Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Cl:3]C1C=C(C(C2CCCCC2)CN2CCNCC2)C=CC=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]([CH:47]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)[C:32]([N:34]2[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]2)=O)[CH:28]=[CH:29][CH:30]=1>>[ClH:3].[ClH:24].[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]([CH:47]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)[CH2:32][N:34]2[CH2:35][CH2:36][NH:37][CH2:38][CH2:39]2)[CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(c2cccc(Cl)c2)C2CCCCCC2)CC1
Reactant: Clc1cccc(C(CN2CCNCC2)C2CCCCC2)c1
Agent: Cl
Product: Clc1cccc(C(CN2CCNCC2)C2CCCCCC2)c1

Procedure:
In an analogous manner to Example 1, step 2, 1-[2-(3-chlorophenyl)-2-cyclohexylethyl]piperazine dihydrochloride was prepared from tert-butyl 4-[(3-chlorophenyl)(cycloheptyl)acetyl]piperazine-1-carboxylate MS (ES) m/z 321.2; HRMS: calcd for C19H29ClN2+H, 321.20975; found (ESI, [M+H]+), 321.2105.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16]C)=[O:15])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([OH:16])=[O:15])(=[O:10])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NS(=O)(=O)c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
A mixture of methyl 2-{[(tert-butoxycarbonyl)amino]sulfonyl}benzoate 1a (400 mg, 1.3 mmol, 1 equiv) and lithium hydroxide (1.6 g, 39 mmol, 30 equiv) in tetrahydrofuran (10 mL) and water (2.5 mL) was stirred at RT for 18 h. The reaction was partially concentrated, acidified with 1N HCl and the product extracted into ethyl acetate. The organic layer was dried and concentrated to afford 2-{[(tert-butoxy carbonyl)amino]sulfonyl}benzoic acid (1b) as a white solid (200 mg, 51% yield). 1H NMR (300 MHz, DMSO) δ 7.94 (m, 1H), 7.71 (m, 3H), 1.26 (s, 9H). ES-LCMS m/z 300.08 (M−H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([O:7][CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)(=[O:18])=[O:17]
Reactant: OCc1ccco1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccco1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To the solution of furan-2-ylmethanol (500 mg, 5.1 mmol) in CH2Cl2 (10 mL) and triethylamine (1.54 g, 15.3 mmol) at 0° C. was added dropwise methanesulfonyl chloride (695 mg, 6.1 mmol). The mixture was stirred at 0° C. for 15 min and was quenched with 10 mL of water. The layers were separated and the aqueous layer was extracted with CH2Cl2 (1×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.[Br-].C([N+]1(C)[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)C1C=CC=CC=1>C(O)C.O>[CH3:7][O:8][C:9]1[CH:15]=[CH:14][C:12]([N:13]2[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)=[CH:11][CH:10]=1
Reactant: COc1ccc(N)cc1
Reactant: C[N+]1(Cc2ccccc2)CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(N2CCC(=O)CC2)cc1
Temperature: 100 °C

Procedure:
Anhydrous potassium carbonate was added to a solution of 4-methoxyaniline (1.2 g, 9.8 mmol) in ethanol (10 mL) followed by a dropwise addition of a solution of compound of example 116 (2.77 g, 9.8 mmol) in water (3.0 mL). The reaction mixture was heated at 100° C. for 1 h., allowed to cool to room temperature, poured into ice water (100 mL) and extracted using EtOAc (3×50 mL). The organic extract was washed with water, dried (anhydrous Na2SO4) and concentrated to get the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][CH:25]([CH3:27])[CH3:26])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][N:32]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[CH2:23][N:24]([CH:25]([CH3:26])[CH3:27])[C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:31]([C:30]([F:41])([F:29])[F:40])=[N:32][CH:33]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28]
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Reactant: CC(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1
Product: CC(C)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(=O)c1ccc(C(F)(F)F)nc1

