Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Br)#[N:2].[F:4][C:5]([F:48])([F:47])[C:6]([C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][C:37]=2[C:43]([F:46])([F:45])[F:44])=[CH:31][CH:30]=1)([C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=2[C:25]([F:28])([F:27])[F:26])=[CH:13][CH:12]=1)[C:7]([F:10])([F:9])[F:8].C[C:50]([N:52](C)C)=O>C(=O)(O)[O-].[Na+].O>[F:4][C:5]([F:47])([F:48])[C:6]([C:29]1[CH:30]=[CH:31][C:32]([O:35][C:36]2[CH:41]=[CH:40][C:39]([NH:42][C:1]#[N:2])=[CH:38][C:37]=2[C:43]([F:44])([F:45])[F:46])=[CH:33][CH:34]=1)([C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:50]#[N:52])=[CH:20][C:19]=2[C:25]([F:28])([F:26])[F:27])=[CH:15][CH:16]=1)[C:7]([F:10])([F:9])[F:8]
Reactant: CC(=O)N(C)C
Reactant: Nc1ccc(Oc2ccc(C(c3ccc(Oc4ccc(N)cc4C(F)(F)F)cc3)(C(F)(F)F)C(F)(F)F)cc2)c(C(F)(F)F)c1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: N#CNc1ccc(Oc2ccc(C(c3ccc(Oc4ccc(NC#N)cc4C(F)(F)F)cc3)(C(F)(F)F)C(F)(F)F)cc2)c(C(F)(F)F)c1
Reaction time: 12 h
Yield: 98.2 %

Procedure:
Bromocyanogen in an amount of 63.5 g, and 25.2 g of sodium bicarbonate were dissolved in a mixed solvent of 75 ml of water and 50 ml of dimethylacetamide with sufficient stirring (in a cooled state). To the resulting solution, a solution obtained by dissolving 98.1 g of 1,1,1,3,3,3-hexafluoro-2,2-bis[4-(4-amino-2-trifluoromethylphenoxy)phenyl]propane in 300 ml of dimethylacetamide was added dropwise in about 4 hours while maintaining the cooled state at 0° to 10° C. After dropwise addition, aging was conducted for 12 hours. The resulting reaction solution was dropped in 1000 ml of water with stirring to deposit a pale yellow precipitate. The precipitate was separated by filtration with suction. The resulting precipitate was charged into 1000 ml of water again, washed with water, filtered again and washed with water. The resulting filtered solid was subjected to filtration under reduced pressure (drying conditions; temperature 30° C., pressure 10 mmHg, period 12 hours) to yield 104.8 g of crystals of the objective compound, 1,1,1,3,3,3-hexafluoro-2,2-bis[4-(4-cyanoamino-2-trifluoromethylphenoxy)phenyl]propane (yield 98.2%). The resulting compound (p-HFCTP-2) had a melting point of 55° to 60° C. IR spectrum of said compound is shown in FIG. 4 and NMR spectrum of said compound is shown in FIG. 3.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:8]([OH:9])=[C:7]([N+:10]([O-])=O)[CH:6]=[CH:5][CH:4]=1.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:10][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:13])[F:14])[C:8]=1[OH:9]
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc(C(F)(F)F)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
A mixture of 6-trifluoromethyl-2-nitrophenol (1.84 g, 8.67 mmol) and tin (II) chloride (6.0 g, 26.2 mmol) in ethanol (150 mL) was heated at 80° C. under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2CH2) gave the desired product (1.35 g, 88%). 1H NMR (CD3OD): d 6.93 (d, 1H), 6.82 (t, 1H), 6.78 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[NH:8][CH2:9]2)=[CH:4][CH:3]=1.[C:20]([O:24][C:25]([N:27]([CH2:38][CH:39]=O)[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[N+:35]([C:32]1[CH:31]=[CH:30][C:29]([CH2:28][N:27]([CH2:38][CH2:39][N:8]2[CH:7]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[CH2:6][C:5]3[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:9]2)[C:25](=[O:26])[O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:34][CH:33]=1)([O-:37])=[O:36]
Reactant: CC(C)(C)OC(=O)N(CC=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: Fc1ccc(CC2Cc3ccc(F)cc3CN2)cc1
Product: CC(C)(C)OC(=O)N(CCN1Cc2cc(F)ccc2CC1Cc1ccc(F)cc1)Cc1ccc([N+](=O)[O-])cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 117-d) using 7-fluoro-3-(4-fluorobenzyl)-1,2,3,4-tetrahydroisoquinoline obtained in Example 56-c) and [N-(tert-butoxycarbonyl)-N-4-nitrobenzylamino]acetaldehyde to obtain a title compound as a light yellow oily substance.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:18][C@@H:19]([OH:43])[C@@H:20]([N:28](CC3C=CC=CC=3)CC3C=CC=CC=3)[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.O.[CH3:45][S:46]([OH:49])(=[O:48])=[O:47]>[OH-].[OH-].[Pd+2].C1COCC1>[CH3:45][S:46]([OH:49])(=[O:48])=[O:47].[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:18][C@@H:19]([OH:43])[C@@H:20]([NH2:28])[CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:11])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: [Pd+2]
Agent: CS(=O)(=O)O
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CN(C[C@@H](O)[C@@H](N)Cc1ccccc1)S(=O)(=O)c1ccc2c(c1)OCO2
Reaction time: 16 h

