Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[OH-:9].[Na+].Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl.Cl>O>[O:14]([CH2:15][CH2:16][O:9][C:8]1[CH:7]=[CH:6][CH:5]=[CH:3][C:1]=1[OH:2])[CH2:13][CH2:12][O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: [OH-]
Reactant: ClCCOCCCl
Reactant: Oc1ccccc1O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Oc1ccccc1OCCOCCOc1ccccc1O
Yield: 23 %

Procedure:
A vigorously agitated mixture of 220 grams (2 gram-mols) of catechol, 2000 ml. of water, 80 grams (2 gram-mols) of sodium hydroxide and 143 grams (1 grammol) of bis(beta-chloroethyl)ether is reacted at reflux at 102°-103°C. for 16 hours under nitrogen. It is then acidified with concentrated hydrochloric acid. When unreacted bis(2-chloroethyl)ether and 1000 ml. of water have been removed by distillation, the mixture separates into two layers. The organic layer is recovered and treated with 700 ml. of methanol and chilled with ice water. The crystals that subsequently form are filtered off, washed with cold methanol, and dried. The 2,2'-(oxydiethylenedioxy)-diphenol product, 67 to 74 grams (23 to 25.5% yield), melts at 85°C. and analyzes as follows (a typical example.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[N-:23]=[N+:24]=[N-:25].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][C:4]([O:7][CH2:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]3[NH:25][N:24]=[N:23][N:14]=3)=[CH:11][CH:10]=2)=[CH:5][CH:6]=1
Reactant: N#Cc1ccc(COc2ccc(-c3ccccc3)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-c2ccc(OCc3ccc(-c4nnn[nH]4)cc3)cc2)cc1
Temperature: 125 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
The above benzonitrile (3.00 g, 10.5 mmol) was dissolved in N,N-dimethylformamide (50 mL), and sodium azide (1.03 g, 15.8 mmol) and ammonium chloride (0.84 g, 15.8 mmol) were added and the mixture was stirred 16 hours at 125° C. The mixture was cooled to room temperature and water (50 mL) was added. The suspension was stirred overnight, filtered, washed with water and dried in vacuo at 50° C. for 3 days to give crude 3.07 g (89%) of the title compound. From the mother liquor crystals were collected and washed with water, dried by suction to give 0.18 g (5%) of the title compound as a solid.
Reaction SMILES: [BrH:1].[C:2]1([CH2:8][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C>[BrH:1].[Br:1][CH:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: O=C(Cc1ccccc1)c1cccnc1
Agent: Br
Solvent: CC(=O)O
Product: O=C(c1cccnc1)C(Br)c1ccccc1

Procedure:
120 g of 2-phenyl-1-(3-pyridyl)-ethanone hydrobromide are heated to 75° in 1000 ml of acetic acid. The heating bath is then removed and, while stirring, a solution of 75.8 g of bromine in 30 ml of acetic acid is added in portions each of 5 ml. While then stirring, the mixture is gradually allowed to cool to 60°, then is cooled to 20° by means of an ice-bath, filtered with suction, washed first once with 100 ml of cold acetic acid and then twice with 200 ml of diethyl ether each time, and dried under reduced pressure. 2-Bromo-2-phenyl-1-(3-pyridyl)-ethanone hydrobromide having a melting point of 216°-219° is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([O-:8])=O)[CH3:2].[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[NH2:14].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9])=[O:8])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In 200 ml of methylene chloride were dissolved 5.0 g of monoethylmalonate and 6.12 g of 3,5-dichloroaniline. Under cooling with ice, to the mixture was added 8.57 of N,N'-dicyclohexylcarbodiimide, followed by stirring at room temperature for 5 hours. Insoluble materials were removed by filtration. The filtrate was diluted with ethyl acetate, washed with 1N hydrochloric acid and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (silica gel:250 g) using a mixed solvent of chloroform and acetone (20:1 by volume) to obtain 6.57 g of the oily titled comouond.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:16](=[O:17])[C:15]2[N:18]3[C:8](=[C:9]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25][NH:26][CH3:27])=[CH:21][CH:20]=4)[N:10]=[C:11]3[CH:12]=[CH:13][CH:14]=2)[CH2:7]1.O.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>>[F:38][C:37]([F:40])([F:39])[C:35]([O-:41])=[O:36].[CH3:27][NH2+:26][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:9]2[N:10]=[C:11]3[N:18]4[C:15]([C:16](=[O:17])[NH:6][CH2:7][C:8]=24)=[CH:14][CH:13]=[CH:12]3)=[CH:24][CH:23]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CNCc1ccc(-c2nc3cccc4n3c2CN(Cc2ccc(OC)cc2OC)C4=O)cc1
Solvent: O
Product: C[NH2+]Cc1ccc(-c2nc3cccc4n3c2CNC4=O)cc1
Product: O=C([O-])C(F)(F)F