Procedure:
2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol (compound 132) was coupled with 6-trifluoromethyl-nicotinic acid following procedure D2. LC-MS showed the product had the expected M+H+ of 570. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 9.5 (s, 1H)) 8.6 (d, 1H) 8.5 (s, 1H) 8.2 (d, 1H) 8.1 (s, 1H) 7.9 (m, 2H) 7.5 (m, 1H) 7.4 (m, 2H) 7.2 (s, 1H) 6.9 (d, 1H) 5.7 (s, br, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 3.1 (m, 1H) 3.0 (m, 2H) 1.2 (d, 6H).
Reaction SMILES: [CH2:1]([C:3]1([C:9]([O:11]CC2C=CC=CC=2)=[O:10])[CH2:6][C:5]([F:8])([F:7])[CH2:4]1)[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([C:3]1([C:9]([OH:11])=[O:10])[CH2:4][C:5]([F:7])([F:8])[CH2:6]1)[CH3:2]
Reactant: CCC1(C(=O)OCc2ccccc2)CC(F)(F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC1(C(=O)O)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.7 %

Procedure:
To a solution of Intermediate 301A (0.2 g, 0.787 mmol) in ethanol (5 mL) and water (1 mL) was added a 5N aq. solution of NaOH (0.787 mL, 3.93 mmol) and the reaction mixture was stirred at RT for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water and extracted with diethyl ether (3×5 mL). The pH of the aqueous solution was adjusted to 7.0 using a 2N aq. solution of HCl and the aqueous phase was extracted with DCM (3×10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford Intermediate 301B as a pale yellow liquid (50 mg, 38.7%). 1H NMR (300 MHz, DMSO-d6) δ ppm 12.63-12.75 (m, 1H), 2.80-2.97 (m, 2H), 2.57-245 (m, 2H), 1.77 (q, J=7.55 Hz, 2H), 0.81 (t, J=7.37 Hz, 3H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:17])=[C:10]([S:13](Cl)(=[O:15])=[O:14])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH3:18]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:17])=[C:10]([S:13]([NH2:18])(=[O:15])=[O:14])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(Br)c(S(=O)(=O)Cl)cc21
Reactant: N
Product: CC(=O)N1CCc2cc(Br)c(S(N)(=O)=O)cc21
Yield: 64.6 %

