2.2, CHCl3), 1H-NMR (CDCl3, 200 Hz): δ 1.48-2.03 (m, 8H), 2.2 (s, 1H), 2.47 (dt, 2H), 3.69 (t, J=6.9 Hz, 2H), 3.74-4.02 (m, 3H), 4.34 (dt, 2H), 6.78-7.0 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]2[CH2:22][C:23]([O:25]C)=[O:24])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C1COCC1.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]2[CH2:22][C:23]([OH:25])=[O:24])(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CC1c2ccccc2CCN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1c2ccccc2CCN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of methyl 2-(2-(3,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)-acetate (14.84 g, 33.2 mmol), THF (200 ml) and water (120 ml) was a and stirred at room temperature. After 4 h, aqueous NaOH solution (6 M, 60 ml) was again added, and stirring was carried out overnight at room temperature. The reaction solution was concentrated under reduced pressure. 6 M HCl solution (125 ml) and DCM (400 ml) were added. After phase separation, the organic phase was washed with saturated NaCl solution, dried (sodium sulfate) and concentrated. For purification, the product was recrystallised from 2-propanol.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[C:15]([N:23]([CH3:25])[CH3:24])[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:26][NH:27][CH3:28]>>[CH3:26][N:27]([CH2:2][C:3]([N:5]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[C:15]([N:23]([CH3:25])[CH3:24])[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4])[CH3:28]
Reactant: CNC
Reactant: COCOc1ccc(CN(C(=O)CCl)c2ccccc2)cc1N(C)C
Product: COCOc1ccc(CN(C(=O)CN(C)C)c2ccccc2)cc1N(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To the compound (2) (1.68 g, 4.63 mmol) obtained above was added a 50% aqueous solution of dimethylamine (8 ml) under ice-cooling. After being stirred at room temperature for 1.5 hours, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel to give the object compound (3). Yield 1.57 g (91%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[NH:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[C:5]([CH:16]=[CH2:17])[CH:4]=1)#[N:2]>CO.[C].[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[NH:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[C:5]([CH2:16][CH3:17])[CH:4]=1)#[N:2]
Reactant: C=Cc1cc(C#N)ccc1C1NC(=O)NC1=O
Agent: [Pd]
Solvent: CO
Product: CCc1cc(C#N)ccc1C1NC(=O)NC1=O

Procedure:
A solution of 5-(4-cyano-2-vinylphenyl)hydantoin (75 mg, 0.35 mmol) in methanol (20 ml) was shaken with 10% palladium-carbon (10 mg) under an atmosphere of hydrogen for 0.5 hours at 25 p.s.i. The catalyst was removed by filtration to give 5-(4-cyano-2-ethylphenyl)hydantoin in a quantitative yield as a colourless oil.
Reaction SMILES: Cl[CH2:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.O>CN(C)C=O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3](=[O:13])[CH2:2][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:7][CH:8]=1
Reactant: c1c[nH]cn1
Reactant: O=C(CCl)CCc1ccc(Cl)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(Cl)cc1)Cn1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
1-Chloro-4-(4-chlorophenyl)-2-butanone (110 g) was added portionwise over half an hour to a stirred suspension of imidazole (175 g) in dimethylformamide (150 ml) at 0° C. and the mixture stirred overnight at ambient temperature. The resulting solution was poured into water (1500 ml) with seeding at the first sign of turbidity, and the precipitate filtered off and washed well with water and hexane. Chromatography of the product on silica gel (1 Kg.), eluting with 7% methanol in methylene chloride gave 100 g of 1-[4-(4-chlorophenyl)butan-2-on-1-yl]imidazole.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:39][CH2:40][C@H:41]([OH:53])[CH2:42][N:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1>C(Cl)Cl>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[CH2:10][CH2:11][C:12]([NH:39][CH2:40][C@H:41]([OH:53])[CH2:42][N:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1)=[O:14]
Reactant: NC[C@H](O)CN1CCc2ccccc2C1
Reactant: O=C(O)CCc1nc2ccccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(CCc1nc2ccccc2[nH]1)NC[C@H](O)CN1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.6 %

