Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#CC3C=CC(CC(OC)=O)=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C1C=CC(I)=CC=1)C.C(N([CH2:48][CH3:49])CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:9]2([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:11][CH2:10]2)=[C:48]([CH3:49])[CH:18]=1)#[CH:17]
Reactant: CCN(CC)CC
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCOC(=O)c1ccc(I)cc1
Product: C#Cc1ccc(C2(OCc3ccccc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3-methyl-benzene (Intermediate 76, 90.0 mg, 0.34 mmol) and ethyl-4-iodo benzoate (Reagent A, 95.0 mg, 0.34 mmol) in triethylamine (6 mL) was treated with copper(I)iodide (23.0 mg, 0.12 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (80 mg, 0.11 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 68.0 mg (54%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[CH:14][N:4]2[N:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([CH2:18][CH2:17][CH2:16][NH:15][C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]3=[N:12][N:13]=[CH:14][N:4]3[N:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Clc1nn2cnnc2c2c1CCCC2
Reactant: NCCCN1CCCC1
Product: c1nnc2c3c(c(NCCCN4CCCC4)nn12)CCCC3

Procedure:
A solution of 5.0 g of 6-chloro-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine in 25 ml of 1-(3-aminopropyl)pyrrolidine was heated at reflux for 15 hours. Excess amine was removed by distillation and the resulting residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and concentrated. The brown residue obtained was triturated with ether and the resulting solid was recrystallized from toluene to give 6-[3-(1-pyrrolidinyl)propylamino]-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine melting at about 169°-171° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[CH3:33]C1(C)CC=C(OS(C(F)(F)F)(=O)=O)C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC1=2>>[CH3:32][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:33])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 1), 250.0 mg (0.522 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-2-naphthalenyl)ethynyl]benzoate (Compound G) was converted into the title compound (colorless solid) using 249.0 mg (1.827 mmol) of zinc chloride, 24 mg (0.02 mmol) of tetrakis(triphenylphosphine)palladium(0) in 2.0 ml of THF, and 4-ethylphenyl lithium (prepared by adding 167.7 mg (1.54 ml, 2.62 mmol) of tert-butyllithium (1.7M solution in pentane) to a cold solution (−78° C.) of 244.0 mg (1.305 mmol) of 4-ethylbromobenzene in 2.0 ml of THF). 1H NMR (CDCl3): δ 7.99 (2H, d, J=8.4 Hz), 7.51 (2H, d, J=8.4 Hz), 7.42-7.24 (7H, m), 5.99 (1H, t, J=4.7 Hz), 4.37 (2H, q, J=7.1 Hz), 2.71 (2H, q, J=7.6 Hz), 2.35 (2H, d, J=4.7 Hz), 1.39 (3H, t, J=7.1 Hz), 1.34 (6H, s).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:11]1[CH:12]=[C:13]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:14]([O:28][CH3:29])=[C:15]([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([OH:26])[CH:20]=2)[CH:16]=1)([CH3:10])([CH3:9])[CH3:8].Cl[C:36]1[N:41]=[CH:40][N:39]=[C:38]([C:42]([N:44]2[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]2)=[O:43])[CH:37]=1.O>CN(C)C=O>[C:7]([C:11]1[CH:12]=[C:13]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:14]([O:28][CH3:29])=[C:15]([NH:17][C:18]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH:20]=2)[O:26][C:36]2[N:41]=[CH:40][N:39]=[C:38]([C:42]([N:44]3[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]3)=[O:43])[CH:37]=2)=[O:27])[CH:16]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: COc1c(NC(=O)c2ccc(C)c(O)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cl)ncn2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(NC(=O)c2ccc(C)c(Oc3cc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)ncn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 144 h