Procedure:
4-(2,4-dimethoxybenzyl)-2-{4-[(methylamino)methyl]phenyl}-3,4-dihydro-5H-1,4,8b-triazaacenaphthylen-5-one was dissolved in TFA:H2O:TIPS=8.0:1.5:0.5 (0.1 M) and heated to 120° C. for 30 min at microwave apparatus. The solvent was reduced in vacuo and the crude was purified by reverse phase HPLC (column: C18), using H2O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents, the desired fractions were lyophilized to yield (15% over two steps) the title compound. 1H NMR (400 MHz, DMSO-d6, 300K) δ 8.76 (1H, bs), 8.68 (1H, s) 7.86 (2H, d, J=8.0 Hz), 7.68 (1H, d, J=9.0 Hz), 7.57 (2H, d, J=8.0 Hz), 7.37 (1H, d, J=7.0 Hz), 7.30 (1H, dd, J=9.0, 7.0 Hz), 5.28 (2H, s), 4.17 (2H, s), 2.60 (3H, s). MS (ES+) C17H16N4O requires: 292, found: 293 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([SH:12])[CH:9]=[C:8]([CH3:13])[C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([N:32]1[C:36](=[O:37])[CH:35]=[CH:34][C:33]1=[O:38])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:14]([N:32]1[C:33](=[O:38])[CH2:34][CH:35]([S:12][C:10]2[CH:9]=[C:8]([CH3:13])[C:6]([NH2:7])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=2)[C:36]1=[O:37])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCCCCCN1C(=O)C=CC1=O
Reactant: Cc1cc(S)cc(C(C)(C)C)c1N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN1C(=O)CC(Sc2cc(C)c(N)c(C(C)(C)C)c2)C1=O
Yield: 56.4 %

Procedure:
A stirred solution of 2.8 g (14 mmol) of 2-tert-butyl-4-mercapto-6-methylaniline, 5.0 g (14 mmol) of N-octadecylmaleimide and 0.1 g (1 mmol) of triethylamine in 50 mL of toluene is heated at 50° C. for 18 hours. The solvent is removed in vacuo and the residue is purified by preparative HPLC (silica gel, 4:1, heptane:ethyl acetate eluent) to give 4.3 g (55%) of the title compound as a caramel-colored liquid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=O)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[OH2:20].[CH2:21]1[CH2:25][O:24][CH2:23][CH2:22]1>>[CH3:2][C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)=[CH:22][C:23]([O:24][CH2:25][CH3:21])=[O:20]
Reactant: C1CCOC1
Reactant: CC(=O)c1ccncc1
Reactant: O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCOC(=O)C=C(C)c1ccncc1
Temperature: 25 °C

