Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[C:4]#[N:5].B1(/[CH:20]=[CH:21]/[CH2:22][O:23][CH3:24])OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](/[CH:20]=[CH:21]/[CH2:22][O:23][CH3:24])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(N)cccc1Br
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COC/C=C/c1cccc(N)c1C#N
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-6-bromobenzonitrile (1.0 g, 5.0 mmol), (E)-2-(3-methoxypropenyl)-4,4,5,5-tetramethyl-(1,3,2)-dioxaboroane (1.2 g, 6.0 mmol), and K2CO3 (1.38 g, 10.0 mmol) in DME/H2O (4:1, 20 mL) was added Pd(PPh3)4 (289 mg) at room temperature under nitrogen. The reaction mixture was warmed to 85° C. and stirred at that temperature under nitrogen overnight. After it was cooled down to room temperature, the reaction solution was diluted with EtOAc, washed with brine (2×), and dried over Na2SO4. After removal of the solvent, the residue was purified by chromatography on silica gel eluting with 30% EtOAc in hexanes to give the title compound as a pale-yellow solid. 1H NMR (400 MHz, CDCl3) δ 3.40 (s, 3H), 4.12 (dd, J=6.0, 1.8 Hz, 2H), 4.42 (s, 2H), 6.42 (dt, J=16.0, 5.8 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.85 (d, J=16.0 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H). 13C NMR (CDCl3) δ 58.2, 72.7, 95.4, 113.6, 115.0, 116.6, 128.5, 130.9, 133.4, 140.3, 150.1. MS 189 (MH+).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:23])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[CH3:10].I[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH2:9]([O:11][C:12](=[O:23])[CH:13]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[CH3:10]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 77.2 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (430.55 mL of a 0.3M stock solution, 129.16 mmol) was cooled to −78° C. and then treated with a solution of (4-nitro-phenyl)-acetic acid ethyl ester (26.32 g, 125.83 mmol) in tetrahydrofuran/hexamethylphosphoramide (312.5 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction mixture was treated with a solution of iodomethylcyclopentane (27.75 g, 132.1 mmol) in hexamethylphosphoramide (27.75 mL). The mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. At this time, the reaction mixture was quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (250 mL). This mixture was concentrated in vacuo, diluted with water (250 mL), and extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with a saturated aqueous lithium chloride solution (2×250 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 98/2 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid ethyl ester (28.30 g, 77.2%) as a yellow oil: EI-HRMS m/e calcd for C16H21NO4 (M+) 291.1470, found 291.1470.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:32])=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([S:28](O)(=[O:30])=[O:29])=[CH:24][CH:23]=5)[CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O=S(Cl)[Cl:35].CN(C=O)C>O=P(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:32])=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([S:28]([Cl:35])(=[O:30])=[O:29])=[CH:24][CH:23]=5)[CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(S(=O)(=O)Cl)cc1
Temperature: 75 °C

Procedure:
5′-[(1-Benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl)-amino]-2′-methylbiphenyl-4-sulfonic acid (1.9 g, 4.3 mmol) was dissolved in POCl3 (30 mL) followed by the addition of SOCl2 (3 mL) and DMF (100 μl). The reaction mixture was heated at 70-80° C. for 15 min. The reagents were evaporated and re-evaporated with chloroform-toluene. The residual brown oil was diluted with chloroform (22 mL) and immediately used for sulfonylation. ESI-MS m/z calc. 469.0. found 470.1 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]([F:20])([F:19])[O:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.Br[C:22]1[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:7][C:8]([F:20])([F:19])[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:22]2[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:12][CH:11]=1
Reactant: Nc1ncccc1Br
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncccc1-c1ccc(OC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A mixture of sodium carbonate (0.903 g), tetrakis(triphenylphosphine)palladium(0) (0.246 g), 4-(trifluoromethoxy)phenylboronic acid (1.14 g) and 3-bromopyridin-2-amine (0.737 g) in 1,2-dimethoxyethane (50 mL) and water (10 mL) was stirred under a nitrogen atmosphere at 80° C. overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.069 g) as a pale-yellow solid.
Reaction SMILES: [CH:1]1([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:22]=[CH:21][O:20][N:19]=4)=[CH:14][CH:13]=3)[C:10](=[O:23])[C:9]([OH:24])=[C:8]2[C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>ClCCl>[CH:1]1([CH:7]2[N:11]([C:12]3[CH:13]=[CH:14][C:15]([C:18]4[CH:22]=[CH:21][O:20][N:19]=4)=[CH:16][CH:17]=3)[C:10](=[O:23])[C:9]([OH:24])=[C:8]2[C:25](=[O:34])[C:26]2[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(C(=O)C2=C(O)C(=O)N(c3ccc(-c4ccon4)cc3)C2C2CCCCC2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(C1=C(O)C(=O)N(c2ccc(-c3ccon3)cc2)C1C1CCCCC1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 30.6 %