Procedure:
Part B: To the THF solution of crude 1-(N-[(1,3-benzodioxol-5-yl)sulfonyl]-N-(2-methylpropyl)amino]-3(S)-[bis(phenylmethyl)amino]-4-phenyl-2(R)-butanol was added water (500 mL) followed by methane sulfonic acid (531 g, 5.5 moles). The solution was stirred to insure complete mixing and added to a 5 gallon autoclave. Pearlman's catalyst (200 g of 20% Pd(OH)2 on C/50% water) was added to the autoclave with the aid of THF (500 mL). The reactor was purged four times with nitrogen and four times with hydrogen. The reactor was charged with 60 psig of hydrogen and stirring at 450 rpm started. After 16 hours, HPLC analysis indicated that a small amount of the mono-benzyl intermediate was still present. Additional catalyst (50 g) was added and the reaction was allowed to run overnight. The solution was then filtered through celite (500 g) to remove the catalyst and concentrated under vacuum in five portions. To each portion, toluene (500 mL) was added and removed under vacuum to allotropically removed residual water. The resulting solid was divided into three portions and each washed with methyl t-butyl ether (2 L) and filtered. The residual solvent was removed at room temperature in a vacuum oven at less than 1 torr to yield the 2714 g of the expected salt.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24](O)=[O:25])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:59][NH:60][CH2:61][C:62]1[CH:73]=[CH:72][C:65]([CH2:66][N:67]2[CH2:70][CH:69]([OH:71])[CH2:68]2)=[CH:64][CH:63]=1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:60]([CH2:61][C:62]3[CH:63]=[CH:64][C:65]([CH2:66][N:67]4[CH2:70][CH:69]([OH:71])[CH2:68]4)=[CH:72][CH:73]=3)[CH3:59])=[O:25])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Reactant: CNCc1ccc(CN2CC(O)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N(C)Cc3ccc(CN4CC(O)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (40 mg, 0.105 mmol), EDCI (28 mg, 0.158 mmol), HOBt (21 mg, 0.16 mmol), DIPEA (0.04 mL, 0.21 mmol), 1-{4-[(methylamino)methyl]benzyl}azetidin-3-ol dihydrochloride (40 mg, 0.12 mmol) and DCM (10 mL).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:6][N:7]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:8][CH2:9][C:10]=1[C:11]1[CH:32]=[CH:31][C:14]2[C:15]3[N:19]([CH2:20][CH2:21][O:22][C:13]=2[CH:12]=1)[CH:18]=[C:17]([C:23]1[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=1)[N:16]=3)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[C:36]([O:35][C:33]([N:7]1[CH2:8][CH2:9][C:10]([C:11]2[CH:32]=[CH:31][C:14]3[C:15]4[N:19]([CH2:20][CH2:21][O:22][C:13]=3[CH:12]=2)[CH:18]=[C:17]([C:23]2[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=2)[N:16]=4)=[C:5]([C:3]([OH:4])=[O:2])[CH2:6]1)=[O:34])([CH3:38])([CH3:39])[CH3:37]
Reactant: COC(=O)C1=C(c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)CCN(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=C(C(=O)O)CN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Temperature: 25 °C
Yield: 50.5 %