Procedure:
4-Acetyl pyridine (9 ml, 83 mmol) was added to a cooled solution of triethylphosphonoacetate (16.5 ml, 83 mmol) and lithium bis(trimethylsilyl)amide (1 M in THF, 90 ml, 90 mmol) in THF (100 ml) at 0° C. The mixture was allowed to warm to room temperature and poured into water. The mixture was extracted with EtOAc. The organic layers were dried and evaporated in vacuo. The crude product was purified by chromatography eluting with 30-50% EtOAc in hexane to give the product as a yellow oil. M/z 192.
Reaction SMILES: [C:1]([O:10]C)(=O)[CH2:2][CH2:3][CH:4]=[CH:5][CH:6]=[CH:7][CH3:8].[NH2:12][NH2:13]>CO.O>[C:1]([NH:12][NH2:13])(=[O:10])[CH2:2][CH2:3][CH:4]=[CH:5][CH:6]=[CH:7][CH3:8]
Reactant: CC=CC=CCCC(=O)OC
Reactant: NN
Solvent: CO
Solvent: O
Product: CC=CC=CCCC(=O)NN
Reaction time: 24 h

Procedure:
Diene component: To a solution of methyl octa-4,6-dienoate (16) (6 g) in methanol (10 ml) was added hydrazine (3 ml) at room temperature. After 24 h, the solution was diluted with water (50 ml). The crystalline precipitate was isolated by filtration to afford octa-4,6-dienoic acid hydrazide (17) as colorless microcrystals, yield 5.7 g. Dextran (nominal MW 10 kDa, Pharmacia) was diafiltered through a YM10 membrane (MW cutoff 10 kDa, Millipore) using 3 changes of water. The solution that passed through the membrane was diafiltered through a YM3 (MW cutoff 3000 Da) membrane, suing five changes of water. The material retained by the membrane was lyophilized. A stirred solution of the dextran 18 thus obtained (22.5 mg, 2.25 μmol, corresponding to 139 μmol of glucose) in H2O (2.2 ml) at 5° C. (ice bath) was equipped with a temperature-sensing pH electrode, and 0.1 M NaOH was added with a 100 μL microsyringe until the pH reached 10.5. To this solution was added BrCN (50 μL of a 5 M solution in acetonitrile). The pH of the solution was maintained between 10.5 and 10.8 by addition of 0.1 M NaOH with a microsyringe. After 6 min, the solution was adjusted to pH 8.5 by addition of pH 8.0 phosphate buffer (ca. 1 ml). To the reaction mixture was immediately added a solution of octa-4,6-dienoic acid hydrazide (3.5 mg, 235 μmol) in 0.5 ml dimethyl sulfoxide. The pH of the reaction mixture rose to 8.95, at a temperature of 9° C. The ice bath was removed and the stirred solution was allowed to reach 25° C. After 2.5 h, the pH was 8.18 and remained unchanged over 5 min. The solution of 20 was diafiltered through a YM-3 membrane using 5 changes of water (4 ml each).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[CH2:13]=[C:14]1[O:18][C:16](=[O:17])[CH2:15]1>F>[C:16]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1])(=[O:17])[CH2:15][C:14]([CH3:13])=[O:18]
Reactant: COc1ccc2ccccc2c1
Reactant: C=C1CC(=O)O1
Agent: F
Product: COc1ccc2ccccc2c1C(=O)CC(C)=O
Yield: 88 %