Procedure:
To a mixture of 5-cyclohexyl-3-hydroxy-1-(4-isoxazol-3-ylphenyl)-4-(4-methoxybenzoyl)-1,5-dihydropyrrol-2-one (0.229 g, 0.5 mmol) and dichloromethane (10 mL), 1M boron tribromide in dichloromethane (5.0 mL, 5 mmol) was added under ice-cooling conditions and the mixture was stirred at r.t. for 3 days. Small amount of potassium carbonate was added under ice-cooling conditions to degrade excess boron tribromide. 1N aqueous sodium hydroxide was added and the mixture was washed with ethyl acetate. The aqueous layer was neutralized with 1N hydrochloric acid, the precipitate was collected by filtration and washed with hot ethyl acetate to give 5-cyclohexyl-3-hydroxy-4-(4-hydroxybenzoyl)-1-(4-isoxazol-3-ylphenyl)-1,5-dihydropyrrol-2-one (0.068 g, 31%) as colorless crystals.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)#[N:13].C([O-])([O-])=O.[K+].[K+].S1(CCCC1)(=O)=O.[OH-].[Na+]>O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:20][C:17]2[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: CS(=O)(=O)c1ccc(Oc2ccc(C#N)cc2)cc1
Temperature: 150 °C
Yield: 28.1 %

Procedure:
A mixture of 5.23 g (0.0300 mole) of 4-fluorophenyl methyl sulfone, 7.15 g (0.0600 mole) of 4-cyanophenol, 8.29 g (0.0600 mole) of anhydrous K2CO3 and 90 ml of sulfolane was heated at 150° C. for 3.5 hrs. The mixture was cooled and poured into a solution of 100 ml of 20% aqueous NaOH and 500 ml of water. Extraction of the basic solution with diethyl ether afforded 2.3 g (28% yield) of product after removal of solvent in vacuo. The product was purified by column chromatography using silica gel as the support and chloroform as the eluent. The purified 4-(4-(methylsulfonyl)phenoxy)benzonitrile was found to have a melting point of 127°-128.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[CH2:10][NH:9]/[C:8](=[N:11]\[C:12]([C:14]2[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=2)=[O:13])/[NH:7]1.C(N(CC)CC)C.[C:30]1([CH2:36][S:37](Cl)(=[O:39])=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[C:30]1([CH2:36][S:37]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]2[CH2:10][NH:9]/[C:8](=[N:11]\[C:12]([C:14]3[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=3)=[O:13])/[NH:7]2)(=[O:39])=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCCCC[C@H]1CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc(N)c(C(=O)/N=C2\NC[C@H](CCCCNS(=O)(=O)Cc3ccccc3)N2)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [(S)-4-(4-amino-butyl)-imidazolidin-(2E)-ylidene]-amide (Intermediate T) (0.023 g, 0.071 mmol) in DMF (2 ml) is added triethylamine (0.010 ml, 0.071 mmol) followed by alpha-toluenesulfonyl chloride (0.014 g, 0.071 mmol). The suspension is stirred at room temperature for 30 minutes. Purification by reverse phase chromatography (Isolute™ C18, 0-100% MeCN in water−0.1% TFA) followed by catch and release resin (SCX-2) eluting with MeOH and 7M NH3 in MeOH gives the title compound as a yellow solid; [M+H]+481.0
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23](O)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.N1C=CC=CC=1>CN(C)C=O.O>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23]([N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])=[O:24])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:13][CH:12]=2)[CH2:8][CH2:9]1)([CH3:2])[CH3:3]
Reactant: CC(C)N1CCC(Oc2ccc(C3(C(=O)O)CCOCC3)cc2)CC1
Reactant: CCNCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)C1(c2ccc(OC3CCN(C(C)C)CC3)cc2)CCOCC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 9.6 %

