Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH:13]=[CH2:14])=[C:11]2[CH2:15][N:16]([CH:19]([CH3:21])[CH3:20])[C:17](=[O:18])[C:10]2=[N:9]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH:13]=[CH:14][C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)=[C:11]2[CH2:15][N:16]([CH:19]([CH3:21])[CH3:20])[C:17](=[O:18])[C:10]2=[N:9]1
Reactant: Clc1ccc(I)cc1
Reactant: C=Cc1c2c(nn1-c1ccccc1Cl)C(=O)N(C(C)C)C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)N1Cc2c(nn(-c3ccccc3Cl)c2C=Cc2ccc(Cl)cc2)C1=O

Procedure:
To a stirred solution of 2-(2-chloro-phenyl)-5-isopropyl-3-vinyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one 1A-8 (42 mg), palladium acetate (3 mg) and 4-chloroiodobenzene (300 mg) were stirred for 18 hours. The reaction was concentrated and chromatographed on silica gel (gradient 30% to 60% ethyl acetate/hexanes) to afford the title compound (1A-39), 44 mg. 1H NMR in d6-DMSO (ppm): δ 7.78 (d, 1H), 7.63-7.38 (m, 5H), 7.13 (d, 1H), 6.61 (d, 1H), 4.62 (s, 2H ), 4.40 (m, 1H), 1.23 (d, 6H); ms (LCMS) m/z=412.3 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[C:12]1[C:13]2[N:14]([C:19]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][C:26]=3[F:31])=[O:23])=[CH:20][N:21]=2)[N:15]=[C:16]([Cl:18])[CH:17]=1>C1COCC1.CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:12]2[C:13]3[N:14]([C:19]([C:22]([NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][C:26]=4[F:31])=[O:23])=[CH:20][N:21]=3)[N:15]=[C:16]([Cl:18])[CH:17]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Reactant: Nc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccncc1F)c1cnc2c(Nc3cccc(Br)n3)cc(Cl)nn12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a solution of 6-bromopyridin-2-amine (1.24 g, 7.17 mmol) in THF (10.00 mL) was added 60% NaH (294 mg, 7.35 mmol). The mixture was stirred for 30 min until cessation H2 evolution. The resulting dark green solution was added by syringe to a suspension of 8A (800 mg, 2.453 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature overnight, and then added to ice water. The brown solid was collected by filtration and dried under vacuum to give 17A (1.125 g, 89%) MS (m+1)=462. HPLC Peak Rt=3.696 minutes (Chromolith column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=O.[OH-].[Na+].[CH3:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[O:25][CH3:26])=[O:16].Cl>C(O)C.O>[CH3:26][O:25][C:18]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:17]=1[C:15](=[O:16])[CH:14]=[CH:1][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: COc1ccc(OC)c(C(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(OC)c(C(=O)C=Cc2cccc(C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a solution of 3-formylbenzoic acid (2.0 g, 13.3 mmol) and sodium hydroxide (1.32 g, 33 mmol) in 400 mL of ethanol/water (1:1) is added 2,5-dimethoxyacetophenone (2.4 g, 13.3 mmol) and the resulting solution is stirred overnight at room temperature. The mixture is acidified with concentrated hydrochloric acid and the resulting solid is collected by filtration after diluting the mixture with water (200 mL) to provide 2.9 g of the title compound; mp 152°-155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[N+:12]=[N-:13])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[C:15]#[CH:16]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:12]([N:13]=[C:15]([C:14]([O:18][CH2:19][CH3:20])=[O:17])[CH:16]=3)[C:7](=[O:11])[N:8](/[CH:16]=[CH:15]\[C:14]([O:18][CH2:19][CH3:20])=[O:17])[C:9]=2[CH:10]=1
Reactant: [N-]=[N+]=C1C(=O)Nc2cc(Cl)ccc21
Reactant: C#CC(=O)OCC
Solvent: Cc1ccccc1C
Product: CCOC(=O)/C=C\n1c(=O)n2nc(C(=O)OCC)cc2c2ccc(Cl)cc21
Temperature: 25 °C
Yield: 59 %

