Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([N:6]([CH:17]([CH3:19])[CH3:18])[C:7]1[CH:16]=[CH:15][C:10]2[N:11]=[C:12]([SH:14])[S:13][C:9]=2[CH:8]=1)=[O:5])#[N:2].[CH2:20]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH3:21].N1CCCCC1>C(O)C>[C:1]([C:3](=[CH:32][C:29]1[CH:28]=[CH:27][C:26]([S:23](=[O:25])(=[O:24])[NH:22][CH2:20][CH3:21])=[CH:31][CH:30]=1)[C:4]([N:6]([CH:17]([CH3:19])[CH3:18])[C:7]1[CH:16]=[CH:15][C:10]2[N:11]=[C:12]([SH:14])[S:13][C:9]=2[CH:8]=1)=[O:5])#[N:2]
Reactant: CCNS(=O)(=O)c1ccc(C=O)cc1
Reactant: CC(C)N(C(=O)CC#N)c1ccc2nc(S)sc2c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCNS(=O)(=O)c1ccc(C=C(C#N)C(=O)N(c2ccc3nc(S)sc3c2)C(C)C)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
α-cyano-N-isopropyl-N-(2-mercaptobenzothiazol-6-yl)acetamide (71 mg, 0.244 mmol) and N-ethyl-4-formylbenzenesulfonamide (52 mg, 0.244 mmol) were combined in absolute ethanol (1 ml). The mixture was stirred 15 minutes with activated 4A molecular sieves in a sealed vessel. Piperidine (27 μL, 0.268 mmol) was added and the mixture was heated to 80° C. After 1.5 hours, the solution was concentrated in vacuo and purified by preparative TLC (50% ethyl acetate, 50% hexanes) to yield 19 mg (16%). 1H NMR(CDCl3) δ=1.08 (t, 3H), 1.20 (m, 6H), 2.99 (t, 2H), 4.98 (m, 1H), 5.41 (m, 1H), 7.17 (d, 1H), 7.32 (m, 3H), 7.81 (d, 2H), 7.88 (d, 2H), 7.96 (s, 1H).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>>[CH2:13]([N:17]([CH2:18][CH2:19][CH2:20][CH3:21])[C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCNCCCC
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N(CCCC)CCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and dibutylamine as starting materials to give the aimed compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:28]=2)=[O:24])[CH:20]=[C:19]([Cl:41])[C:18]=1O.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:18]1[C:17]([Cl:16])=[CH:22][C:21]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][Si:34]([C:37]([CH3:39])([CH3:38])[CH3:40])([CH3:35])[CH3:36])[CH:28]=2)=[O:24])=[CH:20][C:19]=1[Cl:41])(=[O:5])=[O:4]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CNC(=O)c2cc(Cl)c(O)c(Cl)c2)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(CNC(=O)c2cc(Cl)c(OS(=O)(=O)C(F)(F)F)c(Cl)c2)c1
Temperature: -70 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
Trifluoromethanesulfonic anhydride (3.55 mL, 21.1 mmol) was added to a cooled (−75° C. ) solution of 2,6-dichloro-4-[[[[3-[[(1,1-dimethylethyl)dimethyl-silyl]oxy]phenyl]methyl]amino]carbonyl]phenol (7.50 g, 17.6 mmol) and triethylamine (9.8 mL, 70.4 mmol) in dry dichloromethane (70 mL). After stirring for 3 h at ˜−70° C., the reaction was quenched with solid ammonium chloride (6 g). The solvent was evaporated and ethyl acetate was added. The solution was washed with 1 N HCl, saturated aqueous sodium bicarbonate and brine. The organic layer was dried (MgSO4), filtered, evaporated and dried under high vacuum to give trifluoromethanesulfonic acid, 2,6-dichloro-4-[[[[3-[[(1,1-dimethylethyl)dimethyl-silyl]oxy]phenyl]methyl]amino]carbonyl]phenyl ester (9.46 g, 97%) as pale orange oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[CH2:25][CH:24]([CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:29][CH2:28]3)[C:22](=[O:23])[C:17]2=[CH:18][C:19]=1[O:20][CH3:21]>C(OCC)(=O)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[CH2:25][CH:24]([CH2:26][CH:27]3[CH2:28][CH2:29][N:30]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:31][CH2:32]3)[C:22](=[O:23])[C:17]2=[CH:18][C:19]=1[O:20][CH3:21].[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C

Procedure:
Para-toluenesulfonic acid (1.902 g, dissolved in 35 ml of absolute ethanol) is slowly added to a solution of Donepezil (3.79 g) in ethyl acetate (70 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 170.8° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([N:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=1.C([Li:15])CCC.CCCCCC>CCOCC>[CH3:7][N:6]([CH3:8])[C:5]1[CH:9]=[CH:10][C:2]([Li:15])=[CH:3][CH:4]=1
Reactant: [Li]CCCC
Reactant: CN(C)c1ccc(Br)cc1
Solvent: CCCCCC
Solvent: CCOCC
Product: [Li]c1ccc(N(C)C)cc1
Reaction time: 4 h

