Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]1[CH2:6][O:5][C:4]2[CH:7]=[CH:8][C:9]3[CH2:10][CH2:11][C@@H:12]([CH2:14][CH2:15][NH2:16])[C:13]=3[C:3]1=2.O.[OH-].[Na+].[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>O1CCCC1>[CH2:2]1[CH2:6][O:5][C:4]2[CH:7]=[CH:8][C:9]3[CH2:10][CH2:11][C@@H:12]([CH2:14][CH2:15][NH:16][C:20](=[O:23])[CH2:21][CH3:22])[C:13]=3[C:3]1=2
Reactant: NCC[C@@H]1CCc2ccc3c(c21)CCO3
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)NCC[C@@H]1CCc2ccc3c(c21)CCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a mixed solution of (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride (74 kg, 309 mol) in tetrahydrofuran (185 L) and city water (259 L) were added 30% aqueous solution of sodium hydroxide (70 L) and propionyl chloride (32.8 kg), and stirred at room temperature for 1 hr. To the reaction solution was added city water (592 L), and cooled. The precipitated crystals were collected by filtration, and dried under reduced pressure to give title compound (78.0 kg, yield 97.4%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=[O:21])=[CH:12]1>>[CH2:2]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=[O:21])=[CH:12]1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: O=C(CBr)c1ccccc1
Product: O=Cc1cn(CC(=O)c2ccccc2)c2ccccc12
Yield: 56.8 %

Procedure:
The same procedures used in Example 1 were repeated except for using 2.88 g of bromoacetophenone and 2.00 g of indole-3-carbaldehyde as a starting material to give 2.06 g of 1-phenacylindole-3-carbaldehyde as pale yellow crystals. The yield thereof was found to be 57%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([NH2:19])=[O:18])[C:5]([CH3:20])=[CH:4][N:3]=1>CN(C=O)C.CO.[Pt]=O>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([NH2:19])=[O:18])[C:5]([CH3:20])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1C#Cc1ccccc1CC(N)=O
Agent: O=[Pt]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cnc(Cl)nc1CCc1ccccc1CC(N)=O
Reaction time: 40 h

Procedure:
A suspension of 2-(2-((2-chloro-5-methylpyrimidin-4-yl)ethynyl)phenyl)acetamide (I9) (5.01 g, 17.5 mmol) in DMF (231 mL) and MeOH (80 mL) containing platinum oxide (0.995 g, 4.38 mmol) was stirred under a hydrogen atmosphere for 40 hours. The resulting mixture was filtered through a pad of Celite and the filtrate concentrated in vacuo. The resulting residue was diluted with ice water (400 mL) to give a precipitate, which was filtered and dried to give the title compound K6 (4.23 g, 83%); 1H NMR (300 MHz, d6-DMSO) δ 8.47 (s, 1H), 7.44 (brs, 1H), 7.21-7.24 (m, 1H), 7.12-7.15 (m, 3H), 6.92 (brs, 1H), 3.47 (s, 2H), 2.99 (s, 4H), 2.15 (s, 3H). LCMS-B: rt 5.528 min; m/z 290 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([Cl:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>>[Cl:10][C:4]1[CH:3]=[C:2]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[F:11])[CH:8]=[C:7]([Cl:9])[C:5]=1[NH2:6]
Reactant: Nc1c(Cl)cc(Br)cc1Cl
Reactant: OB(O)c1ccccc1F
Product: Nc1c(Cl)cc(-c2ccccc2F)cc1Cl
Yield: 75.4 %

Procedure:
The title compound (0.367 g) was prepared from 4-Bromo-2,6-dichloro aniline (0.5 g, 1.9 mmol) and 2-fluorophenylboronic acid (0.363 g, 2.6 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.50 (t, J 6.3, 1H), 7.43 (s, 2H), 7.39-7.31 (m, 1H), 7.29-7.21 (m, 2H), 5.73 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[O:21][CH3:20])=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: COc1ccccc1CN
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1ccccc1OC
Yield: 89 %