Procedure:
4-{4-[(1-Isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-carboxylic acid (86 mg, 0.2 mol), diethylamine (27 μL, 0.26 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (108 mg, 0.29 mmol), pyridine (53 uL, 0.66 mmol) were combined and dissolved in dimethylformamide (1.5 mL). The reaction mixture was stirred at 60° C. for 5 hours. Further diethylamine was added (500 μL). The reaction mixture was stirred at ambient temperature for 60 hours. The reaction mixture was diluted with water (25 mL), and extracted with ethyl acetate (2×35 mL). The combined organics were dried using Na2SO4, filtered and concentrated in vacuo. The compound was purified by column chromatography using 15 g of silica gel, eluting with dichloromethane:methanol:ammonia (96:4:0.4) to dichloromethane:methanol:ammonia (90:10:1) to give the title compound as a clear yellow oil (10 mg, 11%). 1H NMR (400 MHz, CD3OD) δ7.2 (d, 2H), 6.95 (d, 2H), 4.4 (m, 1H), 3.85-3.7 (m, 4H), 3.3 (m, 2H), 3.05-2.9 (m, 5H), 2.6 (m, 2H), 2.25 (d, 2H), 2.0 (m, 4H), 1.8 (m, 2H), 1.1 (m, 9H), 0.63 (m, 3H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[NH2:44][C:45]1[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=1[C:47]#[N:48]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([NH:44][C:45]4[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=4[C:47]#[N:48])[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#Cc1ccccc1N
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(Nc4ccccc4C#N)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 50 %

Procedure:
In a manner analogous to that described in Example 3 a), the amination of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-4-(5-bromo-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]amine (intermediate C4.1) with 2-aminobenzonitrile yielded the title compound (50% yield) as an off-white foam. MS (ISP): m/z=691.3 [M+H]+.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([CH3:26])=[N:9]2)=CC=1.[CH3:29][N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36](O)=[O:37])[C:31]1=[O:39]>>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:36]([C:32]2[C:31](=[O:39])[N:30]([CH3:29])[CH:35]=[CH:34][CH:33]=2)=[O:37])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([CH3:26])[C:11]=12
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: Cn1cccc(C(=O)O)c1=O
Product: Cc1n[nH]c2nccc(Oc3ccc(NC(=O)c4cccn(C)c4=O)cc3F)c12
Yield: 99 %

Procedure:
Prepared by a 2-step process from 3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline (prepared according to Example 5, Step D) and 1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid according to the procedure described for Example 21 (Steps A and B). The crude was purified by silica gel flash column chromatography (3% MeOH in CH2Cl2) to afford 16 mg (99%) of the desired product. LRMS (ESI pos) m/e 394.2 (M+1). 1H NMR (400 MHz, CD3OD) δ 8.56 (dd, 1H), 8.26 (d, 1H), 8.02 (m, 2H), 7.47 (m, 1H), 7.39 (t, 1H), 6.62 (t, 1H), 6.29 (d, 1H), 3.72 (s, 3H), 2.72 (s, 3H); 19F-NMR (376 MHz, CD3OD) δ −130.0.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH:18]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[C@H:19]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:20][CH2:21][C:22](=O)[OH:23].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[NH:18]([C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:36])[C@H:19]([C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[CH2:20][CH2:21][C:22]([NH:1][C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6])=[O:23]
Reactant: CCCC[C@H](N)C(=O)OCc1ccccc1
Reactant: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
The resulting H-Nle-OBzl.HCl was dissolved in methylene chloride (30 mL) and the resulting reaction solution was maintained at 0° C. To the reaction solution, Z-Glu-OBzl (N-α-carbobenzoxy-L-glutamic acid α-benzyl ester, 0.70 g, 1.90 mM), triethylamine (0.29 mL, 1.1 eq., 2.10 mM), HOBt.H2O (1-hydroxybenzotriazole hydrate, 0.32 g, 1.1 eq., 2.10 mM), and WSC.HCl (0.41 g, 1.1 eq., 2.10 mM) was added. The temperature of the reaction solution was gradually raised and stirred at room temperature overnight (16 hours). Then, the reaction mixture was concentrated under reduced pressure, ethyl acetate (100 mL) was added to the resulting residue, and the organic phase was then washed once with water (30 mL), twice with a 5% aqueous solution of citric acid (30 mL), once with a saturated common salt solution (30 mL), twice with a 5% aqueous solution of sodium hydrogen carbonate (30 mL) and once with a saturated common salt solution (30 mL). Then, the organic phase was dried over anhydrous magnesium sulfate. The magnesium sulfate was removed through filtration and the filtrate was concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate and n-hexane, the crystals thus obtained were collected through filtration and dried under reduced pressure to give crystals of Z-Glu(Nle-OBzl)-OBzl (0.91 g).
Reaction SMILES: [Cl:1][C:2](=[CH2:13])[CH2:3][N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8].[NH:14]([CH2:16]C(O)=O)[CH3:15]>C1(C)C=CC=CC=1>[Cl:1][C:2]12[CH2:3][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:10][CH:11]1[N:14]([CH3:16])[CH2:15][CH2:13]2
Reactant: C=C(Cl)CN(CC=O)C(=O)OCC
Reactant: CNCC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2N(C)CCC2(Cl)C1