Procedure:
4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (0.629 g, 1.18 mmol) and lithium hydroxide monohydrate (4.8 mmol) in THF (4 mL) and water (2 mL) were heated at 60° C. overnight. The reaction mixture was cooled to RT, THF removed in vacuo and the residue acidified to pH 3 with 1M HCl. The resultant solid was filtered off, washed with water and dried. The resultant solid was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester (0.31 g, 51%). 1H NMR 300 MHz (CDCl3) δ: 8.27 (1H, d, J=8.34 Hz), 7.93 (1H, s), 7.17 (1H, s), 7.07 (1H, dd, J=8.31, 1.80 Hz), 6.55 (1H, s), 6.10 (1H, m), 4.40 (2H, m), 4.14 (4H, m), 3.67 (2H, m), 2.50 (2H, m), 1.63 (6H, d, J=6.58 Hz), 1.54 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH2:24])=[O:23])[CH:17]=1>CN(C=O)C.CCOC(C)=O.O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH2:24])=[O:23])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(O)cn1
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Oc2ccc(N)nc2)ccn1
Temperature: 80 °C
Yield: 50 %

Procedure:
To a mixture of 6-aminopyridin-3-ol (220 mg, 2 mmol) and t-BuOK (225 mg, 2.16 mmol) in DMF (2.5 mL) was added 4-chloropicolinamide (315 mg, 2 mmol). The reaction was heated to 80° C. for 5 hours, then cooled to rt and diluted with EtOAc (50 mL) and H2O (50 mL). The organic phase was concentrated in vacuo and the residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=30/1) to give the title compound as a brown solid (230 mg, 50%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7](CC#N)=[CH:6][CH:5]=1.[C:13]([OH:16])(=[O:15])[CH3:14]>Br>[Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:14][C:13]([OH:16])=[O:15])=[CH:6][CH:5]=1
Reactant: CC(=O)O
Reactant: N#CCc1ccc(CCBr)cc1
Agent: Br
Product: O=C(O)Cc1ccc(CCBr)cc1

