Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH:10]([CH3:14])[C:11](Cl)=[O:12])=[CH:7][CH:6]=1.C(O)(=O)CC.S(Cl)(Cl)=O.[CH2:31]([Cl:34])[CH2:32][OH:33]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[Cl:34][CH2:31][CH2:32][O:33][C:11](=[O:12])[CH:10]([O:9][C:8]1[CH:15]=[CH:16][C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:2]=2[Cl:1])=[CH:6][CH:7]=1)[CH3:14]
Reactant: CC(Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1)C(=O)Cl
Reactant: OCCCl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCC(=O)O
Product: CC(Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1)C(=O)OCCCl
Reaction time: 1 h

Procedure:
A solution of 0.06 mol=20.73 g of 2-[4'-(2",4"-dichlorophenoxy)phenoxy]-propionic acid chloride, prepared from 2-[4'-2",4"-dichlorophenoxy)phenoxy]-propionic acid and thionyl chloride, in 60 ml absolute toluene was added dropwise at room temperature to a solution of 0.06 mol=4.83 g of ethylene chlorohydrin (2-chloroethanol) and 0.06 mol=6.06 g of triethylamine in 60 ml absolute toluene. After the addition, stirring of the mixture was continued for 1 hour at 50° C., the precipitated triethylamine chloride was filtered off, and the filtrate was washed with dilute sodium hydroxide solution and with water. The toluene solution was dried over sodium sulfate and the solvent was distilled off under reduced pressure. 21.25 g=91% of the theory of 2-[4'-(2",4"-dichlorophenoxy)-phenoxy]-propionic acid 2-chloroeth-1-yl ester were obtained having a refractive index nD24 of 1.5672. ##STR13##
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:3]\[CH2:4][OH:5].C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH3:1][C:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:3][CH:4]=[O:5]
Reactant: CCCCC/C(C)=C/CO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCCCCC(C)=CC=O
Reaction time: 0.5 h

Procedure:
(E)-3-Methyl-2-octenol (XX; 3 g; 21.4 mmol) was dissolved in 45 ml CH2Cl2. To the solution, was added 10 g 4A° molecular sieves (Aldrich), NMO (4.9 g; 41.8 mmol; Aldrich) and TPAP (0.44 g; 1.25 mmol; Aldrich). The suspension was stirred in the dark under argon for 30 min. The product was purified via silica chromatography (eluent: CH2Cl2). XXI was unstable and was used the same day or stored under argon at −78° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][C:15](=[N:18][O:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]2)[CH2:14][CH2:13]1.[OH:28][NH:29][C:30](=N)[CH:31]([CH3:33])[CH3:32]>C(OCC)(=O)C.[Cl-].[Cl-].[Zn+2]>[CH:31]([C:30]1[N:27]=[C:26]([N:23]2[CH2:24][CH2:25][CH:20]([O:19][N:18]=[C:15]3[CH2:16][CH2:17][N:12]([C:3]4[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:7][C:2]=4[F:1])[CH2:13][CH2:14]3)[CH2:21][CH2:22]2)[O:28][N:29]=1)([CH3:33])[CH3:32]
Reactant: CC(C)C(=N)NO
Reactant: CS(=O)(=O)c1ccc(N2CCC(=NOC3CCN(C#N)CC3)CC2)c(F)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)c1noc(N2CCC(ON=C3CCN(c4ccc(S(C)(=O)=O)cc4F)CC3)CC2)n1
Reaction time: 1 h

Procedure:
68b (35 mg, 0.066 mmol) and 68a (8 mg, 0.08 mmol) were combined in ethyl acetate (1 mL) and 1N ZnCl2 (80 μL, 0.08 mmol) was added dropwise. After 1 h, the solvent was evaporated. 1 mL of ethanol and 0.5 mL of concentrated HCl were added and the mixture was heated to reflux. The solvent was removed and the crude mixture was purified on preparative HPLC to give 68-1: LC-MS 480.2 (MH+), tR=5.57 (Method 5).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].F[C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][N:19]=1)[C:14]([OH:16])=[O:15]>>[Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:17]1[CH:18]=[N:19][CH:11]=[CH:12][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: Nc1ccc(I)cc1Cl
Reactant: O=C(O)c1ccnc(F)c1
Product: O=C(O)c1ccncc1Nc1ccc(I)cc1Cl

