Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[CH:3]=1.[O:22]1[CH:26]=[CH:25][C:24]([C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:28])=[CH:23]1.C(N(C(C)C)C(C)C)C>C(#N)C>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:4]1[CH:3]=[C:2]([N:32]2[CH2:33][CH2:34][N:29]([C:27]([C:24]3[CH:25]=[CH:26][O:22][CH:23]=3)=[O:28])[CH2:30][CH2:31]2)[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:10]=[C:6]2[N:5]=1
Reactant: Clc1cc(-c2ccco2)nc2cc(-c3ccccc3)nn12
Reactant: O=C(c1ccoc1)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(c1ccoc1)N1CCN(c2cc(-c3ccco3)nc3cc(-c4ccccc4)nn23)CC1
Temperature: 100 °C
Yield: 99.2 %

Procedure:
A mixture of 7-chloro-5-(furan-2-yl)-2-phenylpyrazolo[1,5-a]pyrimidine (0.148 g, 0.5 mmol, 1.0 eq), furan-3-yl(piperazin-1-yl)methanone (0.180 g, 1.0 mmol, 2.0 eq,) and N-ethyl-N-isopropylpropan-2-amine (0.129 g, 1.0 mmol, 2.0 eq) in acetonitrile (5.0 mL) was heated at 100° C. for 3 hr. The completed reaction was purified by chromatography (Biotage 25 g, EtOAc/Hexane) to afford (4-(5-(furan-2-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)(furan-3-yl)methanone (0.218 g, 99%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.03-8.00 (m, 2H), 7.83 (m, 1H), 7.62 (m, 1H), 7.52-7.47 (m, 3H), 7.45-7.41 (m, 1H), 7.23 (dd, J=3.5, 0.7 Hz, 1H), 6.93 (s, 1H), 6.65 (m, 1H), 6.62 (dd, J=3.5, 1.8 Hz, 1H), 6.60 (s, 1H), 4.08 (b, 4H), 3.92 (b, 4H). 13C NMR (125 MHz, CDCl3) δ 164.1, 155.4, 152.4, 151.8, 150.1, 148.5, 144.3, 143.8, 143.2, 132.9, 129.0, 128.7, 126.4, 120.6, 112.6, 110.9, 110.1, 92.9, 88.9, 48.3. LCMS retention time: 3.20 min; purity at 215 nm=100%. HRMS m/z calculated for C24H27N5O2 ([M+H]+): 440.1717. found 440.1715.
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[C:16]([CH2:19][NH:20][C:21]1[C:22]([I:37])=[C:23]([C:34](Cl)=[O:35])[C:24]([I:33])=[C:25]([NH:28][CH2:29][C:30](=[O:32])[CH3:31])[C:26]=1[I:27])(=[O:18])[CH3:17].CC([N:41](C)C)=O>>[C:16]([CH2:19][NH:20][C:21]1[C:22]([I:37])=[C:23]([C:34]([NH:41][CH:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:35])[C:24]([I:33])=[C:25]([NH:28][CH2:29][C:30](=[O:32])[CH3:31])[C:26]=1[I:27])(=[O:18])[CH3:17]
Reactant: NCCCCCCCCCCCC(=O)O
Reactant: CC(=O)CNc1c(I)c(NCC(C)=O)c(I)c(C(=O)Cl)c1I
Reactant: CC(=O)N(C)C
Product: CCCCCCCCC(CCC(=O)O)NC(=O)c1c(I)c(NCC(C)=O)c(I)c(NCC(C)=O)c1I
Temperature: 82.5 °C
Reaction time: 39 h

Procedure:
To a solution of 12-aminododecanoic acid (1.1 g, 4.9 mmol) in DMA (25 mL) was added MDTA-Cl (X) (2.5 g, 3.8 mmol) and the mixture stirred at 80-85° C. for 39 h. DMA was removed and the product was purified by a CHP-20 column to furnish the pure title compound XIIId (1.6 g, 50%).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.O>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:24]2[C:25]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:21]=[CH:22][CH:23]=2)[C:11]=1[CH3:12]
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
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: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2cccc3ccccc23)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C