Procedure:
7.5 g (0.039 mole) of 6-chloro-3-diazooxindole is suspended in 400 ml of xylene and 8.4 g (0.086 mole) of ethyl propiolate added. The reaction mixture is heated 7 hours in a 160° silicone oil bath under nitrogen. A brown solid forms on cooling to room temperature (9.0 g, 59% yield). Recrystallization from dichloromethanemethanol gives 8.5 g of analytically pure title compound, m.p. 215°-217°.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]3[C:19]([NH2:23])=[N:20][CH:21]=[CH:22][C:17]=3[S:16][CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:24]N1C(=O)CCC1=O>CN(C=O)C>[I:24][C:22]1[C:17]2[S:16][CH:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:13][CH:12]=3)[C:18]=2[C:19]([NH2:23])=[N:20][CH:21]=1
Reactant: Nc1nccc2scc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Nc1ncc(I)c2scc(-c3ccc(Oc4ccccc4)cc3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
A solution of Example 219B (5 g, 15.7 mmol) in DMF (100 mL) was treated with N-iodosuccinimide (4.23 g, 18.8 mmol), stirred at ambient temperature for 2 hours, concentrated to half the original volume, and poured into 5% sodium thiosulfate (400 mL). The mixture was filtered and the filter cake was washed with water and dried. The solids were dissolved in dichloromethane (300 mL), treated with silica gel (80 g), and concentrated. The residue was transferred to a silica gel column (600 g) and chromatographed with ethyl acetate/heptane (1:6) to provide 5.2 g (75%) of the desired product. 1H NMR (CD2Cl2, 400 MHz) δ 7.95 (s, 1H), 7.33–7.29 (m, 4H), 7.12 (s, 1H), 7.10 (t, 1H), 7.02–6.99 (m, 4H), 4.76 (br s, 1H); 13C NMR (CD2Cl2, 400 MHz) δ 158.4, 156.8, 154.7, 154.4, 148.6, 138.4, 131.3, 131.2, 130.4, 124.4, 122.9, 120.0, 119,9, 118.8, 72.0.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.C(O)(=[O:15])C>C(OCC)C.O>[O:8]1[C:9]2[C:4](=[CH:3][C:2]([CH:1]=[O:15])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]1=[O:12]
Reactant: CC(=O)O
Reactant: Cc1ccc2oc(=O)ccc2c1
Solvent: O
Solvent: CCOCC
Product: O=Cc1ccc2oc(=O)ccc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
6-Methylcoumarin (400 mg, 2.50 mmol) was dissolved in 1.0 mL of diethyl ether, 1.0 mL of acetic acid, and 1.0 mL of water. After addition of ceric ammonium nitrate (5.5 g, 1.0 mmol) at room temperature, the reaction mixture was stirred at 100° C. for 1 h. The resulting mixture was diluted with water, and the solution was extracted with ethyl acetate. The extract was washed with water, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=75/25 to 50/50) to obtain the title compound as a pale yellow powder (80 mg, 18%).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:23])([CH2:17][CH2:18]1)[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.[BrH:24]>C(Cl)(Cl)Cl>[Br:24][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:23])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C
Reactant: Br
Solvent: ClC(Cl)Cl
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](Br)C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2α, 3α-Epoxy-5α-pregnan-20-one (356 mg.) was dissolved in chloroform (20 ml.) and hydrobromic acid (48%, 7 ml.) was added. The mixture was stirred at room temperature for 30 minutes and then poured into chloroform (100 ml.). The organic solution was washed with dilute sodium bicarbonate solution and with water, then dried over sodium sulphate and evaporated to give a crystalline residue which was recrystallised from ethyl acetate containing some ether to give title compound (144 mg.) as colourless needles m.p. 171°-175°, [α]D + 117°.
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:10]1[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=[C:2]1[Br:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Product: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccccc1