Procedure:
synthesized as intermediate 1 by reacting 15.7 mmol of 2-chloro-4-iodoaniline with 23.55 mmol 2-fluoroisonicotinic acid. LC/MS [(5.9 min; 376 (M+1)].
Reaction SMILES: [OH-].[K+].BrBr.[OH:5][C:6]1[C:7](C(N)=O)=[N:8][C:9]([CH3:12])=[CH:10][N:11]=1.Cl.[OH-].[NH4+:18]>O>[NH2:18][C:7]1[C:6]([OH:5])=[N:11][CH:10]=[C:9]([CH3:12])[N:8]=1
Reactant: Cc1cnc(O)c(C(N)=O)n1
Reactant: [NH4+]
Agent: BrBr
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1cnc(O)c(N)n1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of KOH (6 g, 154 mmol) in water (46 mL) at 5° C. is added slowly bromine followed by 3-hydroxy-6-methyl-pyrazine-2-carboxylic acid amide (2.6 g, 17.0 mmol) with rapid stirring. The reaction mixture is warmed to 85° C. and stirred for 1 h 30 min. The reaction is cooled to 20° C. and acidified with HCl conc, basified with ammonium hydroxide conc. and left stand overnight at r.t. The solid obtained is filtered and washed with cold water, dried with air and then dried further in a vacuum oven at 60° C. to give 3-amino-5-methyl-pyrazin-2-ol as a beige solid (1.63 g, 76%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:16]([CH3:33])[C:17](=[O:32])[CH2:18][N:19]2[C:24]3[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:23]=3[O:22][CH2:21][C:20]2=[O:31])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:34][C:35]([O:38][C:39]([NH:41][C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1)=[O:40])([CH3:37])[CH3:36].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:30][C:26]1[C:27]([Cl:29])=[CH:28][C:23]2[O:22][CH2:21][C:20](=[O:31])[N:19]([CH2:18][C:17]([N:16]([CH3:33])[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([C:45]4[CH:44]=[CH:43][C:42]([NH:41][C:39](=[O:40])[O:38][C:35]([CH3:36])([CH3:34])[CH3:37])=[CH:47][CH:46]=4)=[CH:3][CH:4]=3)[CH2:9][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[O:32])[C:24]=2[CH:25]=1
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Yield: 39.7 %

Procedure:
To a solution of N-[1-(4-bromophenyl)-2-(4-morpholinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide (1.64 g, 2.9 mmol) and [4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)phenyl]boronic acid (0.77 g, 3.2 mmol) in DMF (10 mL) was added Pd(dppf)Cl2 (0.12 g, 0.15 mmol) and 2N aqueous solution of Na2CO3 (0.26 mL, 0.52 mmol). The resultant mixture was stirred at 80° C. for 16 h. The mixture was filtered through a 0.45 uM filter and concentrated under reduce pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with 5% NaHCO3 (100 mL) and brine (100 mL). The organic layer was dried over MgSO4 and concentrated. The residue was recrystallized in methanol to give 0.77 g (40%) white solid. The mother liquid was concentrated and was purified by using a Gilson preparative HPLC (Phenomenex, 100×50 mm, 10 micron, 90 mL/min, A: acetonitrile B: water, A: 10 to 90% over 15 min, UV detection at 214 nm) to give 0.10 g (5%) of the title compound as yellow oil. Total yield 45%. MS (ES) m/e 669.4 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:3].[I:11]Cl.O.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[I:11][C:6]1[CH:5]=[C:4]([CH:2]([CH3:3])[CH3:1])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: CC(C)c1ccc(O)cc1
Reactant: ClI
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1ccc(O)c(I)c1
Yield: 49.6 %