Procedure:
A microwave vessel was charged with 2,4-dichloro-5,7-difluoro-3-methylquinoline (250 mg, 1.008 mmol), 2-naphthylboronic acid (225 mg, 1.310 mmol), tetrakis(triphenylphosphine)palladium(0) (87 mg, 0.076 mmol), sodium carbonate (534 mg, 5.04 mmol), toluene (8.06 mL), and water (2.02 mL). The mixture was heated at 100° C. for 2 h, then cooled to rt and partitioned between EtOAc and water. The organic layer was washed with brine, dried (MgSO4), and concentrated. The resulting crude material was purified by flash chromatography, eluting with a gradient of 0-6% EtOAc in hexane to give 4-chloro-5,7-difluoro-3-methyl-2-(naphthalen-1-yl)quinoline. Mass Spectrum (ESI) m/e=340.0 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C([O-])([O-])=O.[Na+].[Na+].[N+:12]([C:15]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18])([O-:14])=[O:13].Cl>O.O1CCOCC1>[N+:12]([C:15]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:16]=1[C:17]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:18])([O-:14])=[O:13]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: NCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CNC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
To an ice cold suspension of glycine (1.01 g, 13.56 mmol) in water (20 mL) was added Na2CO3 (1.437 g, 13.56 mmol) and stirred for 10 min. A solution of 2,4-dinitrobenzoyl chloride (prepared from 2,4-dinitrobenzoic acid, 2.3 g with SOCl2, 20 mL) in dioxane (20 mL) was added to the above solution and stirred at rt for 4 h. The reaction mixture was diluted with ice cold water and acidified with cold dil. HCl (pH: 6.0). The solution was extracted with EtOAc (5×100 mL) and the combined organic layer was dried over anhyd Na2SO4 and filtered. The solution was evaporated and the residue was chromatographed over silica gel column using chloroform:methanol (95:5) as eluents to give the product as a white color solid (2.5 g, 85%), mp 188-190° C. 1H NMR (400 MHz, DMSO-d6): δ 12.79 (1H, br s), 9.29 (1H, t, J=5.4 Hz), 8.77 (1H, d, J=2.0 Hz), 8.64 (1H, dd, J=8.4, 2.0 Hz), 7.89 (1H, d, J=8.4 Hz), 3.99 (2H, d, J=6.0 Hz); LC-MS (negative ion mode): m/z 268 (M−H)−.
Reaction SMILES: ClCC1C=CC(C#N)=CC=1.Br[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1.[CH2:19]([NH:26][C:27]([C:29]1[S:33][C:32]([N:34]2[CH2:38][CH2:37][NH:36][C:35]2=[O:39])=[N:31][C:30]=1[CH3:40])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([NH:26][C:27]([C:29]1[S:33][C:32]([N:34]2[CH2:38][CH2:37][N:36]([CH2:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:35]2=[O:39])=[N:31][C:30]=1[CH3:40])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Reactant: BrCC1CCCCO1
Agent: N#Cc1ccc(CCl)cc1
Product: Cc1nc(N2CCN(CC3CCCCO3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 27 %

Procedure:
Following the procedure as described in Example 23, making variations as required to replace 4-(chloromethyl)benzonitrile with 2-(bromomethyl) tetrahydro-2H-pyran to react with N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 27% yield: 1H NMR (300 MHz, CDCl3) δ 7.34-7.30 (m, 5H), 5.86 (s, 1H), 4.56 (d, J=3.0 Hz, 2 H), 4.08 (t, J=9.0 Hz, 2H), 3.98-3.94 (m, 1H), 3.84-3.3.63 (m, 2H), 3.55-3.35 (m, 3H), 3.18-3.16 (m, 1H), 2.62 (s, 3H), 1.86-1.83 (m, 1H), 1.60-1.22 (m, 5H); MS (ES+) m/z 415.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:6]1[CH:19]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][C:5]2=1.[Li+].[OH-].C(OCC)(=O)C.Cl>C(O)C.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:6]1[CH:19]([CH2:24][C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][C:5]2=1
Reactant: CCOC(=O)CC1CCCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(F)cc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(O)CC1CCCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(F)cc21
Temperature: 25 °C