Procedure:
8-Bromo-3-methyl-3,7-dihydropurine-2,6-dione and benzyl bromide were reacted and purified as described in the General procedure G, step A, to afford 77A.
Reaction SMILES: [O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([OH:12])=O)[CH2:7][C:6]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][C:20]3[N:21]=[C:22]4[N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25][CH2:24][N:23]4[CH:35]=3)=[CH:16][C:5]=2[CH2:4][N:3]1[CH2:36][C:37]([F:40])([F:39])[F:38].[CH2:41]([OH:48])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].[ClH:49].O1CCOCC1>>[ClH:49].[O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([O:48][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:12])[CH2:7][C:6]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][C:20]3[N:21]=[C:22]4[NH:27][CH2:26][CH2:25][CH2:24][N:23]4[CH:35]=3)=[CH:16][C:5]=2[CH2:4][N:3]1[CH2:36][C:37]([F:38])([F:39])[F:40]
Reactant: CC(C)(C)OC(=O)N1CCCn2cc(CCOc3ccc4c(c3)CN(CC(F)(F)F)C(=O)[C@H](CC(=O)O)C4)nc21
Reactant: CCCCCCCO
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCCCOC(=O)C[C@@H]1Cc2ccc(OCCc3cn4c(n3)NCCC4)cc2CN(CC(F)(F)F)C1=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
70.0 mg (0.124 mmol) of (4S)-3-oxo-8-[2-(8-tert-butoxycarbonyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidin-2-yl)ethoxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetic acid obtained in Example 5-(a) and 88 μL (0.62 mmol) of heptyl alcohol were mixed, 1.55 mL (6.20 mmol) of 4N hydrogen chloride/1,4-dioxane solution was added to the mixture, and the resulting mixture was stirred under nitrogen gas atmosphere at 50° C. for 4 hours.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: COCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f28) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH2:37].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH:37][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:32])[F:1])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:29]
Reactant: NCc1ccccc1Cl
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1Cl)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with 2-chlorobenzylamine (16 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was concentrated, the residue was suspended in water, and the solid was collected by vacuum filtration to afford 48 mg of the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[C:27]1([CH:37]=O)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:37][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Reactant: O=Cc1cccc2ccccc12
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2cccc3ccccc23)CC1
Yield: 59.6 %

Procedure:
4-Amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (2.1 g) as starting compound and 1-naphthaldehyde (1.13 g) were reacted and treated in the same manner as in Example 121 to give 1.71 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(1-naphthylmethylamino)pentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([NH2:14])[CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[O:7])([CH3:4])(C)C.Cl[C:16](OCC=C)=O>ClCCl.C(N(C(C)C)CC)(C)C>[CH2:1]([O:5][C:6]([CH:8]([NH2:14])[CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[O:7])[CH:4]=[CH2:16]
Reactant: C=CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)C(N)CCCCN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)C(N)CCCCN
Temperature: 0 °C