Procedure:
4-(1-Methylethyl)phenol (27.2 g., 0.20 moles) is dissolved in acetic acid (100 ml.). Iodine monochloride (32.5 g., 0.20 mole) in acetic acid (50 ml.) is then added slowly. The dark mixture is refluxed for 6 hours, cooled and poured into cold water (1 l.) containing a little sodium bisulfite. The black oil that separates is extracted with ether and the extract is washed with water and saturated brine and dried over magnesium sulfate. The ether is evaporated and the residue is purified by distillation to obtain 2-iodo-4-(1-methylethyl)phenol (26 g.), b.p. 137°-140° C. (15 mm.).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:7][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:9][CH2:10][C:11]=2[N:12]=1>[O-2].[O-2].[Mn+4].C1C=CC=CC=1>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]2[O:7][CH:8]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:9][CH2:10][C:11]=2[N:12]=1)=[O:1]
Reactant: OCc1ccc2c(n1)COC(c1ccccc1)O2
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: O=Cc1ccc2c(n1)COC(c1ccccc1)O2
Reaction time: 8 h

Procedure:
To a suspension of 38.8 g. (0.4 mole) of activated manganese dioxide in 400 ml. of benzene is added 48.6 g. (0.2 mole) of 6-hydroxymethyl-2-phenyl-4H-pyrido[3,2-d]-1,3-dioxin in 250 ml. of the same solvent, and the mixture stirred at the reflux temperature overnight. The mixture is filtered while hot (50° C.) and the filtrate concentrated under vacuum to an oily foam, 49.7 g. The intermediate product is purified by chromatographing on a silica gel column (1 kg. 60-200 mesh silica gel; 8 cm × 75 cm column), the product being eluted with ethyl acetate. The eluates are combined and evaporated to dryness, 11.75 g., m.p. 110°-114° C.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([CH:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:32]=O)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].O>ClCCl>[Br:2][C:1]([Br:5])=[CH:32][CH:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCC(C=O)CCCCCC
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCC(C=C(Br)Br)CCCCCC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 90 %

Procedure:
Carbon tetrabromide (218 g, 657 mmol) is dissolved in anhydrous dichloromethane (1600 cm3) and cooled to 0° C. Triphenylphosphine (345 g, 1.32 mol) is added in one portion, the mixture exothermed to 15° C. and is re-cooled to 0° C., whilst stirring for 45 minutes. 2-Hexyldecan-1-al (Price, S. C.; Stuart, A. C.; You, W.; Macromolecules 2010, 43, 797-804) (79.0 g, 329 mmol) is added dropwise over 45 minutes and the mixture is allowed to warm to 23° C. After 2 hours, the reaction mixture is carefully poured into water (2000 cm3), the organic phase is separated, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product is dissolved in dichloromethame (2000 cm3) and passed twice through a plug of silica eluting with petroleum ether (40-60° C.) to yield the title product as a pale yellow oil (117.4 g, Yield: 90%). NMR (1H, 400 MHz, CDCl3): δ 6.15 (d, J=9.6 Hz, 1H); 2.38 (m, 1H); 1.29 (m, 24H); 0.91 (m, 6H).
Reaction SMILES: BrCC1C=CC(F)=CC=1.Br[CH2:11][CH:12]1[CH2:14][CH2:13]1.[O:15]=[C:16]1[NH:20][N:19]=[CH:18][N:17]1[C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][N:30]=1)[C:24]([O:26][CH3:27])=[O:25]>>[CH:14]1([CH2:13][N:20]2[C:16](=[O:15])[N:17]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][N:30]=3)[C:24]([O:26][CH3:27])=[O:25])[CH:18]=[N:19]2)[CH2:12][CH2:11]1
Reactant: BrCC1CC1
Reactant: COC(=O)c1ccnc(-n2cn[nH]c2=O)c1
Agent: Fc1ccc(CBr)cc1
Product: COC(=O)c1ccnc(-n2cnn(CC3CC3)c2=O)c1
Yield: 65 %