Procedure:
A solution of [4-(2-bromoethyl)phenyl]acetonitrile (56.0 g., 0.25 mole) in 48% hydrobromic acid (200 ml.) and acetic acid (600 ml.) is boiled under reflux for 4 hours. The solution is reduced to one-third volume by distillation at reduced pressure. The residue is diluted with 400 ml. of water to force out the oily product which is taken up in ether, washed with water, and dried over sodium sulfate. Evaporation of the solvent leaves the title compound as a residual oil.
Reaction SMILES: [CH2:1]1[O:34][C:33]2[CH:32]=[CH:31][C:5]([CH2:6][N:7]([S:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([O:28][CH3:29])=[CH:23][C:22]=3[CH3:30])(=[O:20])=[O:19])[C@H:8]([CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:9]([OH:11])=O)=[CH:4][C:3]=2[O:2]1.[CH2:35]([O:42][NH2:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH2:35]([O:42][NH:43][C:9](=[O:11])[C@H:8]([N:7]([CH2:6][C:5]1[CH:31]=[CH:32][C:33]2[O:34][CH2:1][O:2][C:3]=2[CH:4]=1)[S:18]([C:21]1[C:26]([CH3:27])=[CH:25][C:24]([O:28][CH3:29])=[CH:23][C:22]=1[CH3:30])(=[O:20])=[O:19])[CH2:12][NH:13][S:14]([CH3:17])(=[O:15])=[O:16])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CNS(C)(=O)=O)C(=O)O)c(C)c1
Reactant: NOCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CNS(C)(=O)=O)C(=O)NOCc2ccccc2)c(C)c1
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To a mixture of 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-methanesulfonylamino-propionic acid (1 g, 1.9 mmol), O-benzylhydroxylamine (0.95 ml, 6 mmol) and 1-hydroxybenzotriazole hydrate (370 mg, 1.9 mmol), and N-methylmorpholine (0.7 ml, 5.7 mmol) in anhydrous dimethylformamide (20 ml) was added 1-ethyl-3(3-dimethylamino)-propyl carbodiimide hydrochloride salt. The mixture was stirred overnight and then condensed on the roto-evaporator. The remainder was taken up in ethyl acetate (60 ml) and partitioned with an equal volume of 5% aqueous hydrochloric acid. The ethyl acetate phase was collected and washed consecutively with equal volumes of 5% sodium bicarbonate and brine. The aqueous phases were back extracted with ethyl acetate (2×60 ml) and the organic layers combined, dried with magnesium sulfate, filtered and condensed. The residue was purified by preparative thin layer chromatography using 65% ethyl acetate-hexanes as eluant providing N-benzyloxy 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-methanesulfonylamino-propionamide as a yellow viscous oil (591 mg).
Reaction SMILES: [N+](=[CH2:3])=[N-].[N+:4]([C:7]1[CH:37]=[CH:36][C:10]([CH2:11][O:12][C:13]([C:15]2[N:20]3[C:21](=[O:34])[C@@H:22]([NH:23][C:24](=[O:33])[CH2:25][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@H:19]3[S:18][CH2:17][C:16]=2[OH:35])=[O:14])=[CH:9][CH:8]=1)([O-:6])=[O:5]>C(Cl)(Cl)Cl>[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([CH2:11][O:12][C:13]([C:15]2[N:20]3[C:21](=[O:34])[C@@H:22]([NH:23][C:24](=[O:33])[CH2:25][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@H:19]3[S:18][CH2:17][C:16]=2[O:35][CH3:3])=[O:14])=[CH:36][CH:37]=1)([O-:6])=[O:5]
Reactant: C=[N+]=[N-]
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Solvent: ClC(Cl)Cl
Product: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3 ml of an ethereal diazomethane solution (0.5 molar, 1.5 equivalents) are added in the course of about 10 minutes to a solution, cooled to 0° C., of 485 mg of 7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester in 10 ml of dry chloroform. The pale yellow solution is stirred for 1 hour at 0° C., flushed with nitrogen in order to remove excess diazomethane and concentrated in vacuo. The residue is recrystallised from methylene chloride and gives 7β-phenoxyacetamido-3-methoxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester of melting point 140.5°-142° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][CH3:35])[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][CH3:35])[C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[CH:23][CH:22]=1
Reactant: CCN(c1ccc(I)cc1)c1ncccn1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: CCN(c1ccc(/C=C/CC(NC(=O)c2c(Cl)cccc2Cl)C(=O)OC)cc1)c1ncccn1
Yield: 72.9 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (214 mg) was reacted with N-(4-iodophenyl)-N-ethylpyrimidin-2-amine (254 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(ethyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (258 mg). Column chromatography (silica gel, eluent: hexane/ethyl acetate=4/1→hexane/ethyl acetate=2/1 hexane/ethyl acetate=1/2) was used for purification.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([O:22]CC)=[CH2:21])[CH:14]=[CH:13]2>C1COCC1.O>[Br:8][CH2:22][C:20]([C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[CH:18][CH:19]=[C:10]([Br:9])[CH:11]=2)[N:16]=1)=[O:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)c1ccc2cc(Br)ccc2n1
Solvent: C1CCOC1
Solvent: O
Product: O=C(CBr)c1ccc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
NBS (407 mg, 2.287 mmol) was added to a solution of 6-bromo-2-(1-ethoxyvinyl)quinoline (530 mg, 1.91 mmol) in THF (10 mL) and water (2.5 mL) and the mixture was stirred at rt for 2 h. The reaction mixture was partitioned between EtOAc and brine and the organic layer was concentrated. The crude material was purified by flash silica gel chromatography (eluted with Et2O/hexanes, gradient from 0 to 5% Et2O) to yield 2-bromo-1-(6-bromoquinolin-2-yl)ethanone (380 mg) as white solid. LC-MS retention time 3.988 min; m/z 329.84 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[O:7][CH:6]=[C:5]([CH:8]=[O:9])[CH:4]=1.C([N-]C(C)C)(C)C.[Li+].[CH3:20][C:21](=[O:34])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:35]([O:9][CH:8]([C:5]1[CH:4]=[C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])[O:7][CH:6]=1)[CH2:20][C:21](=[O:34])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:37])[CH3:36]
Reactant: CCCCCCCCCCCCC(C)=O
Reactant: CC(=O)OC(C)=O
Reactant: C[Si](C)(C)c1cc(C=O)co1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCCCCCCCCCCC(=O)CC(OC(C)=O)c1coc([Si](C)(C)C)c1

Procedure:
5-Trimethylsilyl-3-furaldehyde is treated with lithium diisopropylamide and 2-tetradecanone, followed by acetic anhydride to give 3-(1-acetoxy-3-ketopentadecanyl)-5-trimethylsilylfuran. Oxidation by the method described in Example 1 gives 4-(1-acetoxy-3-ketopentadecanyl)-5-hydroxy-2(5H)-furanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:29]3[C:28]4[CH2:27][CH2:26][N:25]([C:30](=[O:40])[CH:31]=[CH:32][CH2:33][CH2:34]OS(C)(=O)=O)[CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:47][NH:48][CH3:49]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:29]3[C:28]4[CH2:27][CH2:26][N:25]([C:30](=[O:40])[CH:31]=[CH:32][CH2:33][CH2:34][N:48]([CH3:49])[CH3:47])[CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CNC
Reactant: CS(=O)(=O)OCCC=CC(=O)N1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(C)CCC=CC(=O)N1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Temperature: 50 °C
Yield: 20 %