Procedure:
Mono-t-butyloxycarbonyl (BOC) 1,5-pentanediamine was synthesized by using 1,5-diaminopentane (12.5 g, 122 mmol) in place of 1,3-diaminopropane in the synthesis of mono-allyloxycarbonyl-1,3-diaminopropane described in Example 1 above, yielding 10 g (49 mmol) of mono-tert-butyloxycarbonyl-1,5-diaminopentane (1). The mono-tert-butyloxycarbonyl-1,5-diaminopentane (1) (5.8 g, 28.7 mmol) was dissolved in 75 mL of dichloromethane with 7.5 mL of diisopropylethylamine and cooled to 0° C. A solution of allyl chloroformate (3.3 mL) in dichloromethane (25 mL) was added over five minutes. The reaction was allowed to warm to room temperature for one hour and then solvent was removed by rotary evaporation. The residue was dissolved in 100 mL of ethyl acetate and washed with three 100 mL portions of 10% citric acid, once with 100 mL saturated aqueous sodium bicarbonate and once with 100 mL of saturated aqueous sodium chloride. The organic phase was dried over magnesium sulfate and solvent was removed by rotary evaporation. The resulting oil (2) was treated with 25 mL of trifluoroacetic acid for 30 minutes. The trifluoroacetic acid was removed by rotary evaporation and the resulting reside was twice dissolved in dichloromethane and then evaporated to remove residual solvent. The residue was dissolved in 50 mL of 3N hydrochloric acid and washed with two 50 mL portions of dichloromethane. The aqueous phase was cooled in an ice bath and the pH was adjusted to approximately 13 with 50% aqueous sodium hydroxide. The basic aqueous phase was extracted with three 100 mL portions of dichloromethane, the combined organics were washed with 100 mL of saturated aqueous sodium chloride and then dried over potassium carbonate. The mixture was filtered, the solvent removed first by rotary evaporation and then by high vacuum to yield 3.95 g of mono-allyloxycarbonyl-1,5-diaminopentane (3) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:10](=[O:11])[CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:16][CH:15]=1
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: Nc1ccc(F)cc1
Product: COc1cccc(CC(=O)Nc2ccc(F)cc2)c1
Yield: 97.9 %

Procedure:
The title compound was prepared as described in Example 1.A, using 3-methoxyphenylacetyl chloride (3.29 g, 18.0 mmol) and 4-fluoroaniline (1.98 g, 18.0 mmol) to afford the title compound (4.57 g, 98% yield): ES-MS (m/z) 259.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1>CC(=O)CC>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][CH2:14][CH2:13][CH2:19][S:16]([OH:18])(=[O:17])=[O:15]
Reactant: COc1cccc(CN)c1OC
Reactant: O=S1(=O)CCCO1
Solvent: CCC(C)=O
Product: COc1cccc(CNCCCS(=O)(=O)O)c1OC
Temperature: 25 °C

Procedure:
To a solution of 2,3-dimethoxybenzylamine (2.2 mL, 15.0 mmol) in 2-butanone (20 mL) was added 1,3-propane sultone (1.97 g, 15.8 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. The crude product was suspended in 90% Acetone/MeOH (75 mL). The suspension was stirred at reflux for 30 seconds, the solid was collected by filtration, and dried in vacuo; affording compound AZ, 1.95 g (45%).
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.[O:66]=[C:67]([N:80]1[C@H:88]([C:89]2[NH:90][C:91]([C:94]3[CH:103]=[CH:102][C:101]4[C:96](=[CH:97][CH:98]=[C:99]([C:104]5[CH:109]=[CH:108][C:107]([C:110]6[NH:114][C:113]([C@@H:115]7[CH2:119][CH2:118][CH2:117][NH:116]7)=[N:112][CH:111]=6)=[CH:106][CH:105]=5)[CH:100]=4)[CH:95]=3)=[CH:92][N:93]=2)[CH2:87][C:82]2([O:86][CH2:85][CH2:84][O:83]2)[CH2:81]1)[C@@H:68]([NH:75][C:76](=[O:79])[O:77][CH3:78])[CH:69]1[CH2:74]COC[CH2:70]1.Cl>>[CH3:60][O:59][C:57](=[O:58])[NH:56][CH:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:48]([N:116]1[CH2:117][CH2:118][CH2:119][C@H:115]1[C:113]1[NH:114][C:110]([C:107]2[CH:106]=[CH:105][C:104]([C:99]3[CH:98]=[CH:97][C:96]4[C:101](=[CH:102][CH:103]=[C:94]([C:91]5[NH:90][C:89]([C@@H:88]6[CH2:87][C:82]7([O:86][CH2:85][CH2:84][O:83]7)[CH2:81][N:80]6[C:67](=[O:66])[C@@H:68]([NH:75][C:76]([O:77][CH3:78])=[O:79])[CH:69]([CH3:70])[CH3:74])=[N:93][CH:92]=5)[CH:95]=4)[CH:100]=3)=[CH:109][CH:108]=2)=[CH:111][N:112]=1)=[O:61]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc4cc(-c5ccc(-c6cnc([C@@H]7CCCN7)[nH]6)cc5)ccc4c3)[nH]1)OCCO2)C1CCOCC1
Agent: Cl
Product: COC(=O)NC(C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H]6CC7(CN6C(=O)[C@@H](NC(=O)OC)C(C)C)OCCO7)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1