Procedure:
Following the procedure as described in Preparation 17, making variations as required to replace 1-(bromomethyl)-4-fluorobenzene with (bromomethyl)cyclopropane to react with methyl 2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)isonicotinate, methyl 2-(1-(cyclopropylmethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)isonicotinate was obtained as a colorless solid in 65% yield: MS (ES+) m/z 275.1 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([CH:20]([CH3:22])[CH3:21])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:7]([CH3:19])([CH3:18])[CH2:6]1)=[O:4].C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.[N:39]([CH:42]([CH3:44])[CH3:43])=[C:40]=[O:41]>C(Cl)Cl>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C@H:2]([NH:1][C:40]([NH:39][CH:42]([CH3:44])[CH3:43])=[O:41])[CH:20]([CH3:22])[CH3:21])[CH2:6][C:7]2([CH3:18])[CH3:19])=[CH:12][CH:13]=1
Reactant: CC(C)[C@@H](N)C(=O)N1CCN(c2ccc(Cl)cc2)C(C)(C)C1
Reactant: CC(C)N=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)N[C@@H](C(=O)N1CCN(c2ccc(Cl)cc2)C(C)(C)C1)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-2-amino-1-(4-(4-chlorophenyl)-3,3-dimethylpiperazin-1-yl)-3-methylbutan-1-one, TFA (30 mg, 0.07 mmol) and DIPEA (0.14 mmol) in CH2Cl2 (1 mL), was added 2-isocyanatopropane (7.00 mg, 0.08 mmol). The mixture was stirred at rt for 2 h and concentrated. The residue was purified by preparative HPLC to afford (R)-1-(1-(4-(4-chlorophenyl)-3,3-dimethylpiperazin-1-yl)-3-methyl-1-oxobutan-2-yl)-3-isopropylurea (11 mg, TFA salt) as a white solid. MS found 409.15 (M+H)+.
Reaction SMILES: S1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].Cl.NCCC(OC)=[O:19].C(=O)C1OC=CC=1>>[O:19]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CCNCc1cccs1
Reactant: COC(=O)CCN
Agent: Cl
Solvent: O=Cc1ccco1
Product: COC(=O)CCNCc1ccco1

Procedure:
Methyl 3-[(2-furanylmethyl)amino]propanoate (22) was prepared in the manner methyl 3-[(2-thienylmethyl)amino]propanoate (15) was prepared, as described above in Example 15, on a 6.5 mmol scale from methyl β-alaninate hydrochloride and furfural to yield 0.28 g (28%) of product.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:15]4=[N:16][C:17]([C:20]5[CH:21]=[N:22][N:23]([CH2:25][CH2:26][O:27]C6CCCCO6)[CH:24]=5)=[CH:18][N:19]=[C:14]4[N:13]=[N:12]3)=[CH:9][C:4]2=[CH:3][CH:2]=1.C1N2CN3CN(C2)CN1C3.N.O.C[C:47](O)=[O:48].O>>[OH:27][CH2:26][CH2:25][N:23]1[CH:24]=[C:20]([C:17]2[N:16]=[C:15]3[N:11]([CH2:10][C:8]4[CH:7]=[CH:6][N:5]5[N:1]=[CH:2][C:3]([CH:47]=[O:48])=[C:4]5[CH:9]=4)[N:12]=[N:13][C:14]3=[N:19][CH:18]=2)[CH:21]=[N:22]1
Reactant: CC(=O)O
Reactant: c1cc2cc(Cn3nnc4ncc(-c5cnn(CCOC6CCCCO6)c5)nc43)ccn2n1
Agent: C1N2CN3CN1CN(C2)C3
Agent: N
Solvent: O
Product: O=Cc1cnn2ccc(Cn3nnc4ncc(-c5cnn(CCO)c5)nc43)cc12
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-6-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine 311-a (125 mg, 0.28 mmol) in AcOH/H2O (2 mL/1 mL) was added HMTA (79 mg, 0.56 mmol). The reaction mixture was stirred at 110° C. for 2 h, then treated with NH3.H2O to bring pH to 8. The resulting mixture was then concentrated and purified by prep-TLC to afford the title compound (67 mg). MS (m/z): 389.37 (M+1)+.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH3:14][O:15][C:16](=[O:43])[C@H:17]([O:21][C:22]1[CH:23]=[C:24]([CH:40]=[CH:41][CH:42]=1)[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=2)[C:28]([CH3:38])=[C:27]1[CH3:39])[CH:18]([CH3:20])[CH3:19]>>[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:35]([C:31]2[CH:30]=[C:29]3[C:34](=[CH:33][CH:32]=2)[N:26]([CH2:25][C:24]2[CH:23]=[C:22]([CH:42]=[CH:41][CH:40]=2)[O:21][C@H:17]([CH:18]([CH3:20])[CH3:19])[C:16]([O:15][CH3:14])=[O:43])[C:27]([CH3:39])=[C:28]3[CH3:38])=[O:36])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: COC(=O)[C@H](Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1)C(C)C
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: COC(=O)[C@H](Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1)C(C)C