Procedure:
The compound prepared in Example 3 was reacted with 2-methoxy-benzylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[NH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13](O)=O>>[NH2:9][C:10]1[CH:11]=[C:12]([C:13]2[O:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: Nc1ccccc1O
Reactant: Cc1ccc(C(=O)O)cc1N
Product: Cc1ccc(-c2nc3ccccc3o2)cc1N

Procedure:
Prepared by the method of Example 1a), from 2-aminophenol (720 mg, 7.0 mmol) and 3-amino-4-methylbenzoic acid (1.00 g, 7.0 mmol) the subtitle compound was obtained, 942 mg (57%). 1H NMR (DMSO) δ 7.67(m, 2H), 7.42(s, 1H), 7.31(m, 2H), 7.24(d, 1H), 7.07(d, 1H), 2.43(s, 3H). MS 225 m/z (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:39])([C:6](=[O:38])[C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[N:14]=2)[N:9]([Si](C(C)C)(C(C)C)C(C)C)[CH:8]=1)[CH2:3][C:4]#[N:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]([CH3:39])([C:6](=[O:38])[C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=3)[N:14]=2)[NH:9][CH:8]=1)[CH2:3][C:4]#[N:5]
Reactant: COc1cc(-c2cnc3c(n2)c(C(=O)C(C)(C)CC#N)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C(C)(C)CC#N)c3n2)cc(OC)c1OC
Yield: 8.9 %

Procedure:
A solution of 3,3-dimethyl-4-oxo-4-[5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-butyronitrile (0.093 g, 0.17 mmol) and 0.3 mL of trifluoroacetic acid in 2 mL of dichloromethane was stirred for 15 h, then concentrated. The resulting residue was redissolved in dichloromethane and washed with a sat. aq. NaHCO3 solution, dried over MgSO4, filtered and concentrated to a residue. Column chromatography (0->100% EtOAc/hexanes) afforded 0.006 g (9%) of 3,3-dimethyl-4-oxo-4-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-butyronitrile as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[N:7]([N:8]=[C:9]([C:15]([NH2:17])=[O:16])[CH:10]=3)[C:6]=2[CH:18]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>O1CCOCC1>[CH3:21][N:22]([CH3:24])[CH:23]=[N:17][C:15]([C:9]1[CH:10]=[C:11]2[N:7]([N:8]=1)[C:6]1[CH:18]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:14][CH2:13][CH2:12]2)=[O:16]
Reactant: NC(=O)c1cc2n(n1)-c1cc(Br)ccc1OCC2
Reactant: COC(OC)N(C)C
Solvent: C1COCCO1
Product: CN(C)C=NC(=O)c1cc2n(n1)-c1cc(Br)ccc1OCC2
Temperature: 100 °C
Yield: 97.1 %

Procedure:
A mixture of 9-bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acid amide (1.11 g, 3.60 mmol) and dimethylformamide dimethylacetal (1.44 mL, 10.8 mmol) in dry 1,4-dioxane (25 mL) was heated at 100° C. for 2 h, then concentrated in vacuo. The resultant residue was triturated in diethyl ether to give 9-Bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acid 1-dimethylaminomethylideneamide as a yellow solid (1.27 g, 97%). LCMS: RT=3.27 min, M+H+=363/365.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.[CH3:18][NH2:19]>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:19][CH3:18])=[O:8]
Reactant: CN
Reactant: O=C(O)c1cc(Br)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.1 %