Procedure:
Eiglmeier, in U.S. 4,082,807, teaches the acylation of 2-methoxynaphthalene in anhydrous hydrogen fluoride with diketene to yield 1-acetoacetyl-2-methoxynaphthalene in 88% yield at -25° C. to -35° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:14](N1C2C=CC=CC=2CN2C(C)=CC=C2C1)=[O:15].[Cl:31]C1C=C(N2C=CC(C)=N2)C=CC=1C(O)=O.C(Cl)(=O)C(Cl)=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:14]([Cl:31])=[O:15]
Reactant: Cc1ccn(-c2ccc(C(=O)N3Cc4ccc(C)n4Cc4ccccc43)c(Cl)c2)n1
Reactant: Cc1ccn(-c2ccc(C(=O)O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccn(-c2ccc(C(=O)Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Step e) [2-Chloro-4-(3-methylpyrazol-1-yl)-phenyl]-(3-methyl-5H,11H-pyrrolo[2,1-c][1,4]-benzodiazepin-10-yl)-methanone: A mixture of 2-chloro-4-(3-methylpyrazol-1-yl)-benzoic acid (0.18 g) from step c) of Example 10, oxalyl chloride (0.18 g) and one drop of dimethylformamide in dichloromethane (10 ml), was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo, and the residue was redissolved in dichloromethane and reconcentrated in vacuo to yield 2-chloro-4-(3-methyl-pyrazol-1-yl)-benzoyl chloride. A slurry of the acid chloride in dichloromethane (25 ml) was added dropwise to a solution of 10,11-dihydro-3-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.12 g) and diisopropylethylamine (0.10 g) in dichloromethane (25 ml). The mixture was stirred at room temperature for 18 h, and washed with water and saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The solution was concentrated in vacuo and triturated with diethyl ether to yield 0.115 g of product as colorless crystals, m.p. 178-180° C., MS m/z: 417.3 (M+H)+, 833.3 (2M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:4]=1[OH:5].[CH3:11][OH:12]>>[OH:5][C:4]1[C:3]([O:2][CH3:1])=[CH:9][C:8]2[O:10][C:11](=[O:12])[C:6]([CH2:4][CH2:3][OH:2])=[C:7]([CH3:8])[C:7]=2[CH:6]=1
Reactant: COc1cc(O)ccc1O
Reactant: CO
Product: COc1cc2oc(=O)c(CCO)c(C)c2cc1O
Yield: 54 %