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(3-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [C:1]1([C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][C:12]=2[CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]=1.[CH:21]1[CH:22]=[CH:23][N:24]2[CH2:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[NH:27][CH2:26][C:25]=12>>[CH:21]1[CH:22]=[CH:23][N:24]2[CH2:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[N:27]([C:15]([C:14]3[CH:18]=[CH:19][C:11]([C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH2:4][CH2:3][CH:2]=4)=[C:12]([CH3:20])[CH:13]=3)=[O:16])[CH2:26][C:25]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1cc(C(=O)O)ccc1C1=CCCc2ccccc21
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1C1=CCCc2ccccc21
Yield: 85.7 %

Procedure:
4-(3,4-Dihydro-naphthalen-1-yl)-3-methyl-benzoic acid of Step B (0.220 g, 0.832 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.169 g, 0.915 mmol) were reacted in the manner of Example 15, Step D. Purification by flash column chromatography on silica gel, eluting with 15% ethyl acetate in hexane, followed by recrystallization from petroleum ether afforded the title compound (0.307 g) as white crystals, m.p. 108° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[BH3-]C#N.[Na+]>CO>[O:16]1[CH2:17][CH2:18][N:13]([CH2:1][C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])[CH2:14][CH2:15]1
Reactant: C1COCCN1
Reactant: COC(=O)c1cccc(C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(CN2CCOCC2)c1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 90579.6 %

Procedure:
To a solution of methyl 3-formylbenzoate (100 mg, 0.61 mmol) in MeOH (5 mL) was added morpholine (100 mg, 1.15 mmol) and the resulting mixture was stirred for 10 min at 20° C. To the mixture was added NaBH3CN (100 mg, 1.59 mmol) and the reaction mixture was stirred for 30 min at 20° C. The solution was concentrated and the residue was purified by prep-TLC to afford the title compound (130 g, Yield 90.9%). 1H NMR (CD3OD, 400 MHz): δ 7.98-8.05 (m, 1H), 7.92 (td, J=1.4, 7.7 Hz, 1H), 7.57-7.62 (m, 1H), 7.37-7.53 (m, 1H), 3.90 (s, 3H), 3.66-3.71 (m, 4H), 3.57 (s, 2H), 2.41-2.49 (m, 4H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[CH2:10]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)/[CH:11]=[C:12](/[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])\[CH3:13]>O1CCCC1>[CH2:10]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)=[O:26])=[CH:28][CH:29]=1)/[CH:11]=[C:12](/[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])\[CH3:13]
Reactant: Nc1cccnc1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)Nc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 32.4 %

Procedure:
Sodium hydride(0.74 g) and 3-aminopyridine(0.87 g) were stirred in tetrahydrofuran(30 ml) for 1 hour while being cooled with ice. 4-geranyloxybenzoic acid(2.54 g) and N,N'-carbonyldiimidazole(1.65 g) was stirred in tetrahydrofuran(10 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. After being stirred for 20 minutes at room temperature, the reaction mixture was concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 1.05 g of the aimed compound.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]#[N:8].C(O[C:12]([C:14]1[N:15]([N:24]=[CH:25]N(C)C)[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:18]=1)=[O:13])C.CC(O)=O>C1COCC1>[CH2:22]([O:21][C:19]([C:16]1[N:15]2[N:24]=[CH:25][C:6]([C:7]#[N:8])=[C:12]([OH:13])[C:14]2=[CH:18][CH:17]=1)=[O:20])[CH3:23]
Reactant: CCOC(=O)c1ccc(C(=O)OCC)n1N=CN(C)C
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc2c(O)c(C#N)cnn12
Reaction time: 0.33 h
Yield: 50.9 %