Procedure:
75 mg potassium-tert-butoxide are added at ambient temperature under an argon atmosphere to 225 mg N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-3-hydroxy-4-methyl-benzamide in 3 ml N,N-dimethylformamide. After ten minutes 210 mg tert-butyl 4-(6-chloro-pyrimidin-4-carbonyl)-piperazine-1-carboxylate are added, and the reaction mixture is stirred for six days at ambient temperature. For working up the reaction mixture is mixed with water and extracted with ethyl acetate. The combined ethyl acetate extracts are washed with saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with cyclohexane/ethyl acetate (50:50→20:80).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C@H:6]([NH2:15])[CH2:7][C:8]([CH2:13][F:14])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C@H:6]([NH2:15])[CH2:7][C@:8]([CH2:13][F:14])([CH3:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: CC1(CF)C[C@@H](N)c2ccc(Cl)cc2O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@]1(CF)C[C@@H](N)c2ccc(Cl)cc2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.4 %

Procedure:
A solution of (4R)-7-chloro-2-(fluoromethyl)-2-methylchroman-4-amine (2.21 g, 9.62 mmol) in THF (10 ml) was cooled to 0° C. Lithium bis(trimethylsilyl)amide (1M in THF, 20.2 mL, 20.2 mmol) was added slowly and the reaction was warmed to room temperature. After 4 hours, the reaction mixture was diluted with EtOAc (200 mL) and washed with 2N NaOH (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was purified on SiO2 (3% MeOH/EtOAc) to give the title compound (715 mg, 32%). MS (ESI+) M/Z 230 (M+H)+
Reaction SMILES: [S:1]1[C:5]([CH2:6][OH:7])=[CH:4][N:3]=[CH:2]1.[C:8]([Si:12](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:11])([CH3:10])[CH3:9].N1C=CN=C1.O>ClCCl>[C:8]([Si:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[O:7][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1cncs1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1cncs1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2.12 g of 1,3-thiazol-5-ylmethanol in 48 ml of dichloromethane were added 5.2 ml of tert-butyl (chloro)diphenylsilane and 2.5 g of imidazole at 0° C., followed by stirring at room temperature for 15 hours. To the reaction mixture was added water, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 6.47 g of 5-({[tert-butyl (diphenyl)silyl]oxy}methyl)-1,3-thiazole.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8][NH:7][CH2:6]1.[OH-].[NH4+]>C(O)(=O)C>[CH2:22]([O:21][C:19]([C:9]1[C:10]2[NH:11][C:12]3[CH:13]=[C:14]([N+:1]([O-:4])=[O:2])[CH:15]=[CH:16][C:17]=3[C:18]=2[CH2:5][CH2:6][NH:7][CH:8]=1)=[O:20])[CH3:23]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)C1=CNCCc2c1[nH]c1cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 8.3 %

Procedure:
A solution of nitric acid (90%, 50 μL, 1 mmol) in acetic acid (3 mL) was added dropwise to a stirred solution of ethyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (256 mg, 1 mmol) in acetic acid (5 mL) at 10° C. The mixture was allowed to warm to ambient temperature and stirred for another 1.5 hours, then poured into a mixture of ammonium hydroxide and ice and extracted with DCM. The combined extracts was washed with brine, dried with sodium sulfate, and evaporated in vacuo. The crude product was purified by chromatography on silica gel eluting with hexane-EtOAc (75:25) to give 8-nitro-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (25 mg); 1H-NMR (CDCl3): δ 11.52 (1H, s), 8.78 (1H, d), 8.43 (1H, m), 7.92 (1H, d), 7.82 (1H, dd), 7.46 (1H, d), 4.24 (2H, q), 3.52 (2H, m), 3.07 (2H, m), 1.27 (3H, t); MS (ES): 301 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[C:30]2[CH3:34])[N:25]=[N:26][CH:27]=1>>[ClH:21].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:22]2[CH:23]=[C:24]([CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[C:30]3[CH3:34])[N:25]=[N:26][CH:27]=2)=[CH:4][C:3]=1[C:17]([F:18])([F:19])[F:20]
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: CC1(C)OB(c2ccc(F)c(C(F)(F)F)c2)OC1(C)C
Product: Cc1nccn1Cc1cc(-c2ccc(F)c(C(F)(F)F)c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=337.2 (M+H+), was prepared from 2-(4-fluoro-3-trifluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-ylmethyl)-pyridazine.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)[CH:2]=[CH2:3].[CH2:9]([Cl:12])[CH:10]=[CH2:11].C1(C)C=CC=CC=1>C(#N)C>[Cl-:12].[CH2:1]([N+:4]1[CH:8]=[CH:7][N:6]([CH2:11][CH:10]=[CH2:9])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCn1ccnc1
Reactant: C=CCCl
Solvent: Cc1ccccc1
Solvent: CC#N
Product: C=CCn1cc[n+](CC=C)c1
Product: [Cl-]
Temperature: 70 °C
Reaction time: 24 h
Yield: 78.3 %