Procedure:
Process F; starting material: methoxyhydroquinone; yield 54%; m.p. 229°-235° C. (from methanol).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[Cl:13][C:14]1[CH:15]=[N+:16]([O-:39])[CH:17]=[C:18]([Cl:38])[C:19]=1[CH2:20][C@@H:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[OH:22].[O:40]=[C:41]1[C:50](=[O:51])[NH:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:42]1[CH2:52][C:53](O)=[O:54]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[N+:16]([O-:39])[CH:17]=[C:18]([Cl:38])[C:19]=1[CH2:20][C@@H:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[O:22][C:53](=[O:54])[CH2:52][N:42]1[C:43]2[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=2)[NH:49][C:50](=[O:51])[C:41]1=[O:40]
Reactant: O=C(O)Cn1c(=O)c(=O)[nH]c2ccccc21
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Cn1c(=O)c(=O)[nH]c2ccccc21)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC HCl) (59 mg, 0.309 mmol) was added to a solution of compounds (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (100 mg, 0.238 mmol), 2-(2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)acetic acid (63 mg, 0.286 mmol) and 4-dimethylaminopyridine (6 mg, 0.048 mmol) in CH2Cl2 (1 mL) at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature overnight. The mixture was then diluted with CH2Cl2 (5 mL) and washed with NaHCO3 saturated solution (5 mL), HCL 0.1 N (5 mL) and brine (5 ml). The organic phase was dried over Na2SO4 and the solvent was evaporated, to yield 70 mg of the title compound (80% yield). MS/ESI+ 621.09 [MH]+
Reaction SMILES: [CH2:1]([C:5]1([CH2:41][CH2:42][CH2:43][CH3:44])[C:17]2[CH:16]=[C:15]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:22][CH:21]=3)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([C:39]#[CH:40])=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].C([N:47]([C:58]1[CH:63]=[CH:62][C:61](I)=[CH:60][CH:59]=1)[CH2:48][CH2:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([OH:57])=[CH:53][CH:52]=1)C.[C:65]1(C)C=CC=C[CH:66]=1.CCN(CC)CC>[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>[CH2:41]([C:5]1([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]2[CH:7]=[C:8]([C:39]#[C:40][C:59]3[CH:60]=[CH:61][C:62]([CH2:63][CH2:58][NH:47][CH2:48][CH2:49][O:50][C:51]4[CH:52]=[CH:53][C:54]([OH:57])=[CH:55][CH:56]=4)=[CH:66][CH:65]=3)[CH:9]=[CH:10][C:11]=2[C:12]2[C:17]1=[CH:16][C:15]([C:18]#[C:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:24][CH:25]=1)=[CH:14][CH:13]=2)[CH2:42][CH2:43][CH3:44]
Reactant: Cc1ccccc1
Reactant: C#Cc1ccc2c(c1)C(CCCC)(CCCC)c1cc(C#Cc3ccc(N(CCCCCC)CCCCCC)cc3)ccc1-2
Reactant: CCN(CCOc1ccc(O)cc1)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCCCCN(CCCCCC)c1ccc(C#Cc2ccc3c(c2)C(CCCC)(CCCC)c2cc(C#Cc4ccc(CCNCCOc5ccc(O)cc5)cc4)ccc2-3)cc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
The air is purged from a solution of 5b (155.9 mg, 0.266 mmol) and 6b (132.6 mg, 0.346 mmol) in 1.2 mL of toluene/Et3N (5/1) by argon bubbling for 20 min. Then, CuI (1.0 mg, 0.005 mmol) and Pd(PPh3)2Cl2 (3.7 mg, 0.005 mmol) are added, and the mixture is agitated at 40° C. for 16 h. The solvent is evaporated under reduced pressure, and the raw product is purified by chromatography in a silica gel column (heptane/CH2Cl2 70:30 then 20:80) to yield 127.9 mg (57%) of 1.
Reaction SMILES: N[C:2]1[S:3][CH:4]=[C:5]([CH:7]([CH3:46])[C:8]([NH:10][C:11]2[CH:45]=[CH:44][C:14]([CH2:15][C@@H:16]3[CH2:20][CH2:19][C@H:18]([C@H:21]([O:29][Si](C(C)(C)C)(C)C)[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[N:17]3C(OC(C)(C)C)=O)=[CH:13][CH:12]=2)=[O:9])[N:6]=1.Cl>CO>[F:28][C:24]1[CH:23]=[C:22]([C@@H:21]([OH:29])[C@@H:18]2[NH:17][C@H:16]([CH2:15][C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[CH:7]([C:5]4[N:6]=[CH:2][S:3][CH:4]=4)[CH3:46])=[CH:45][CH:44]=3)[CH2:20][CH2:19]2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C(=O)Nc1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3cccc(F)c3)N2C(=O)OC(C)(C)C)cc1)c1csc(N)n1
Agent: Cl
Solvent: CO
Product: CC(C(=O)Nc1ccc(C[C@@H]2CC[C@H]([C@H](O)c3cccc(F)c3)N2)cc1)c1cscn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8 mg (0.01 mmol) of tert-butyl (2S,5R)-2-(4-{[2-(2-amino-1,3-thiazol-4-yl)propanoyl]amino}benzyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(3-fluorophenyl)methyl]pyrrolidine-1-carboxylate (isomer 1) in 0.20 mL methanol from Step A was added 0.20 mL conc. HCl and the reaction mixture stirred at room temperature for 1 h. Azeotrop with toluene (2×) to remove water. The residue was taken up in acetonitrile/water/MeOH (9:1:1) and purified on the Gilson HPLC eluting with a 0-50% gradient of acetonitrile/water with 0.05% TFA buffer. The fractions containing the product were combined, frozen, and lyophilized to give a white foam (Example 274) (5.1 mg, 88%). m/z (ES) 440 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@H:9]([OH:12])[CH2:8][C@@H:7]1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:27])([CH3:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][C:14]=1[O:28]CC1C=CC=CC=1)=[O:5])[CH3:2]>[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@H:9]([OH:12])[CH2:8][C@@H:7]1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:26])([CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][C:14]=1[OH:28])=[O:5])[CH3:2]
Reactant: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2C(=O)OCC)c(OCc2ccccc2)c1
Agent: [Pd]
Product: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2C(=O)OCC)c(O)c1
Yield: 77.1 %

Procedure:
Using the procedure of Example 4, 423 mg (0.878 mmole) of N-ethoxycarbonyl-cis-2-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidinol and 210 mg of 5% palladium on carbon (50% wet) provides 265 mg (77%) of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]([NH:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])=S.CI>>[ClH:20].[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[NH:13][C:11]1[NH:10][C:3]2[C:4]([F:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1cc(F)cc(F)c1NC(=S)Nc1c(Cl)cccc1Cl
Solvent: CI
Product: Cl
Product: Fc1cc(F)c2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1