Procedure:
To a mixture of 5-bromo-2-fluorobenzoic acid (200 mg, 0.91 mmol) in dichloromethane (5 mL) was added oxalyl chloride (0.16 mL, 1.8 mmol), followed by 1 drop of N,N-dimethylformamide. The reaction was stirred at room temperature for 1.5 hours. The reaction was concentrated and the resulting residue was dissolved in dichloromethane (3 mL) and cooled to 0° C. Methylamine (2.3 mL, 5 mmol, 2 M in tetrahydrofuran) was added and the reaction was allowed to stir at 0° C. for 30 minutes. The reaction was quenched with water and the mixture was concentrated. The residue was diluted with water and the resulting solids were filtered, rinsed with water, and dried under vacuum to give the title compound (196.6 mg, 93%) as a white solid. +ESI (M+H+1) 234.1; 1H NMR (400 MHz, CDCl3, δ); 8.22 (dd, J=6.83, 2.73 Hz, 1H), 7.55 (ddd, J=8.68, 4.49, 2.63 Hz, 1H), 7.00 (dd, J=11.32, 8.58 Hz, 1H), 6.67 (br. s., 1H), 3.02 (dd, J=4.88, 1.17 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:34])([CH3:25])[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CC(C)c1ccccc1N=C=O
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4C(C)C)cc3)c2cc1OC
Yield: 20 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (44 mg) was dissolved in toluene (5 ml) with heat, 2-isopropylphenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 80 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 14 mg of the title compound (yield: 20%).
Reaction SMILES: [C:1]([O:12][CH2:13][CH3:14])(=[O:11])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C=O)C>[CH2:21]([O:9][C:8]1[CH:10]=[C:2]([CH:3]=[C:4]([O:5][CH2:8][CH:6]=[CH2:4])[C:6]=1[O:7][CH2:3][CH:2]=[CH2:1])[C:1]([O:12][CH2:13][CH3:14])=[O:11])[CH:22]=[CH2:23]
Reactant: CCOC(=O)c1cc(O)c(O)c(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(C(=O)OCC)cc(OCC=C)c1OCC=C

Procedure:
Ethyl gallate (7.92 g, commercially available, Fluka), and K2CO3 (27.6 g) in DMF (40 ml) were treated with allyl bromide (13.5 ml) as above, to give ethyl 3,4,5-triallyloxybenzoate acid (14 g): NMR (CDCl3) 1.49 (t, 3H); 4.35 (q, 2H); 4.62 (m, 6H); 5.15-5.48 (m, 6H); 6.00-6.28 (m, 3H); 7.29 (s, 1H). This crude ester was hydrolysed essentially as above to give 3,4,5-triallyloxybenzoic acid (10.4 g): NMR (CDCl3) 4.64 (m, 6H); 5.15-5.51 (m, 6H); 6.00-6.20 (m, 3H); 7.35 (s, 1H).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Cl-].[CH3:11][O:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][NH2+:16]1)=[O:14].Cl[C:22]1[O:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>C(#N)C>[O:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[N:16]1[CH2:17][CH2:18][CH2:19][CH2:20][C@H:15]1[C:13]([O:12][CH3:11])=[O:14]
Reactant: Clc1nc2ccccc2o1
Reactant: COC(=O)[C@@H]1CCCC[NH2+]1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-Ethyldiisopropylamine (6.52 ml) was added to a solution of (2S)-2-(methoxycarbonyl)piperidinium chloride (3.057 g) [see Preparation 1] and 2-chlorobenzoxazole (2.13 ml) in acetonitrile (50 ml). The reaction mixture was stirred at room temperature for 18 hours and then at 50° C. for a further 2 hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water, the organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 80:10:0, changing to 0:100:0, followed by 0:95:5, by volume, hexane:ethyl acetate:methanol, to afford methyl (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylate (3.18 g) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[Li]C(C)(C)C.Cl([O-])(=O)(=O)=O.[CH2:19]1[C:26]2[CH2:25][CH2:24][CH2:23][N+:22]=2[CH2:21][CH2:20]1>CCCCC>[Br:8][C:6]1[CH:7]=[C:2]([C:26]23[CH2:25][CH2:24][CH2:23][N:22]2[CH2:21][CH2:20][CH2:19]3)[CH:3]=[N:4][CH:5]=1
Reactant: C1CC2=[N+](C1)CCC2
Reactant: Brc1cncc(Br)c1
Agent: [Li]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCCCC
Product: Brc1cncc(C23CCCN2CCC3)c1
Temperature: -95 °C
Yield: 28.4 %