Procedure:
To 230 mg of the ester from Step 1 in 3.0 mL of ethanol was added 2.2 mL of 0.5M aqueous LiOH and the resultant mixture heated at reflux for 8 h. The reaction mixture was then cooled to room temperature, poured into ethyl acetate and acidified with concentrated HCl. The organic layer was separated, washed with 1N HCl and brine (2x) and dried over MgSO4. Concentration gave a yellow oil which solidified on standing. Trituration with hexane gave the title compound. IR (KBr) 1710 cm-1. 'H NMR (CDCl3, 250 MHz) w 1.35-1.70 (m, 2H), 1.80-2.12 (m, 4H), 2.50-2.65 (m, H), 2.54 (d,d, J=6.5, 16.0 Hz, 1H), 2.72 (d,d, J=8.5 Hz, 1H), 2.95-3.06 (m, 1H), 3.46-3.58 (m, 1H), 5.28 (d, J=7.5 Hz, 1H), 5.43 (d, J=7.5 Hz, 1H), 6.80-6.92 (m, 1H), 6.83 (d, J=8.0 Hz, 2H), 7.26 (d,d, J=4.0, 9.0 Hz, 1H), 7.16 (d,d, J=2.5, 10.0 Hz, 1H), 7.21 (d, J=8.0 Hz, 2H).
Reaction SMILES: [CH3:1][NH2:2].O=[C:4]([C:11]1[C:12]([C:17]([F:20])([F:19])[F:18])=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:27]([O:34][C:35]1[CH:36]=[C:37]([C:52](=O)[CH2:53]Br)[CH:38]=[C:39]([N+:49]([O-:51])=[O:50])[C:40]=1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)C.C(O)(=O)C.CN(C)C=O>[CH2:27]([O:34][C:35]1[CH:36]=[C:37]([C:52]2[N:2]([CH3:1])[C:4]([C:11]3[C:12]([C:17]([F:20])([F:19])[F:18])=[N:13][CH:14]=[CH:15][CH:16]=3)=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:53]=2)[CH:38]=[C:39]([N+:49]([O-:51])=[O:50])[C:40]=1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CN
Reactant: O=C(CBr)c1cc(OCc2ccccc2)c(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(=O)c1cccnc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2cc(OCc3ccccc3)c(OCc3ccccc3)c([N+](=O)[O-])c2)n(C)c1-c1cccnc1C(F)(F)F
Temperature: 100 °C

Procedure:
To a stirred solution of methylamine (0.63 mL, 33% EtOH solution, 5 mmol) in a mixture of ethanol (25 mL) and acetic acid (0.5 mL) at room temperature was added ethyl 3-oxo-3-(2-(trifluoromethyl)pyridin-3-yl)propanoate (1.305 g, 5 mmol). The reaction mixture was heated at reflux for two hours whereupon the solvent was removed by evaporation under vacuum. To a solution of the crude product in dimethylformamide (25 mL) was added potassium carbonate (2.07 g, 15 mmol) in one portion followed by 1-(3,4-bis-benzyloxy-5-nitro-phenyl)-2-bromo-ethanone (2.51 g, 5.50 mmol) and the mixture was then stirred at 100° C. Once no starting material was detectable, the reaction mixture was allowed to cool to room temperature and poured onto ice-cold 1 N aqueous hydrochloric acid (100 mL). The resulting precipitate was filtered off, washed with water and dried. The residue was chromatographed over silica gel. Homogeneous fractions were pooled and evaporated to give ethyl 5-(3,4-bis(benzyloxy)-5-nitrophenyl)-1-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrrole-3-carboxylate, 2.492 g (79%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Br[CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1.[C:21]12([C:31](O)=[O:32])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH2:11][CH2:10][N:3]2[C:2]([CH3:1])=[C:6]([CH3:7])[S:5]/[C:4]/2=[N:8]\[C:31]([C:21]23[CH2:30][CH:25]4[CH2:24][CH:23]([CH2:29][CH:27]([CH2:26]4)[CH2:28]2)[CH2:22]3)=[O:32])=[CH:13]1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1nc(N)sc1C
Product: Cc1s/c(=N\C(=O)C23CC4CC(CC(C4)C2)C3)n(CCc2c[nH]c3ccccc23)c1C