Procedure:
In a 25 ml rb flask were placed methanesulfonic acid 5-{4-[3-chloro-4-(pyridine-2-ylmethoxy)-phenylamino]-5,8-dihydro-6H-9-thia-1,3,7-triaza-fluoren-7-yl}-5-oxo-pent-3-enyl ester (0.15 g, 0.25 mmol) in DMF (5.0 ml) and to the solution was added cesium carbonate (0.16 g, 0.5 mmol) followed by dimethylamine (0.5 ml of 2M solution in THF) and heated at 50° C. overnight. The yellow solution was purified by HPLC twice to provide 27.5 mg of light brown solid (20.0%). 1H-NMR (DMSO-d6) δ 8.592-8.574 (m, 1H), 8.378 (s, 1H), 8.181 (s, 1H), 7.890-7.847 (m, 1H), 7.781-7.752 (m, 1H), 7.572-7.552 (d, 1H), 7.514-7.492 (m, 1H), 7.372-7.341 (m, 1H), 7.237-7.207 (m, 1H), 5.271 (s, 2H), 4.942-4.761 (m, 2H), 3.922-3.781 (m, 2H), 3.282-3.169 (m, 4H), 2.343 (m, 2H), 2.127-1.977 (m, 8H). MS m/e 549.1 (M+H), RT=2.26 min
Reaction SMILES: C([O:5][C:6](=[O:32])[C@H:7]([CH2:27][CH2:28][C:29](=[O:31])[NH2:30])[NH:8][S:9]([C:12]1[CH:21]=[C:20]2[C:15]([C:16]([Cl:26])=[CH:17][N:18]=[C:19]2[NH:22][C:23]([NH2:25])=[NH:24])=[CH:14][CH:13]=1)(=[O:11])=[O:10])(C)(C)C.CO.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>C1(C)C=CC=CC=1>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Cl:26][C:16]1[C:15]2[C:20](=[CH:21][C:12]([S:9]([NH:8][C@H:7]([C:6]([OH:32])=[O:5])[CH2:27][CH2:28][C:29](=[O:31])[NH2:30])(=[O:11])=[O:10])=[CH:13][CH:14]=2)[C:19]([NH:22][C:23]([NH2:25])=[NH:24])=[N:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)[C@H](CCC(N)=O)NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N[C@@H](CCC(N)=O)C(=O)O)cc12

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-glutamine tert-butyl ester (15 mg, 0.03 mmol) was dissolved in trifluoroacetic acid (1 ml) and the resultant solution stirred at room temperature for 1 h, diluted with toluene and concentrated to a residue. Trituration with Et2O gave a powder to which was added MeOH and the suspension filtered. The filtrate was concentrated and then triturated with EtOAc to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-glutamine trifluoroacetate (9 mg, 0.02 mmol).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([CH3:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[C:38]([C:40]1([OH:46])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)#[CH:39]>C1(C)C=CC=CC=1.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.[Cu]I>[CH:12]1([CH2:11][C@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([CH3:27])[CH:18]=2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:39]#[C:38][C:40]3([OH:46])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:7][N:6]=2)=[O:28])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C#CC1(O)CCOCC1
Reactant: Cc1cc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)ccc1S(C)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C#CC3(O)CCOCC3)cn2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 55.1 %

Procedure:
A mixture of N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-pheny)-propionamide (prepared as in Example 57, 154 mg, 0.33 mmol), N,N-diisopropylethylamine (0.6 mL, 3.44 mmol), and 4-ethynyl-tetrahydropyran-4-ol (prepared as in Example 46, 85 mg, 0.67 mmol) in toluene (2 mL) was treated with dichlorobis(triphenylphosphine)palladium(II) (14 mg, 0.02 mmol) and copper(I) iodide (7 mg, 0.0367 mmol). The mixture was stirred at 25° C. for 17 h. The reaction mixture was then concentrated in vacuo, and the residue was partitioned with methylene chloride (50 mL) and a 0.2M aqueous hydrochloric acid solution (25 mL) and the layers were separated. The aqueous phase was back-extracted with methylene chloride (25 mL). Each organic layer was washed with a saturated aqueous sodium chloride solution (1 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, gradient elution with mixtures of ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[5-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-pyrazin-2-yl]-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionamide (93 mg, 55%) as a yellow foam: (ES)+-HRMS m/e calcd for C27H33N3O5S (M+H)+ 512.2214, found 512.2219.