Procedure:
3,5-dibromopyridine (500 mg, 2.11 mmol, Aldrich) was dissolved in Et2 O and cooled to -95° C. A solution of 2.5M t-BuLi (1.7M in pentane, 2.7 mL, 4.64 mmol) in pentane was added dropwise. 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (663 mg, 3.2 mmol) was added, and the reaction mixture was allowed to stir and warm to -10° C. and stir for 2 hours. The cold bath was removed, 2N HCl was added, and the phases were separated. The aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2×). The CH2 Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; CHCl3 /MeOH, 98:2) to afford a clear oil (160 mg, 28%): 1H NMR (CDCl3, 300 MHz) 67 1.57-1.71 (m, 2H), 1.79-2.04 (m, 6H), 2.62-2.73 (m, 2H), 3.11-3.20 (m, 2H), 8.04 (dd, J=2.0, 2.0 Hz, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.58 (d, J=2.0 Hz, 1H); MS (CI/NH3) m/z: 267/269 (M+H)+.
Reaction SMILES: C[C@H]1[O:7][C@@H](O[C@H]2C3C(=C(O)C(C(O)=O)=C(C)C=3)C3C(O)=C4C(=O)C5C(=C(O)C=C(OC)C=5)C(=O)C4=CC=3[C@@H]2O)[C@H](O)[C@@H](O[C@@H]2OC[C@@H](O)[C@H](O)[C@H]2O)[C@H]1N(C(OCC1C=CC=CC=1)=O)C.C1C=CC2N(O)N=NC=2C=1.[CH2:76]1[CH2:81][CH2:80][CH:79]([N:82]=[C:83]=[N:84][CH:85]2[CH2:90][CH2:89][CH2:88][CH2:87][CH2:86]2)[CH2:78][CH2:77]1>C1COCC1>[CH:85]1([NH:84][C:83]([NH:82][CH:79]2[CH2:78][CH2:77][CH2:76][CH2:81][CH2:80]2)=[O:7])[CH2:90][CH2:89][CH2:88][CH2:87][CH2:86]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COc1cc(O)c2c(c1)C(=O)c1c(cc3c(c1O)-c1c(cc(C)c(C(=O)O)c1O)[C@H](O[C@@H]1O[C@H](C)[C@H](N(C)C(=O)OCc4ccccc4)[C@H](O[C@@H]4OC[C@@H](O)[C@H](O)[C@H]4O)[C@H]1O)[C@H]3O)C2=O
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 13 (52 mg, 0.058 mmol), HOBT (10 mg, 0.065 mmol) and DCC (16mg, 0.079 mmol) in THF (2 ml) was stirred for 1 hour at room temperature and filtered to remove resulting dicyclohexyl urea. The filtrate was concentrated and the residue was dissolved in 1 ml of 50% aqueous dioxane. To the mixture was added a solution of D-3,4-dihydroxyphenylalanine (D-DOPA) (24 mg, 0.12 mmol) and triethylamine (20 μl, 0.14 mmol) in 1 ml of 50% aqueous dioxane. The mixture was stirred for 1 day at room temperature and then dioxane was removed under reduced pressure. To the residue was added 50 ml of H2O and the mixture was acidified with 1N HCl to pH 2. The precipitate formed was collected by filtration and chromatographed on a column of C-18 silica gel (Bondpak C18, 20 i.d.×200 mm). The column was eluted with 30-40% acetonitrile-1/1000N HCl and the desired fraction was concentrated and lyophilized to give 4'N-CBZ protected title compound (23 mg, yield 37%).
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@@H:18]([CH2:55][CH2:56][CH2:57][CH2:58][NH:59][C:60](=[O:98])[CH2:61][N:62]3[CH2:73][CH2:72][N:71]([CH2:74][C:75](=[O:81])[O:76][C:77]([CH3:80])([CH3:79])[CH3:78])[CH2:70][CH2:69][N:68]([CH2:82][C:83](=[O:89])[O:84][C:85]([CH3:88])([CH3:87])[CH3:86])[CH2:67][CH2:66][N:65]([CH2:90][C:91]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])=[O:92])[CH2:64][CH2:63]3)[C:19](=[O:54])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C@@H:25]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[NH:26][C:27](=[O:46])[NH:28][C@H:29]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:17][C@H:18]([C:19](=[O:54])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C@@H:25]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[NH:26][C:27](=[O:46])[NH:28][C@H:29]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:55][CH2:56][CH2:57][CH2:58][NH:59][C:60](=[O:98])[CH2:61][N:62]1[CH2:73][CH2:72][N:71]([CH2:74][C:75](=[O:81])[O:76][C:77]([CH3:80])([CH3:79])[CH3:78])[CH2:70][CH2:69][N:68]([CH2:82][C:83](=[O:89])[O:84][C:85]([CH3:88])([CH3:87])[CH3:86])[CH2:67][CH2:66][N:65]([CH2:90][C:91]([O:93][C:94]([CH3:95])([CH3:96])[CH3:97])=[O:92])[CH2:64][CH2:63]1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)[C@H](CCCCNC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)[C@@H](N)CCCCNC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 66.2 %