Procedure:
4,5-Dimethylthiazol-2-ylamine, 3-(2-bromo-ethyl)-1H-indole and 1-adamantane carboxylic acid were processed according to the method of Example 47 to afford the title compound. 1H NMR (CDCl3, 500 MHz) δ ppm 1.68-1.75 (m, 6H) 1.91 (d, J=2.50 Hz, 6H) 1.98-2.04 (m, 3H) 2.13 (d, J=4.68 Hz, 6H) 3.04-3.21 (m, 2H) 4.20-4.43 (m, 2H) 6.98 (t, J=7.49 Hz, 1H) 7.09 (t, J=7.64 Hz, 1H) 7.17 (d, J=2.18 Hz, 1H) 7.36 (d, J=8.11 Hz, 1H) 7.68 (d, J=7.80 Hz, 1H) 10.88 (s, 1H); MS (ESI) m/z 434 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[O:4][CH2:5][O:6][CH3:7].[C:18]1([NH:24][CH:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:27][CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl[C:43](Cl)([O:45]C(=O)OC(Cl)(Cl)Cl)Cl>>[C:18]1([N:24]([CH:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:27][CH2:26]2)[C:43](=[O:45])[NH:1][C:2]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=2[O:4][CH2:5][O:6][CH3:7])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COCOc1c(N)cc(OC)cc1C(C)(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=C(NC1CCC(Nc2ccccc2)CC1)OCc1ccccc1
Product: COCOc1c(NC(=O)N(c2ccccc2)C2CCC(NC(=O)OCc3ccccc3)CC2)cc(OC)cc1C(C)(C)C

Procedure:
(2-Amino-4-methoxy-6-tert-butylphenoxy)methoxymethane, N-phenyl-N-(4-benzyloxycarbonylaminocyclohexyl)amine and triphosgene were treated in the same manner as described in Example 53 to give {2-[3-phenyl-3-(4-benzyloxycarbonylaminocyclohexyl)ureido]-4-methoxy-6-tert-butylphenoxy}methoxymethane (melting point: 145°-154° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][C@H:12]([CH2:17][OH:18])[CH2:11]2)([CH3:4])([CH3:3])[CH3:2].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][C@H:12]([CH2:17][O:18][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[CH2:11]2)=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C[C@@H](CO)C2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2Cc3ccc(NC(=O)OC(C)(C)C)cc3C2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 61.6 %

Procedure:
The aforementioned (S)-2-hydroxymethyl-indan-5-yl-carbamic acid tert-butyl ester (2.15 g, 8.16 mmol) was dissolved in 50 mL of CH2Cl2. p-Toluenesulfonyl chloride (1.63 g, 8.54 mmol) and DMAP (1.1 g, 9.0 mmol) were added and the solution was stirred for 22 hours at rt. The reaction mixture was diluted with 50 mL of CH2Cl2 and washed in turn with saturated aqueous NH4Cl, saturated aqueous NaHCO3 and brine (100 mL each). Each wash was extracted with a small portion of CH2Cl2. The extracts were combined, dried over Na2SO4, filtered and evaporated. The residue was dissolved in warm ethyl ether (25 mL) and allowed to crystallize. The solid was filtered, washed with cold ethyl ether and dried to provide a beige solid as toluene-4-sulfonic acid (S)-5-tert-butoxycarbonylamino-indan-2-ylmethyl ester (2.1 g, 86%). 1H-NMR and MS data were compatible with the structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:47])[NH:7][C@H:8]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:9]([N:11]1[CH2:16][CH2:15]C[CH2:13][C@H:12]1[C:17](=[O:40])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][C:27]2[C:28]([C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=3[OH:39])=[N:29][NH:30][CH:31]=2)=[CH:21][CH:20]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].N(C(OC(C)(C)C)=O)[C@@H](C(O)=[O:57])C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:47])[NH:7][C@H:8]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:9]([N:11]1[CH2:16][CH2:15][O:57][CH2:13][C@H:12]1[C:17](=[O:40])[NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]#[C:26][C:27]2[C:28]([C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=3[OH:39])=[N:29][NH:30][CH:31]=2)=[CH:23][CH:24]=1)=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCCC[C@H]1C(=O)Nc1ccc(C#Cc2c[nH]nc2-c2cc(Cl)ccc2O)cc1)c1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCOC[C@H]1C(=O)Nc1ccc(C#Cc2c[nH]nc2-c2cc(Cl)ccc2O)cc1)c1ccccc1