Procedure:
2-(2,6-Dichlorophenylamino)-4,5-difluorobenzimidazole hydrochloride was obtained analogously to the procedure described in example 9b from 2 g of 1-(2-amino-4,6-difluorophenyl)-3-(2,6-dichlorophenyl)thiourea and 6.4 g of methyl iodide. Crystalline solid, m.p.: 232-234° C.
Reaction SMILES: [CH:1]1(/[CH:6]=[C:7](/[C:20]2[NH:25][C:24](=[O:26])[C:23]([CH3:27])=[CH:22][CH:21]=2)\[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]3[CH2:19][CH2:18]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>O1CCCC1.CO.[Pd]>[CH:1]1([CH2:6][CH:7]([C:20]2[NH:25][C:24](=[O:26])[C:23]([CH3:27])=[CH:22][CH:21]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]3[CH2:18][CH2:19]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: Cc1ccc(/C(=C/C2CCCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]c1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(CC2CCCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]c1=O

Procedure:
10% palladium-activated carbon (50 mg) was added to a mixed solution of 6-{(E)-2-cyclopentyl-1-[4-(cyclopropylsulfonyl)phenyl]ethenyl}-3-methylpyridin-2(1H)-one synthesized in Example 1-11 (50 mg) in tetrahydrofuran and methanol (2 mL, 1:1), and the mixture was stirred in a hydrogen gas stream at room temperature for three hours. The reaction solution was filtered through celite, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=1:1→0:1) to give the title compound as a colorless amorphous (33 mg, 60%).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=1)[C@@H:13]([OH:26])[CH2:14][N:15]([CH2:24][CH3:25])[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][C@@H:12]([CH2:27][C:28]1[CH:29]=[C:30]([F:35])[CH:31]=[C:32]([F:34])[CH:33]=1)[C@@H:13]([OH:26])[CH2:14][N:15]([CH2:24][CH3:25])[NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18]
Reactant: [H][H]
Reactant: CCN(C[C@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCN(C[C@H](O)[C@@H](N)Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C

Procedure:
A solution of crude tert-butyl 2-((2S,3S)-3-{[(benzyloxy)carbonyl]-amino}-2-hydroxy-4-(3,5-difluorophenyl)butyl)-2-ethylhydrazinecarboxylate (906 mg, 1.8 mmol) in MeOH (15 mL) was added to 10% Pd/C (95 mg) and stirred in a hydrogen atmosphere (ambient pressure) for 4 h. The catalyst was filtered off over Celite and the filtrate was concentrated under reduced pressure to yield crude tert-butyl 2-((2S, 3S)-3-amino-2-hydroxy-4-(3,5difluorophenyl)butyl)-2-ethylhydrazinecarboxylate. MS (ESI+) for C17H27F2N3O3 m/z 360.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.CS(Cl)(=O)=O.[N-:40]=[N+:41]=[N-:42].[Na+]>C(Cl)Cl>[N:40]([C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:10])=[N+:41]=[N-:42]
Reactant: CCCCCCCCCCCCCCC[C@H](O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCC[C@@H](N=[N+]=[N-])[C@H](C)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To a cold (0° C.) solution of alcohol 94 (48 mg, 0.12 mmol) in CH2Cl2 (1.25 mL), Et3N (52 μL, 0.37 mmol) and MsCl (24 μL, 0.31 mmol) were added. After stirring for 2 h, the mixture was quenched with H2O (10 mL), extracted with CH2Cl2 (3×10 mL), dried over Na2SO4 and concentrated in vacuo. The crude mesylate was dissolved in DMF (0.65 mL) and NaN3 (40.5 mg, 0.62 mmol) was added. The mixture was stirred at 120 C. for 3 h and then quenched with H2O (10 mL), extracted with Et2O (3×10 mL), dried over Na2SO4 and concentrated in vacuo. The crude was purified by column chromatography on silica (hexane/EtOAc 10:1 to 5:1) to obtain azide 95 as a colorless oil (25 mg, 49% yield).