Procedure:
To a solution of (5S,12S,16S)-tri-tert-butyl 1-(9H-fluoren-9-yl)-3,6,14-trioxo-5-(4-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)butyl)-2-oxa-4,7,13,15-tetraazaoctadecane-12,16,18-tricarboxylate (115 mg) containing some impurity in DMF (0.30 mL) and piperidine (0.30 mL) was stirred at rt for 1 hr. Solvents were evaporated under reduced pressure to give a residue, which was purified by Biotage eluting with DCM to 10% MeOH in DCM to give (8S,15S,19S)-tri-tert-butyl 8-amino-2,9,17-trioxo-1-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-3,10,16,18-tetraazahenicosane-15,19,21-tricarboxylate (64 mg, 90%) as a colorless oil. MS (ESI), 1171.6 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=1[B:14]([OH:16])[OH:15].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:11])[F:12])=[CH:5][C:4]=1[B:14]([OH:16])[OH:15]
Reactant: COc1ccc(OC(F)(F)F)cc1B(O)O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: OB(O)c1cc(OC(F)(F)F)ccc1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
A suspension of 2-methoxy-5-(trifluoromethoxy)phenylboronic acid (23.0 g, 97.5 mmol) in dichloromethane (140 mL) was cooled to 0° C. and boron tribromide (9.4 mL, 10 mmol) was added drop-wise over 30 min. After stirring for 3 hours, additional boron tribromide (2 mL) was added. The reaction mixture was poured into ice water and stirred for 20 min. The dichloromethane was removed in vacuo and the white solid collected by filtration and washed with water before drying in vacuo to afford the title compound (20.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:18])=[C:6]([CH2:8][C:9]2[O:13]C=[N:11][C:10]=2C(OC)=O)[CH:7]=1>Cl>[ClH:18].[NH2:11][CH2:10][C:9](=[O:13])[CH2:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[Cl:18]
Reactant: COC(=O)c1ncoc1Cc1cc(Br)ccc1Cl
Agent: Cl
Product: NCC(=O)Cc1cc(Br)ccc1Cl
Yield: 279.2 %