Procedure:
10.3 g (50mmol) of ethyl N-(2-chloroallyl)-N-(2-oxoethyl)-carbamate are heated under reflux overnight with 4.5 g (50 mmol) of sarcosine in 200 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:29])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=3)[C:14]([F:17])([F:16])[F:15])[NH:8]2)=[CH:4][C:3]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31].[H-].[Na+].I[CH2:38][CH3:39].O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:29])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:26])([F:27])[F:28])[CH:19]=3)[C:14]([F:16])([F:15])[F:17])[N:8]2[CH2:38][CH3:39])=[CH:4][C:3]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCI
Reactant: CCOC(=O)c1cc2cc(C(=O)NC(c3ccc(F)c(C(F)(F)F)c3)C(F)(F)F)[nH]c2cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)NC(c3ccc(F)c(C(F)(F)F)c3)C(F)(F)F)n(CC)c2cc1Cl
Yield: 65.7 %

Procedure:
Ethyl 6-chloro-2-({2,2,2-trifluoro-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylate (0.42 g, 0.82 mmol) was dissolved under argon at 0° C. in N,N-dimethylformamide (6 ml). Sodium hydride (60%; 0.028 g, 0.72 mmol) was added and the mixture was stirred while cooling with ice for 2 h. Iodoethane (0.10 g, 0.65 mmol) was added. The reaction mixture was thawed while stirring within 36 h. Water and ethyl acetate were added and the phases were separated. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulphate, and the solvent was removed under reduced pressure. The residue was chromatographed with cyclohexane/ethyl acetate (4/1) and gave 0.23 g (53% of theory) of ethyl 6-chloro-1-ethyl-2-({2,2,2-trifluoro-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylate.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:10])[C:4]=2[CH:3]=[CH:2]1.C(B(CC)CC)C.I[CH2:19][CH2:20][CH3:21].[OH-].[Na+].OO>O1CCCC1>[CH2:19]([CH:8]1[C:9](=[O:10])[C:4]2[CH:3]=[CH:2][S:1][C:5]=2[CH2:6][CH2:7]1)[CH2:20][CH3:21]
Reactant: CCCI
Reactant: O=C1CCCc2sccc21
Agent: CCB(CC)CC
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC1CCc2sccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of KH (30%, 11.44 g) in tetrahydrofuran (160 ml) under N2 was added dropwise 6,7-dihydro-1-benzothiophen-4(5H)-one (8 g) in tetrahydrofuran (40 ml). After 30 min, a triethyl borane (97 ml, 1 M THF) solution was added dropwise over 5 min. After 10 min, iodopropane was and the reaction stirred for 16 h. The reaction mixture was cooled to 0° C. and 1 N NaOH (250 ml) and hydrogen peroxide (12 ml, 30%) was added. The reaction mixture stirred for 1 h and was extracted with 400 ml ethyl acetate. The organic layer was washed with saturated sodium thiosulfate, dried MgSO4, filtered and concentrated. MPLC chromatography on a biotage 40 L with 4% ethyl acetate/heptane provided the title compound as an oil (8.21 g, 80%): 1H NMR (300 MHz, CDCl3) δ) 7.40, 7.07, 3.15-3.01, 2.47, 2.32, 2.07-1.88, 1.53-1.30, 1.27, 0.99-0.88; HRMS (FAB) calcd for C11H14OS+H 195.0844, found 195.0835.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)[CH3:3].Cl[CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:27]=1>O1CCOCC1>[CH2:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:27]=2)([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:10]=1)[CH3:3]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(OCC)cc1
Reactant: Fc1ccc(COCCl)cc1Oc1ccccc1
Agent: [Na]
Solvent: C1COCCO1
Product: CCOC(=O)C(COCc1ccc(F)c(Oc2ccccc2)c1)(C(=O)OCC)c1ccc(OCC)cc1
Temperature: 0 °C
Yield: 52.2 %

Procedure:
Sodium (2.18 g, 35 mmol) was added to diethyl 4-ethoxyphenylmalonate (26.6 g, 95 mmol) dissolved in dioxane (100 ml) and refluxed until the sodium had dissolved. Chloromethyl(4-fluoro-3-phenoxybenzyl)ether (25.4 g, 95 mmol) was added, dropwise, at 40°-50° C. and then heated under reflux for 3 hours. The mixture was added to ice-water, extracted three times with ether, the extracts washed with water, dried over magnesium sulphate and evaporated. After chromatography on silica-gel, using toluene as the eluent, there was obtained 25.3 g of diethyl 2-(4-ethoxyphenyl)-2-(4-fluoro-3-phenoxybenzyloxymethyl)malonate (52% of theory). This was then reduced in a similar manner to Example 1 using lithium aluminium hydride to give crude 2-(4-ethoxyphenyl)-2-(4-fluoro-3-phenoxybenzyloxymethyl)propane-1,3-diol.