Procedure:
An acetonitrile 2.0 mL solution of 1-allylimidazole (1.0 mL: 0.009 mol) was made, and allyl chloride (2.25 mL: 0.028 mol) was added dropwise thereto. Subsequently, this solution was heated at 70° C. and stirred for 24 hours. The acetonitrile was distilled off to give a pale brown viscous liquid. This was added dropwise to 150 mL of toluene, and a viscous liquid that separated out was recovered and dried. The same procedure was repeated once more. The viscous liquid thus obtained was made into an acetonitrile solution, active carbon that had been heated and vacuum-dried was added thereto, and stirring was carried out for about 48 hours. After the acetonitrile was distilled off, the viscous liquid was recovered with dichloromethane, and the solvent was distilled off. The 1,3-diallylimidazolium chloride thus obtained was a liquid at room temperature, the amount collected was 1.33 g (yield; 78.3%), the glass transition temperature (Tg) was −59.9° C., and the ionic conductivity at 30° C. was 0.0773 mS/cm. The results are given in Table 1. The structure was confirmed by 1H-NMR measurement. The results are shown below.
Reaction SMILES: C(N(CC)CC)C.O1CCCC1.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(N1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42])(OCC)=O>O>[C:23]([O:22][C:20]([N:17]1[CH2:16][CH2:15][CH:14]([N:13]2[C:36](=[O:37])[C:35]3[C:34](=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:33]2=[O:42])[CH2:19][CH2:18]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.4 %

Procedure:
16.7 ml of triethylamine was added to 200 ml of a tetrahydrofuran solution containing 16 g of 4-amino-1-tert-butoxycarbonylpiperidine and 17.5 g of N-carboethoxyphthalimide under ice-cooling, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was suspended in ether-hexane, and crystals were collected by filtration to obtain 25.7 g of 2-(1-tert-butoxycarbonyl-4-piperidyl)isoindoline-1,3-dione.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=5)[C:33]([OH:35])=O)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.COC1C=CC(CN(CC2C=CC(OC)=CC=2)C2N=CC(C3C4CCN(C5C=CC(C(O)=O)=CC=5)C=4N=C(N4CCOCC4)N=3)=CN=2)=CC=1.[NH2:99][CH2:100][CH2:101][N:102]1[CH2:107][CH2:106][O:105][CH2:104][CH2:103]1>>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:49][CH:48]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=5)[C:33]([NH:99][CH2:100][CH2:101][N:102]5[CH2:107][CH2:106][O:105][CH2:104][CH2:103]5)=[O:35])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:41][CH:42]=1
Reactant: NCCN1CCOCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)O)c3)cn2)cc1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)NCCN4CCOCC4)c3)cn2)cc1
Yield: 99.9 %

Procedure:
Using 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (69.6 mg, 0.105 mmol) obtained in Step A in Example 1-D-53 instead of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid, and N-(2-aminoethyl)morpholine (27.5 mg, 0.211 mmol) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, amidation was carried out, to obtain a crude product of 3-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide as a yellow solid (81.0 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-123) as a yellow powder (34.2 mg, 60%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[CH:20]=[C:21]([CH:28]=[C:29]([F:32])[C:30]=4[CH3:31])[C:22]([NH:24][CH:25]4[CH2:27][CH2:26]4)=[O:23])[CH:17]=3)[C:12](=[O:33])[N:11]([CH2:34][CH:35]3[CH2:37][CH2:36]3)[CH:10]=2)[CH2:4][CH2:3]1.[CH3:38][C:39]([CH3:41])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:25]1([NH:24][C:22](=[O:23])[C:21]2[CH:28]=[C:29]([F:32])[C:30]([CH3:31])=[C:19]([C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[C:12](=[O:33])[N:11]([CH2:34][CH:35]3[CH2:36][CH2:37]3)[CH:10]=[C:9]4[CH2:8][N:5]3[CH2:6][CH2:7][CH:2]([NH:1][CH:39]([CH3:41])[CH3:38])[CH2:3][CH2:4]3)[CH:20]=2)[CH2:26][CH2:27]1
Reactant: CC(C)=O
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCC(NC(C)C)CC3)c2c1
Reaction time: 0.08 h