Procedure:
Using the same procedure for the preparation of 27A, reaction of compound 29A with BOC-D-Phg-OH (11A) afforded the title compound 30A, which was purified by silica column chromatography eluting with dichloromethane/ethyl acetate (10/1, 4/1, 3/1) to give pure 30A as a white powder in similar yield. 1H NMR (CDCl3, 500 MHz) δ 10.73 (br s, 1H), 8.75 (s, 1H), 8.63 (s, 1H), 7.91 (d, 2H, J=8.5 Hz), 7.84 (s, 1H), 7.58 (d, 2H, J=7.5 Hz), 7.44 (m, 5H), 7.21 (d, 1H, J=9.0 Hz), 6.98 (d, 1H, J=8.0 Hz), 5.48 (d, 1H, J=6.0 Hz), 5.40 (d, 1H, J=5.0 Hz), 5.30 (s, 1H), 4.83 (d, 1H, J=12.0 Hz), 3.79 (d, 1H, J=13□0 Hz), 3.66 (t, 1H, J=13.0 Hz), 3.60 (t, 1H, J=1.0 Hz), 3.44 (dd, 1H, J=11.0, 1.5 Hz), 3.08 (t, 1H, J=10.5 Hz), 1.45 (s, 9H). LCMS (ESI) m/z 678.24 (MNa+), 656.25 (MH+), 600.16, 556.17. HPLC: tR=5.12 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25]C(=O)OC(C)(C)C)[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.NC1C=CC=CN=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:41]([CH3:40])(=[O:43])=[O:42])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Reactant: CS(=O)(=O)Cl
Agent: Nc1ccccn1
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 80.8 %

Procedure:
2-(1-(1-(4-chlorophenyl)cyclobutyl)-3,4-dihydroisoquinolin-7-yloxy)ethanamine (example 1, 100 mg, 0.26 mmol), aminopyridine (34.0 mg, 0.28 mmol), and methanesulfonyl chloride (31.9 mg, 0.28 mmol) were dissolved in THF (5 ml) and stirred for 14 h at RT. Water was added and the mixture was extracted with ethyl acetate. The organic layers were washed with water and saturated NaCl solution, dried with MgSO4, and the solvent was removed. The residue was purified by flash chromatography on silica gel using methylenehloride/MeOH 98:2→95:5 to give N-(2-{1-[1-(4-Chloro-phenyl)-cyclobutyl]-3,4-dihydro-isoquinolin-7-yloxy}-ethyl)-methanesulfonamide (90.0 mg, 0.21 mmol, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([CH3:26])[C:23]([OH:25])=[O:24])=[CH:17][C:16]=2[C:27]([F:30])([F:29])[F:28])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:62]([NH:65][CH2:66][CH2:67]O)(=[O:64])[CH3:63]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([CH3:26])[C:23]([O:25][CH2:67][CH2:66][NH:65][C:62](=[O:64])[CH3:63])=[O:24])=[CH:17][C:16]=2[C:27]([F:30])([F:28])[F:29])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1
Reactant: CC(=O)NCCO
Reactant: CC(Cc1ccc(OCc2cc(Cl)cc3c2OC(C)(C)C3)c(C(F)(F)F)c1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)NCCOC(=O)C(C)Cc1ccc(OCc2cc(Cl)cc3c2OC(C)(C)C3)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A solution of 3-(4-((5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)-2-methylpropanoic acid (38) (50 mg, 0.113 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (54.3 mg, 0.169 mmol), and diisopropylethylamine (39.3 μL, 0.225 mmol) in DMF (1.5 mL) was stirred at room temperature for 30 min, then N-acetylethanolamine (23 mg, 0.226 mmol) was added. The reaction mixture was stirred at room temperature overnight. After evaporation of solvent in vacuo, the residue was purified by preparative HPLC to afford 2-acetamidoethyl 3-(4-((5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)-2-methylpropanoate (155) (45 mg, 70%). 1H NMR (400 MHz, CDCl3) δ: 7.39 (s, 1H), 7.04 (m, 2H), 7.05-7.00 (m, 2H), 5.47 (br, 1H), 5.06 (s, 2H), 4.10 (m, 2H), 3.44-3.37 (m, 2H), 3.05 (s, 2H), 2.96-2.91 (m, 1H), 2.76-2.66 (m, 2H), 1.93 (s, 3H), 1.49 (s, 6H), 1.19 (d, J=6.8 Hz, 3H). LC-MS ESI m/z: found 528.0 [M−H]−.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[I:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(OCC)(=O)C>[I:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccc(I)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1Nc1ccc(I)cc1
Reaction time: 48 h
Yield: 48.2 %