Procedure:
To a solution of n-BuLi (1.6 M in hexanes) (290 μl, 0.465 mmol) in THF (1 ml) was added a solution of CH3CN (19.1 mg, 0.465 mmol) in THF (2 ml) dropwise at 0° C. The mixture was stirred for 20 min, then a solution of 406D (62 mg, 0.221 mmol) in THF (5 ml) was added. After the mixture was stirred for 40 min, the reaction temperature was lowered to −78° C., AcOH (38 μl, 0.663 mmol) was added. The reaction mixture was then stirred at rt overnight. Solvent was removed, 406E (26 mg, 50%) was obtained as a yellowish solid after preparative HPLC purification. LCMS Found: (M+H)+=232.
Reaction SMILES: C(OC([NH:11][CH:12]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C@H:20]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[C:21](=[O:48])[NH:22][C@@H:23]([C:35](=[O:47])[NH:36][C:37]2[CH:38]=[N:39][C:40]3[C:45]([CH:46]=2)=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH2:13]1)=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][CH:12]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C@H:20]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:54])([CH3:53])[CH3:55])[C:21](=[O:48])[NH:22][C@@H:23]([C:35](=[O:47])[NH:36][C:37]2[CH:38]=[N:39][C:40]3[C:45]([CH:46]=2)=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN1CCC(NC(=O)OCc2ccccc2)C1)C(=O)N[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)Nc1cnc2ccccc2c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCCN1CCC(N)C1)C(=O)N[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)Nc1cnc2ccccc2c1
Reaction time: 48 h
Yield: 86.4 %

Procedure:
To a solution of tert-butyl N-[(1S)-4-(3-{[(benzyloxy)carbonyl]amino}pyrrolidin-1-yl)-1-{[(1R)-1-[(quinolin-3-yl)carbamoyl]-2-[4-(trifluoromethyl)phenyl]ethyl]carbamoyl}butyl]carbamate CXIII (170 mg, 0.22 mmol) in methanol (20 mL) was added catalytic amount of 10% Pd/C catalyst. The mixture was hydrogenated at normal pressure for 48 h. The catalyst was filtered through Celite and the filtrate was concentrated to give tert-butyl N-[(1S)-4-(3-aminopyrrolidin-1-yl)-1-{[(1R)-1-[(quinolin-3-yl)carbamoyl]-2-[4-(trifluoromethyl)phenyl]ethyl]carbamoyl}butyl]carbamate CXIV (120 mg, 0.19 mmol, 86.4% yield). ESIMS found for C33H41N6O4F3 m/z 643 (M+H).
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH2:16])[CH2:6]1)[CH:2]=[CH2:3].[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C@H:26]([NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:27]2[CH2:29][O:28]2)[CH:21]=[C:22]([F:24])[CH:23]=1>>[CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:29][C@@H:27]([OH:28])[C@@H:26]([NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:25][C:20]2[CH:19]=[C:18]([F:17])[CH:23]=[C:22]([F:24])[CH:21]=2)[CH2:6]1)[CH:2]=[CH2:3]
Reactant: O=C(N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1)OCc1ccccc1
Reactant: C=CCO[C@@H]1C[C@H](N)c2cc(OC)ccc21
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OCc2ccccc2)c2cc(OC)ccc21
Yield: 34 %

Procedure:
Step W (1): (1S,3R)-3-(Allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-amine from Step U(2) was reacted with benzyl (S)-2-(3,5-difluorophenyl)-1-((S)-oxiran-2-yl)ethylcarbamate according to the conditions described in Step V (1). The crude product was purified using silica gel column chromatography (1-10% MeOH (with 0.1% triethylamine)/chloroform, linear gradient) to provide 1.72 g mg (34% yield) of benzyl (2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-ylcarbamate. HRMS (M+H)+=553.2534; 1H NMR (500 MHz, DMSO-d6) δ 7.21-7.35 (m, 4H) 7.14-7.21 (m, 2H) 7.03 (t, J=9.46 Hz, 1H) 6.87-6.99 (m, 3H) 6.83 (dd, J=8.24, 2.14 Hz, 1H) 5.88-6.00 (m, 1H) 5.30 (dd, J=17.09, 1.83 Hz, 1H) 5.14 (dd, J=10.53, 1.98 Hz, 1H) 4.96-5.02 (m, 1H) 4.83-4.95 (m, 2H) 4.75 (t, J=6.41 Hz, 1H) 4.01-4.13 (m, 2H) 3.91-4.00 (m, 1H) 3.72-3.76 (m, 3H) 3.64-3.72 (m, 1H) 3.44-3.53 (m, 1H) 3.06 (dd, J=13.73, 3.05 Hz, 1H) 2.65-2.75 (m, 1H) 2.54-2.65 (m, 2H) 1.92-2.02 (m, 1H) 1.57-1.67 (m, 1H).