Procedure:
A solution of 1-acetyl-5-bromoindoline-6-sulfonyl chloride (2.30 g, 6.79 mmol) in NH3 (54.3 mL, 27.2 mmol, 0.5M solution in dioxane) was stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo, and the residue was triturated with CH2Cl2 to give the title compound (1.40 g, 65%) as a brown solid. 1H NMR (DMSO-d6) δ 8.73 (s, 1H), 7.63 (s, 1H), 7.15 (s, 2H), 4.15 (t, J=8.5 Hz, 2H), 3.19 (t, J=8.6 Hz, 2H), 2.17 (s, 3H); MS(ESI+) m/z 321.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13](=O)[NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:5])[CH3:2].O.Cl.[OH-].[Na+]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)c[nH]c1CC(=O)NCCN1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(C)c[nH]c1CCNCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
A stirred solution of 4-methyl-2-[(2-morpholin-4-yl-ethylcarbamoyl)-methyl]-1H-pyrrole-3-carboxylic acid ethyl ester (3.48 g, 10.8 mmol) in anhydrous tetrahydrofuran (20 ml) was added dropwise slowly with 1M borane-tetrahydrofuran complex in tetrahydrofuran (32.4 ml, 32.4 mmol) under an argon atmosphere. Upon completion of the addition, the mixture was stirred for 1 hour at room temperature and heated to reflux for another 5 hours. The resulting mixture was added with cold water (5 ml) and 1N hydrochloric acid (15 ml) dropwise, adjusted to pH 10 with 10% aqueous sodium hydroxide solution and extracted with ethyl acetate (10 ml×5). The combined organic extracts were washed with brine (15 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-methyl-2-[2-(2-morpholin-4-yl-ethylamino)-ethyl]-1H-pyrrole-3-carboxylic acid ethyl ester (3.08 g) as a red oil which was used as such.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[C:3]=1[I:11].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[I:11][C:3]1[C:4]2[S:8][CH:7]=[N:6][C:5]=2[CH:9]=[CH:10][C:2]=1[O:1][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1ccc2ncsc2c1I
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc4ncsc4c3I)c2cc1OC
Temperature: 140 °C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
6-Hydroxy-7-iodo-benzothiazole (210 mg), 4-chloro-6,7-dimethoxyquinoline (567 mg), and 4-dimethylaminopyridine (390 mg) were suspended in o-dichlorobenzene (15 ml), and the suspension was stirred at 140° C. for 3 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (151 mg, yield 43%).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[S:20]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1)(=[O:23])(=[O:22])[NH2:21]>>[S:20]([C:24]1[CH:25]=[CH:26][C:27]([CH2:28][NH:29][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])=[CH:30][CH:31]=1)(=[O:22])(=[O:23])[NH2:21]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Product: CCc1cc(-c2cncc(C(=O)NCc3ccc(S(N)(=O)=O)cc3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 4-sulfamoyl-benzyl-amine to afford the title compound. MS: m/e=427 (M+H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=2)[C:11]2[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=3)[C:11]3[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: CCc1cc2c(NCc3ccc(OC)c(Cl)c3)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc(OC)c(Cl)c3)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-ethyl-4-(3-chloro-4-methoxybenzylamino)-thieno[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-ethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].C(N(CC)CC)C.[CH:21]1([NH2:25])[CH2:24][CH2:23][CH2:22]1>ClCCl>[CH:21]1([NH:25][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH2:24][CH2:23][CH2:22]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NC1CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
To a solution of 2-nitrobenzene-1-sulfonyl chloride (6.8 g, 30.8 mol) in dichloromethane (100 mL) at 0° C. was added triethylamine (14 g, 138.6 mol) and cyclobutanamine (2.2 g, 31 mmol) in several portions over 10-15 minutes. The reaction mixture was stirred at room temperature for 4 hours, concentrated and purified by silica gel chromatography to afford the product N-cyclobutyl-2-nitrobenzenesulfonamide (7 g, yield 88.9%). 1H NMR (400 MHz, CDCl3) δ ppm 8.14-8.16 (m, 1H), 7.84-7.87 (m, 1H), 7.72-7.74 (m, 2H), 5.45-5.47 (d, 1H, J=8.8 Hz), 3.93-3.99 (m, 1H), 2.11-2.18 (m, 2H), 1.84-1.90 (m, 2H), 1.59-1.69 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8](O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([N:40]2[C:39](=[O:41])[C:38]3=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]3[C:36]2=[O:46])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OC(Cc1ccccn1)c1cccc(Cl)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C(Cc1ccccn1)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 128.9 %

Procedure:
38.6 g of the 1-(6-chloropyridin-2-yl)-2-(pyridin-2-yl)ethyl alcohol prepared in the Preparative Example 20, 47.8 g of triphenylphosphine and 26.8 g of phthalimide were dissolved in 500 ml of tetrahydrofuran, followed by the addition thereto of 31.7 g of diethyl azodicarboxylate. The obtained mixture was stirred at room temperature overnight and concentrated, followed by the addition thereto of diethyl ether. The obtained mixture was filtered to remove insolubles and the filtrate was purified by silica gel chromatography (with a hexane/ethyl acetate (2:1) mixture) to give 77.1 g of the title compound as a roughly purified product.
Reaction SMILES: [C:1]1(=[O:15])[C:10]2[C:5]3[C:6](=[CH:11][CH:12]=[CH:13][C:4]=3[C:3](=[O:14])[NH:2]1)[CH:7]=[CH:8][CH:9]=2.[Br:16][CH2:17][CH:18](Br)[CH2:19][CH2:20][CH3:21]>>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:2]1[C:3](=[O:14])[C:4]2[CH:13]=[CH:12][CH:11]=[C:6]3[C:5]=2[C:10](=[CH:9][CH:8]=[CH:7]3)[C:1]1=[O:15]
Reactant: CCCC(Br)CBr
Reactant: O=C1NC(=O)c2cccc3cccc1c23
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCBr

Procedure:
This compound was prepared according to GP-1 using benzo[de]isoquinoline-1,3-dione (1) and 1,2 dibromopentane (2c) The crude product was purified by flash column chromatography using EtOAc-hexane to give 3c. 1H NMR (500 MHz, CDCl3) δ 8.63 (d, J=7.5 Hz 2H), 8.24 (d, J=8.0 Hz, 2H), 7.78 (t, J=7.5 Hz, 2H), 4.22 (t, J=7.0, 2H), 3.45 (t, J=7.0 Hz, 2H), 2.01-1.94 (m, 2H), 1.84-1.78 (m, 2H), 1.64-1.57 (m, 2H), MS (ES+) m/z 368 (M+Na)+.
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH2:38][S:39][CH2:40][C@H:41]([O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])[CH2:42][O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:20](=[O:37])[NH:21][C@@H:22]([CH2:35][CH3:36])[C:23](=[O:34])[NH:24][C@@H:25]([C:31](=[O:33])[NH2:32])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(#N)C>[NH2:18][C@@H:19]([CH2:38][S:39][CH2:40][C@H:41]([O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])[CH2:42][O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:20](=[O:37])[NH:21][C@@H:22]([CH2:35][CH3:36])[C:23](=[O:34])[NH:24][C@@H:25]([C:31](=[O:33])[NH2:32])[CH2:26][CH2:27][C:28]([OH:30])=[O:29]
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CC)C(=O)N[C@H](CCC(=O)O)C(N)=O)OCCCCCCCCCCCCCCCC
Solvent: C1CCNCC1
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)N[C@@H](CC)C(=O)N[C@H](CCC(=O)O)C(N)=O)OCCCCCCCCCCCCCCCC
Reaction time: 0.5 h

Procedure:
A solution (4R,7S,10R,14R)-10-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-carbamoyl-7-ethyl-14-(hexadecyloxy)-6,9-dioxo-16-oxa-12-thia-5,8-diazadotriacontan-1-oic acid in acetonitrile (0.1M) was stirred at room temperature. Piperidine (final conc. 20%) was then added and the reaction stirred for 30 min. After concentration, the product was purified by flash chromatography on an ISCO COMBIFLASH® system using a 0-10% MeOH/DCM gradient to give (4R,7S,10R,14R)-10-amino-4-carbamoyl-7-ethyl-14-(hexadecyloxy)-6,9-dioxo-16-oxa-12-thia-5,8-diazadotriacontan-1-oic acid. 1H NMR (DMSO d-6): δ 12.12 (br, s, 1H), 8.56 (d, 1H), 8.14 (t, 2H), 8.12 (d, 1H), 7.25 (s, 1H), 7.05 (s, 1H), 4.21-4.34 (m, 2H), 3.95-3.97 (m, 1H), 3.44-3.52 (m, 3H), 3.32-3.40 (m, 3H), 2.96 (dd, 1H), 2.66-2.78 (m, 4H), 2.19 (t, 2H), 1.89-1.98 (m, 2H), 1.67-1.76 (m, 4H), 1.56-1.64 (m, 2H), 1.42-1.50 (m, 4H), 1.21-1.28 (m, 48H), 0.83-0.89 (m, 9H). LRMS [M+H]=857.7.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@@H:33]6[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:50]([O:52][CH:53]([CH3:55])[CH3:54])=[O:51]>>[Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@@H:33]6[CH2:38][CH2:37][C@H:36]([NH:39][C:50](=[O:51])[O:52][CH:53]([CH3:55])[CH3:54])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](N)CC4)cc3)nc2n1COCC[Si](C)(C)C
Reactant: CC(C)OC(=O)Cl
Product: CC(C)OC(=O)N[C@H]1CC[C@@H](c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O[Si](C)(C)C(C)(C)C)n4COCC[Si](C)(C)C)cc2)CC1

Procedure:
The title compound is prepared from (cis)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanamine and isopropyl chloroformate following a procedure analogous to that described for Intermediate 8.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[CH2:4][C:5]#[N:6].[CH2:13]([N:20]=[N+:21]=[N-:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(C)([O-])C.[K+]>O1CCCC1.O>[C:14]1([CH2:13][N:20]2[C:5]([NH2:6])=[C:4]([C:3]3[C:7]([CH3:12])=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=3[CH3:1])[N:22]=[N:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(-c2nnn(Cc3ccccc3)c2N)c(C)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 60.8 %