Procedure:
Title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(6-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3× HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3× HCl salt. MS (ESI) m/z 881.90 [M+H]+. (14 mg, 16%).
Reaction SMILES: [C:1]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:16][O:17]S(C)(=O)=O)=[CH:9][CH:8]=1)([O:3][CH2:4][CH3:5])=[O:2].[Cl:34][C:35]1[CH:36]=[C:37](O)[CH:38]=[CH:39][CH:40]=1>>[Cl:34][C:35]1[CH:40]=[C:39]([CH:38]=[CH:37][CH:36]=1)[O:17][CH2:16][CH:15]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([I:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:8][CH:9]=1)=[O:33]
Reactant: Oc1cccc(Cl)c1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(I)cc2)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2cccc(Cl)c2)NS(=O)(=O)c2ccc(I)cc2)cc1
Yield: 66.9 %

Procedure:
The procedure described in Example 125 was repeated, except that (RS)-N-(4-(carbethoxymethyl)phenyl)-2-(4-iodobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (380 mg) was reacted with 3-chlorophenol (160 mg) to obtain (RS)-3-(3-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-iodobenzenesulfonylamino)propanamide (267.88 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[CH:13](B1OB(C=C)OB(C=C)O1)=[CH2:14].C([O-])([O-])=O.[K+].[K+].O>COCCOC.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>[CH:13]([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1)=[CH2:14]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: O=C1NCCc2ccc(Br)cc21
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: O
Product: C=Cc1ccc2c(c1)C(=O)NCC2
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 7-bromo-3,4-dihydro-1(2H)-isoquinolinone (0.679 g, 3.004 mmol) and tetrakis(triphenylphosphine)palladium(0) (174 mg, 0.150 mmol) in 1,2-dimethoxyethane (30 ml) was stirred at room temperature for 0.5 h before addition of 2,4,6-trivinylcyclotriboroxane.pyridine complex (for a synthesis see Kerins, Fergal; O'Shea, Donal F. J. Org. Chem. (2002), 67(14), 4968) (295 mg, 1.218 mmol), K2CO3 (415 mg, 3.004 mmol) and water (10 ml). The reaction was heated at reflux for 1.5 h before cooling to room temperature and addition of water (50 ml). The mixture was extracted with 10% methanol/dichloromethane (3×100 ml), the organic layers were dried with magnesium sulphate and evaporated. Chromatography on silica, eluting with 0-100% ethyl acetate/hexane, gave the product (456 mg, 88%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1.C[O:14][C:15]([CH:17]1[CH2:19][CH:18]1[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=1)=[O:16]>>[F:27][C:22]1[CH:21]=[C:20]([CH:18]2[CH2:19][CH:17]2[C:15]([OH:16])=[O:14])[CH:25]=[CH:24][C:23]=1[O:26][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1
Reactant: COC(=O)C1CC1c1ccc(O)c(F)c1
Reactant: CC(C)Sc1cccc(CCl)n1
Product: CC(C)Sc1cccc(COc2ccc(C3CC3C(=O)O)cc2F)n1
Yield: 93 %

Procedure:
2-Chloromethyl-6-isopropylsulfanyl-pyridine (0.029 g, 0.14 mmol) obtained in Step C of Preparation Example 16 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar) (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 64 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.048 g, 93%).