Procedure:
The product of Example 83 (50 mg) was dissolved in dichloromethane (10 mL) and acetone (0.037 mL) added. The solution was stirred for 5 minutes then sodium triacetoxyborohydride (63.3 mg) added. The mixture was stirred at room temperature for 16 hours. The volatiles were removed under reduced pressure and the residue purified by HPLC to give the title compound as a solid (45 mg).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:24][CH2:25][C@@H:26]([C:28]1[CH:29]=[CH:30][C:31]([OH:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[OH:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>CN(C)C=O>[OH:27][C@H:26]([C:28]1[CH:29]=[CH:30][C:31]([OH:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[CH2:25][NH:24][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(NS(=O)(=O)c3cccnc3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(NS(=O)(=O)c4cccnc4)cc3)CC2)ccc1O
Reaction time: 18 h
Yield: 14.6 %

Procedure:
To a stirred mixture of pyridine-3-sulfonic acid-[4-(4-oxo piperidin-1-yl)-phenyl]amide (which was obtained in Example 237) (0.94 g, 2.8 mmol), N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) (0.70 g, 2.8 mmol) in dimethylformamide (10 mL) at room temperature was added sodium triacetoxyborohydride (0.72 g, 3.4 mmol) and glacial acid (0.18 mL, 3.1 mmol). The reaction was stirred under N2 atmosphere for 18 hours. The reaction mixture was poured onto 1:1 water/saturated sodium bicarbonate, extracted with ethyl acetate three times, dried over sodium sulfate and concentrated. The product was purified by flash silica gel chromatography eluting with 10% methanol in methylene chloride and finally with 20% methanol in methylene chloride to give the titled compound as a yellow solid (0.23 g, 15%); 1H NMR (300 MHz, DMSO-d6) δ 1.25–1.45 (m, 2 H), 1.80–1.95(m, 2 H), 2.50–2.80(m, 5 H), 2.92(s, 3 H), 3.40–3.55(m, 2), 4.45–4.60(m, 1 H), 6.85–6.90(m, 5 H), 7.02(dd, J=8.3, 2.0 Hz, 1 H), 7.18(d, J=2.0 Hz, 1 H), 7.59(dd, J=7.4, 4.4 Hz, 1 H), 7.95–8.05(m, 2 H), 8.70–8.80(m, 2 H); MS (ES) m/z: 561.95 (MH+, 100%); HRMS Calcd. for C25H32N5O6S2(MH+): 562.1788. Found: 562.1774.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](O)=[CH:5][CH:4]=1)=[O:2].C(C1C=CC2C(=CC=CC=2)C=1O)=[O:15].C(C1C=C(O)C2C(C=1)=CC=CC=2)=O>>[CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:15])=[O:2]
Reactant: O=Cc1ccc2ccccc2c1O
Reactant: O=Cc1ccc(O)c2ccccc12
Agent: O=Cc1cc(O)c2ccccc2c1
Product: O=Cc1c(O)ccc2ccccc12

Procedure:
4-formyl-1-naphthol; 2-formyl-1-naphthol; 3-formyl-1-naphthol; and 2-anthrol-1-aldehyde.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:16])([CH3:15])[C:7](=[O:14])[N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].CCN(C(C)C)C(C)C.[C:29]1([C@@H:35]([NH2:37])[CH3:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN1C(=O)CCC1>[CH:11]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([N+:17]([O-:19])=[O:18])=[C:2]([NH:37][C@H:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH3:36])[CH:10]=2)[C:6]([CH3:16])([CH3:15])[C:7]1=[O:14])([CH3:13])[CH3:12]
Reactant: CC(C)N1C(=O)C(C)(C)c2cc([N+](=O)[O-])c(F)cc21
Reactant: C[C@H](N)c1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1C(=O)C(C)(C)c2cc([N+](=O)[O-])c(N[C@@H](C)c3ccccc3)cc21
Temperature: 50 °C
Reaction time: 3 h