Procedure:
A mixture of 2,4,6-trimethylbenzyl cyanide (1.0 g, 6.3 mmol), benzyl azide (0.92 g, 6.9 mmol) and potassium t-butoxide (0.78 g, 6.9 mmol) in tetrahydrofuran (10 mL) was stirred at ambient temperature for 2.5 days. The resulting suspension was diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4 and filtered. Solvent was removed in vacuo to give a brown oil. Trituration with ether and filtration afforded a yellow solid (1.12 g, 61% yield): NMR (CDCl3,300 MHz):7.60–7.30 (m, 5H), 7.30–7.20 (m, 2H), 5.50 (s, 2H), 3.18 (br s, 2H), 2.30 (s, 3H), 2.10 (s, 6H); CI-MS: 293 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH2:16]S[CH2:14][CH2:13]1.[O:18]1CCCC1>[Ni].O>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH2:16][O:18][CH2:14][CH2:13]1)[NH2:8]
Reactant: C1CCOC1
Reactant: O=[N+]([O-])c1cc(F)c(N2CCSCC2)c(F)c1
Agent: [Ni]
Solvent: O
Product: Nc1cc(F)c(N2CCOCC2)c(F)c1
Reaction time: 24 h

Procedure:
A solution of 4-(2,6-difluoro-4-nitrophenyl)thiomorpholine (3.00 g, 11.5 mmol) in tetrahydrofuran (60 mL) was added to a Parr bottle containing a mixture of Raney nickel (1 g) in water (15 mL) under N2, and the reaction mixture was shaken on a Parr apparatus under a hydrogen atmosphere at 40 psi for 24 hrs. The catalyst was removed by filtration through Celite, rinsing with tetrahydrofuran and water, the filtrate was diluted with water (50 mL) and EtOAc (50 mL), and the layers were separated. The organic phase was washed with saline (25 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting oil was chromatographed on a Flash 40M 90 g silica gel cartridge eluting with EtOAc/heptane (15/85). Pooling and concentration of those fractions with an Rt=0.19 by TLC (EtOAc/hexanes, 25/75) gave the title compound, mp 85-86° C.; MS (ESI+) for C10H12N2F2S m/z 231 (M+H)+.
Reaction SMILES: [C@H]1(C[N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:14][CH2:13]2)[C@@H]2N(CCCC2)CCC1.[ClH:43].Cl.Cl.NC1CCN([CH2:53][CH2:54][N:55]2[CH2:60][CH2:59][C@H:58]([OH:61])[C@@H:57]([CH3:62])[CH2:56]2)CC1>>[ClH:43].[ClH:43].[OH:61][C@H:58]1[CH2:59][CH2:60][N:55]([CH2:54][CH2:53][N:12]2[CH2:13][CH2:14][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:16][CH2:17]2)[CH2:56][C@@H:57]1[CH3:62]
Reactant: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O
Reactant: COc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)coc2c1
Agent: Cl
Product: COc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized from 4-(6-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (120, see example 86) and amine 14 analogously to the method described in example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([OH:14])=[C:12]([CH:15]=O)[C:11]([CH3:17])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH:18][C:19]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:20]=1[C:21]([NH:23][NH2:24])=[O:22]>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[CH:15][NH:24][NH:23][C:21](=[O:22])[C:20]3[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:19]=3[OH:18])[C:11]([CH3:17])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: NNC(=O)c1ccc(O)cc1O
Reactant: Cc1ccc(-n2nc(C)c(C=O)c2O)cc1C
Solvent: CCO
Product: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=CNNC(=O)c1ccc(O)cc1O
Yield: 69.7 %

Procedure:
46 mg (0.2 mmol) of the 1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-carbaldehyde synthesized in 1) and 34 mg (0.20 mmol) of 2,4-dihydroxybenzoic hydrazide were stirred in 1 ml of ethanol at room temperature for 96 hours. The precipitated solid was collected by filtration and washed with 1 ml of ethanol, 1 ml of ether and 1 ml of methanol successively to obtain 53 mg of the desired product (yield 70%).