Procedure:
To a solution of 3-(1H-benzo[d]imidazol-2-yl)propanoic acid (300 mg, 1.579 mmol) in DCM (10 mL) was added HATU (722 mg, 1.895 mmol) and TEA (478 mg, 4.737 mmol). After stirring for 30 min at room temperature, (S)-1-amino-3-(3,4-dihydro isoquinolin-2(1H)-yl)propan-2-ol (488 mg, 2.368 mmol) was added and the resulting mixture then stirred at room temperature for 16 h. After completion of the reaction the solvent was evaporated at reduced pressure and the residue purified by preparative HPLC to give the title compound (159.1 mg, 26%). 1H NMR (400 MHz, METHANOL-d4) δ=7.51 (br. s., 2H), 7.22-7.16 (m, 2H), 7.13-7.06 (m, 3H), 7.02-6.97 (m, 1H), 3.98-3.90 (m, 1H), 3.66-3.55 (m, 2H), 3.37 (dd, J=4.9, 13.7 Hz, 1H), 3.25-3.17 (m, 3H), 2.89-2.83 (m, 2H), 2.79 (t, J=7.5 Hz, 2H), 2.74-2.69 (m, 2H), 2.50-2.45 (m, 2H). LCMS (m/z): 379.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1>>[Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][N:14]([CH2:24][C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCN(Cc3ccc(F)cc3)CC1)O2

Procedure:
Compound 156 was synthesized using 9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1-(bromomethyl)-4-fluorobenzene and conditions outlined in general procedure W. M.p.=210-211° C.; 400 MHz 1H NMR (CDCl3) δ: 7.91-7.88 (m, 1H), 7.84-7.83 (m, 1H), 7.65-7.62 (m, 1H), 7.30-7.26 (m, 3H), 7.05-7.00 (m, 2H), 3.58 (s, 2H), 2.93 (s, 2H), 2.76-2.72 (m, 2H), 2.50-2.46 (m, 2H), 2.13-2.05 (m, 2H), 1.94-1.83 (m, 2H); LCMS: 488 [M+H].
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([O:15][C:16](=[O:30])[C:17](=[CH:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[CH3:29])[C:18]([CH3:20])=O)[CH3:14]>>[CH2:13]([O:15][C:16]([C:17]1[CH:21]([C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=2[CH3:29])[C:11]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][NH:9][C:10]=2[NH:12][C:18]=1[CH3:20])=[O:30])[CH3:14]
Reactant: CCOC(=O)C(=Cc1cc(C)ccc1C)C(C)=O
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Product: CCOC(=O)C1=C(C)Nc2[nH]nc(-c3ccccc3)c2C1c1cc(C)ccc1C

Procedure:
Starting from 3-phenyl-5-(1H)pyrazolamine and ethyl-2-(2,5-dimethylbenzyliden)acetoacetate.
Reaction SMILES: C(OC([NH:11][CH:12]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:17])[CH2:13][CH2:14][OH:15])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][CH:12]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])=[O:17])[CH2:13][CH2:14][OH:15]
Reactant: CC(C)(C)OC(=O)NCCCN(CCCCNC(=O)C(CCO)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCN(CCCCNC(=O)C(N)CCO)C(=O)OC(C)(C)C
Yield: 91.8 %

Procedure:
1.35 g (2.22 mmols) of 10-(N-benzyloxycarbonyl-DL-homoseryl)-1,5-di-tert-butoxycarbonyl-1,5,10-triazadecane was dissolved in 20 ml of methanol and was catalytically reduced over 0.1 g of palladium black for 8 hours at room temperature at atmospheric pressure. After the reaction, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. 0.91 g (86.4%) of the desired product was obtained as the residual oil.
Reaction SMILES: [Si]([O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH2:18][N:19]2[C:23]3=[N:24][C:25]([CH3:29])=[CH:26][C:27]([CH3:28])=[C:22]3[N:21]=[C:20]2[CH2:30][CH3:31])=[CH:11][C:10]=1[CH2:32][CH2:33][CH3:34])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:29][C:25]1[N:24]=[C:23]2[N:19]([CH2:18][C:12]3[CH:11]=[C:10]([CH2:32][CH2:33][CH3:34])[C:9]([OH:8])=[C:14]([CH2:15][CH2:16][CH3:17])[CH:13]=3)[C:20]([CH2:30][CH3:31])=[N:21][C:22]2=[C:27]([CH3:28])[CH:26]=1
Reactant: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(CCC)c1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(CCC)c1O
Yield: 87.8 %