Procedure:
A mixture of 2-fluoronitrobenzene (14 g, 100 mmol), 4-iodoaniline (11 g, 50 mmol) and triethylamine (14 ml, 100 mmol) was heated under reflux. After 48 h the reaction mixture was allowed to cool and ethyl acetate (300 ml) was added. The solution was washed with water (2×100 ml), aqueous 2M potassium hydroxide (100 ml) and brine (100 ml). The organics were dried over anhydrous magnesium sulphate and the solvent removed under reduced pressure to give an orange solid. Recrystalisation from ethyl acetate gave N-(4-iodophenyl)-2-nitroaniline (8.2 g, 48%) as an orange crystalline solid. deltaH (250 MHz, CDCl3) 9.39 (1H, s), 8.21 (1H, dd, J 8.5, 1.5 Hz), 7.71 (2H, dd, J 8.6, 2.0 Hz), 7.39 (1H, m), 7.24 (1H, m), 7.05 (2H, dd, J 8.6, 1.4 Hz), 6.83 (1H, m).
Reaction SMILES: C(OC1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([NH:36][C:37](=[O:54])[CH2:38][CH:39]([NH:43][C:44]([NH:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:45])[CH2:40][CH:41]=[CH2:42])[C:14](=[O:35])[N:15]([CH2:27][CH:28](OCC)OCC)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:18]=2[O:25][CH3:26])=[CH:8][CH:7]=1)(C)(C)C.[CH:55]([OH:57])=O>>[CH2:47]([NH:46][C:44]([N:43]1[CH:39]([CH2:40][CH:41]=[CH2:42])[CH2:38][C:37](=[O:54])[N:36]2[CH:13]([CH2:12][C:9]3[CH:8]=[CH:7][C:55]([OH:57])=[CH:11][CH:10]=3)[C:14](=[O:35])[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:18]=3[O:25][CH3:26])[CH2:27][CH:28]12)=[O:45])[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: C=CCC(CC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc(OC)c1OC)CC(OCC)OCC)NC(=O)NCc1ccccc1
Reactant: O=CO
Product: C=CCC1CC(=O)N2C(Cc3ccc(O)cc3)C(=O)N(Cc3cccc(OC)c3OC)CC2N1C(=O)NCc1ccccc1
Yield: 38 %

Procedure:
A solution of crude 3-(3-Benzyl-ureido)-hex-5-enoic acid {2-(4-tert-butoxy-phenyl)-1-[(2,2-diethoxy-ethyl)-(2,3-dimethoxy-benzyl)-carbamoyl]-ethyl}-amide (3.7 g, 4.95 mmol) in formic acid (100 mL) was stirred at room temperature for 13 h. The solvent was removed under reduced pressure and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by chromatography and recrystallized on ethyl acetate and hexane to give the 2-Allyl-8-(2,3-dimethoxy-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[1,2-a]pyrimidine-1-carboxylic benzylamide (1.3 g, 3 step yield: 38%). 1H NMR (CDCl3, 300 MHz) δ 7.4˜7.26 (m, 3H), 7.2 (d, J=7.01, 2H), 6.98 (t, J=8.0, 1H), 6.85 (m, 3H), 6.8 (t, J=7.0, 1H), 6.5 (d, J=8.76, 2H), 5.6 (m, 1H), 5.25 (t, J=4.7, 1H), 5.05 (d, J=10.75, 1H) 5.0 (d, J=18.54, 1H), 4.87 (d, J=14.51, 1H), 4.55 (m, 1H), 4.5˜4.25 (m, 4H, OH), 3.82 (s, 3H), 3.66 (s, 3H), 3.5˜3.3 (m, 2H), 3.25˜3.1 (m, 2H), 2.6˜2.4 (m, 2H), 2.2 (t, J=7.2, 2H) MS ESI 599.32 (M+H), 621.38 (M+Na), 637.19 (M+K)