Procedure:
6-Fluoro-1-isopropyl-3,3-dimethyl-5-nitro-1,3-dihydro-indol-2-one E-1.2″ (4.5 g; 16.5 mmol) is dissolved in NMP (20 ml), DIPEA (4.0 ml; 22.3 mmol) and (S)-1-Phenyl-ethylamine (2.65 ml; 20.1 mmol) is added at 20° C. The reaction mixture is stirred for 3 h at 50° C. The reaction mixture is poured into water and extracted with DCM. The combined organic layer is dried over MgSO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography using silica gel (50 μM) with eluting mixture of ethyl acetate and cyclohexane.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([OH:15])[CH2:11][CH2:12][CH:13]=[CH2:14].Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.[OH-].[Na+].[NH2:30][C@H:31]([C:36]([OH:38])=[O:37])[C:32]([CH3:35])([CH3:34])[CH3:33]>O1CCOCC1>[CH3:33][C:32]([CH3:35])([CH3:34])[C@H:31]([NH:30][C:17]([O:15][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])=[O:19])[C:36]([OH:38])=[O:37]
Reactant: CC(C)(C)[C@H](N)C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCCCO
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 147.8 %

Procedure:
Diisopropylethyl amine (9.85 g, 76.2 mmol) was added dropwise to a 0° C. solution of 4-penten-1-ol (7.22 g, 83.9 mmol) and triphosgene (11.3 g, 38.1 mmol) in 160 mL dioxane. The resulting white suspension was stirred for 5 min at 0° C., then allowed to warm to 25° C. over 1 h. The suspension was cooled to 0° C. with an ice bath and 1 N NaOH (76.2 mL) and L-tert-butylglycine (10.0 g, 76.2 mmol) were added. The reaction mixture was warmed to 25° C. and stirred for 18 h. The dioxane was removed in vacuo and the reaction mixture was basified to pH 12 with 1 N NaOH. The aqueous layer was extracted with dichloromethane (3×150 mL), then acidified to pH˜1 with 6 N HCl. The aqueous layer was extracted with dichloromethane (3×150 mL). The combined organic layers were dried over MgSO4 and concentrated to give the compound as a tan oil (13.7 g, 73.9% yield). LRMS (ESI) m/z 244 [(M+H)+; calcd for C12H22NO4 244].
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[Br:26][CH:27]([CH3:39])[C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)=[O:29]>C(#N)C>[Br-:26].[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:5][N+:6]1[CH:10]=[CH:9][N:8]([CH:27]([C:28](=[O:29])[NH:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[CH3:39])[CH:7]=1
Reactant: Cc1ccc(CNC(=O)C(C)Br)cc1
Reactant: Clc1ccc(COC(Cn2ccnc2)c2ccc(Cl)cc2Cl)c(Cl)c1
Solvent: CC#N
Product: Cc1ccc(CNC(=O)C(C)n2cc[n+](CC(OCc3ccc(Cl)cc3Cl)c3ccc(Cl)cc3Cl)c2)cc1
Product: [Br-]

Procedure:
A mixture of 8 parts of 1-[2,4-dichloro-β-(2,4-dichlorobenzyloxy)phenethyl]imidazole, 5.6 parts of 2-bromo-N-(p-methylbenzyl)propionamide and 80 parts of acetonitrile is stirred and refluxed for 20 hours. The reaction mixture is evaporated and the residue is crystallized from a mixture of 4-methyl-2-pentanone and diisopropyl ether, yielding 9 parts of 1-[2,4-dichloro-β-(2,4-dichlorobenzyloxy)phenethyl]-3-{1-[N-(p-methylbenzyl)carbamoyl]ethyl}-imidazolium bromide; mp. 136.2° C.