Procedure:
A THF solution of 5.0 g (10.44 mmol) of the product of Step F was treated with tetrabutylammonium fluoride (1.2 equiv, 1M solution in THF) overnight. THF was removed in vacuo and the residue was flash chromatographed using 30-50% ethyl acetate in hexane as eluent to afford 3.35 g (88%) of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[N:12][N:13]([CH2:15][CH2:16][C@@:17]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:18](O)=[O:19])[CH:14]=1.CN1CCOCC1.[O:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[O:39][NH2:40].O>CC1OCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[N:12][N:13]([CH2:15][CH2:16][C@@:17]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:18]([NH:40][O:39][CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38][O:33]2)=[O:19])[CH:14]=1
Reactant: C[C@@](CCn1cc(-c2nc3ccccc3o2)cn1)(C(=O)O)S(C)(=O)=O
Reactant: NOC1CCCCO1
Solvent: O
Solvent: CC1CCCO1
Solvent: CN1CCOCC1
Product: C[C@@](CCn1cc(-c2nc3ccccc3o2)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of (2R)-4-[4-(1,3-benzoxazol-2-yl)-1H-pyrazol-1-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (0.420 g, 1.16 mmol) in 2-MeTHF (30 mL) was added N-methyl morpholine (0.165 g, 1.62 mmol, 1.4 eq), followed by CDMT (0.244 g, 1.39 mmol, 1.2 eq). The reaction mixture was allowed to stir for one hour. O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.162 g, 1.39 mmol, 1.2 eq) was added, and the reaction was allowed to stir for an additional two hours. Water (20 mL) was added, and the solution was extracted with 2-MeTHF (100 mL). The aqueous layer was re-extracted with 2-MeTHF (150 mL) and the combined organic layers were washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography, eluting with 30%-100% ethyl acetate/heptane to yield (2R)-4-[4-(1,3-benzoxazol-2-yl)-1H-pyrazol-1-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (410 mg, 77% yield) as a colorless oil. LC-MS M−H 461.3.
Reaction SMILES: [CH2:1]([N:8]([C@H:20]([CH2:40][OH:41])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][CH:32]=2)=[O:30])=[CH:24][CH:23]=1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O[N:44]1[C:48]2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.CN>CN(C)C=O.ClCCCl.C(OCC)(=O)C>[CH2:1]([N:8]([C@H:20]([CH2:40][OH:41])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:30])[C:31]2[CH:32]=[CH:33][C:34]([C:35]([NH:44][CH3:48])=[O:37])=[CH:38][CH:39]=2)=[CH:26][CH:27]=1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(C[C@@H](CO)N(Cc3ccccc3)C[C@H](O)COc3ccccc3)cc2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(C(=O)Nc2ccc(C[C@@H](CO)N(Cc3ccccc3)C[C@H](O)COc3ccccc3)cc2)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-[[[4-((2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]-amino]carbonyl]benzoic acid (14.6 mg) in N,N-dimethylformamide (200 μl) were added 1.0 M solution of 1-hydroxybenzotriazole hydrate in N,N-dimethylformamide (31.6 μl) and 1.0 M solution of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide in 1,2-dichloroethane (31.6 μl) at room temperature. To the mixture was added methylamine hydrochloride (2.2 mg) and the whole was stirred overnight. The reaction mixture was diluted with ethyl acetate (10 ml) and washed with water (10 ml×1) and brine (10 ml×1) successively, dried over magnesium sulfate, and evaporated to give a pale yellow paste. The crude product was purified by a recycling preparative high pressure liquid chromatography equipped with a gel permeation chromatography column (eluent: chloroform) to give N1-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]-phenyl]-N4-methylterephthalamide (14.0 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[C:18]2\[CH2:19][N:20]([CH:25]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])[C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[CH2:21][CH2:22][CH:23]\2O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:38]([OH:41])(=[S:40])[CH3:39].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:38]([S:40][CH:23]1[CH2:22][CH2:21][N:20]([CH:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])[C:26]([CH:28]2[CH2:30][CH2:29]2)=[O:27])[CH2:19]/[C:18]/1=[CH:17]\[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:9]=1)(=[O:41])[CH3:39]
Reactant: CC(O)=S
Reactant: CC(C)(C)OC(=O)n1cc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2O)c2ccccc21
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a solution of (E)-3-{[1-(t-butoxycarbonyl)indol-3-yl]methylidene}-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]piperidin-4-ol (1.58 g) in toluene (32 ml) were added thioacetic acid (0.45 ml) and N,N-dimethylformamide dineopentyl acetal (1.75 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. After stirring, to the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:9) as the eluent to afford (E)-4-(acetylsulfanyl)-3-{[1-(t-butoxycarbonyl)indol-3-yl]methylidene}-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]piperidine (0.66 g, yield: 38%) as a pale yellow amorphous solid.