Procedure:
The above 5-bromo-2-chloro-1-(4-methoxycarbonyl-5-oxazolylmethyl)benzene (1.37 g) was heated under reflux in 6N aqueous hydrochloric acid solution (20 ml) overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol, and treated with carbon powder. The carbon powder was filtered off, and the filtrate was evaporated under reduced pressure to give crude 1-(3-amino-2-oxopropyl)-5-bromo-2-chlorobenzene.hydrochloride (1.73 g) as a pale brown solid, which was used in the subsequent step without further purification. APCI-Mass m/Z 262/264 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C:9]=2[CH3:21])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[O:30][C:9]2([CH3:21])[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]3)=[CH:4][CH:3]=1
Reactant: CC1=C(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(c3ccc(Cl)cc3)OC2(C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 4-(4-chlorophenyl)-3-methyl-5,6-dihydropyridine-1(2H)-carboxylate (1.09 g, 3.54 mmol) in methylene chloride (15 mL) was cooled to 0° C. and treated dropwise with a solution of m-CPBA (1.111 g, 4.96 mmol) in methylene chloride (15 mL). The reaction was stirred at 0° C. for 1 hour, then allowed to slowly warm to room temperature and stirred overnight. The mixture was cooled to 0° C., treated with saturated aqueous sodium sulfite (20 mL), and stirred for 1 hour. The layers were separated, and the organic phase was washed once with water, 3× with saturated sodium carbonate, once with water, and once with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified over a 120 g silica gel column, eluting at 85 mL/min with a 0% to 17% ethyl acetate/hexanes gradient followed by 17% ethyl acetate/hexanes to yield the title compound as a colorless oil. MS (ESI+)=268.2 (M−tert-Bu)+, 250.1 (M−tert-BuO)+.
Reaction SMILES: [OH:1][C@H:2]1[C@:6]2([CH3:20])[CH2:7][C@H:8]3[C@H:17]([CH2:18][C@H:5]2[CH2:4][CH2:3]1)[C@@H:16]1[C:11](=[CH:12][C:13](=[O:19])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3>N1C=CC=CC=1.[Pd]>[OH:1][C@H:2]1[C@:6]2([CH3:20])[CH2:7][C@H:8]3[C@H:17]([CH2:18][C@H:5]2[CH2:4][CH2:3]1)[C@@H:16]1[C@@H:11]([CH2:12][C:13](=[O:19])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3
Reactant: C[C@@]12C[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3C[C@H]1CC[C@H]2O
Agent: [Pd]
Solvent: c1ccncc1
Product: C[C@@]12C[C@@H]3CC[C@@H]4CC(=O)CC[C@@H]4[C@H]3C[C@H]1CC[C@H]2O
Reaction time: 3 h
Yield: 98.7 %

Procedure:
To compound 36 (120 mg, 0.44 mmol) in pyridine (40 mL) was added Pd/C (100 mg) at room temperature. Hydrogenation was carried out under 60 psi H2. After 3 h, the pressure was released and the mixture was filtered through Celite® 545 which was washed with EtOAc (100 mL). Solvents were removed and the residue was purified by flash column chromatography (silica gel eluted with 25% EtOAc in hexanes) to give compound 53 (120 mg, 4aR:4aS ratio 2.5:1): 1H NMR (CDCl3) 4aR diastereoisomer δ 3.66 (t, J=8.5 Hz, 1H), 2.58 (t, J=14.0 Hz, 1H), 2.24-0.79 (m, 23H), 0.72 (s, 3H); 13C NMR (CDCl3) δ 213.2, 81.8, 45.3, 44.8, 43.3, 43.0, 40.2, 38.8, 38.6, 36.7, 31.1, 30.4, 29.1, 29.0, 27.4, 25.7, 11.4.
Reaction SMILES: [O:1]([CH:8]([CH3:11])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:10][CH2:9][CH:8]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:11])(=[O:22])=[O:21]
Reactant: CC(CO)Oc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(COS(C)(=O)=O)Oc1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 15.2 g of 2-phenoxy-1-propanol, 20.8 ml of triethylamine and 300 ml of dichloromethane chilled to -10° C. in an ice-salt bath, is added dropwise 7.78 ml of methanesulfonyl chloride over 10 minutes. The solution is stirred at -10° C. for 30 minutes, washed with 100 ml of ice water, 100 ml of cold 10% hydrochloric acid, 100 ml of cold saturated sodium bicarbonate solution, 100 ml of cold saturated sodium chloride solution and dried (magnesium sulfate). The solvent is removed under vacuum to give the product as an oil.