Procedure:
A solution of 20 g (0.1 mol) of p-bromo-N,N-dimethylaniline in 150 mL of anhydrous ether was treated dropwise over 1 h at 0°-5° with a solution of 40 mL of 2.45 M n-butyl lithium in hexane (0.1 mol) in 50 mL of anhydrous diethyl ether. The mixture was stirred at 0.5° for 11/4 h and then allowed to warm to 22°. An additional 1.0 mL of n-butyl lithium solution was added. The mixture was connected to a vacuum line and a distillation receiver bulb cooled in a dry ice bath. The solvents and volatile by-products were removed in vacuo (mechanical pump) at 15°-20°, leaving a pale cream powder of 4-dimethylaminophenyl lithium reagent. The solid was pulverized under argon in the same flask and then further pumped in vacuo at 25° for 20 minutes to remove all volatiles. The lithium reagent was then dissolved in 150 mL of anhydrous ether and treated rapidly with a solution of 5.8 g (5.8 mL×0.03 mol) of di(n-butyl)phosphite in 50 mL of anhydrous ether at 5°-10°. The resulting white slurry was treated with 50 mL of tetrahydrofuran, and the resulting colorless solution was allowed to stir for 12 h at 23°. The mixture was then poured into 200 mL of water and adjusted to neutral pH with a few drops of dilute aqueous sulfuric acid. The organic layer was separated, the aqueous layer was extracted once with 75 mL of diethyl ether, and the combined ether layers were washed (brine) and dried (sodium sulfate) and stripped of solvent to give the crude product as a colorless oil. Addition of 50 mL of fresh ether caused precipitation of 6.6 g (76%) of bis-(4-dimethylaminophenyl)phosphine oxide as a colorless solid, mp 140°-165°. Two recrystallizations from benzene gave 3.1 g (36%) of analytically pure product, mp 150°-170° (in air).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6]1([CH:16]=O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1>CS(C)=O>[C:6]1([C:16]2[C:2]3[NH:1][C:5](=[CH:4][CH:3]=3)[C:16]([C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=[CH:8][CH:7]=3)=[C:5]3[N:1]=[C:2]([CH:3]=[CH:4]3)[C:16]([C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=[CH:8][CH:7]=3)=[C:2]3[NH:1][C:5]([CH:4]=[CH:3]3)=[C:16]([C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=[CH:8][CH:7]=3)[C:5]3=[N:1][C:2]=2[CH:3]=[CH:4]3)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: c1cc[nH]c1
Reactant: O=Cc1cccc2ccccc12
Solvent: CS(C)=O
Product: C1=Cc2nc1c(-c1cccc3ccccc13)c1ccc([nH]1)c(-c1cccc3ccccc13)c1nc(c(-c3cccc4ccccc34)c3ccc([nH]3)c2-c2cccc3ccccc23)C=C1

Procedure:
Tetra-(1-naphthyl) porphine (designated TNP) was prepared from the following reactants in a DMSO solvent: pyrrole and 1-naphthaldehyde. Prior to mixing the reactants, pyrrole was distilled under an argon atmosphere with the fraction boiling at 130° C. collected. The 1-naphthaldehyde was distilled under vacuum to purify. A mixture of 6.0 g of pyrrole, 13.7 g of 1-naphthaldehyde, and 120 ml or DMSO were heated at reflux for 2 hours. The reaction solution was cooled and the DMSO solvent partially removed under vacuum. The solid that was present was filtered off and washed with 60 ml of methanol, 60 ml of hot water, and 12 ml of cold methanol. The resulting solid was then dried in a vacuum oven at ambient temperature overnight.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:10][C@@H:9]2[C:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][N:17]=2)[CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:29][C:30]1([CH3:34])[CH2:33][O:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:29][C:30]1([CH2:34][O:1][C:2]2[CH:3]=[C:4]([C@H:8]3[CH2:10][C@@H:9]3[C:11]([NH:13][C@@H:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[CH:18][N:17]=3)[CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=2)[CH2:33][O:32][CH2:31]1
Reactant: C[C@@H](NC(=O)[C@H]1C[C@@H]1c1cccc(O)c1)c1ccc(OCC(F)(F)F)cn1
Reactant: CC1(CCl)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](NC(=O)[C@H]1C[C@@H]1c1cccc(OCC2(C)COC2)c1)c1ccc(OCC(F)(F)F)cn1
Temperature: 70 °C
Reaction time: 15 h
Yield: 49.1 %

Procedure:
A mixture of (1S*,2S*)-2-(3-hydroxyphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide (15 mg, 0.039 mmol), 3-(Chloromethyl)-3-methyloxetane (24 mg, 0.197 mmol) and potassium carbonate (27 mg, 0.197 mmol) in DMF (2 mL) was heated at 70° C. with stirring for 15 hours. The mixture was poured into water, and the aqueous layer was extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative LC-MS to give 8.9 mg (49% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH3:20])[O:19]CCO2)=[CH:11][C:10]=1[CH2:21][CH2:22][OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:19])[CH3:20])=[CH:11][C:10]=1[CH2:21][CH2:22][O:23][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(c2ccc(OCc3ccccc3)c(CCO)c2)OCCO1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(OCc2ccccc2)c(CCOCc2ccccc2)c1
Temperature: 0 °C

Procedure:
2-[2-Benzyloxy-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]ethanol (9.0 g) was dissolved in N,N-dimethylformamide (100 ml), and 60% sodium hydride in oil (1.26 g) was added to the solution under ice-cooling with stirring. After reaction for an hour at room temperature, benzyl bromide (3.75 ml) was added to the reaction mixture under ice-cooling with stirring, followed by reaction for 16 hours at room temperature. Ice (100 g) and water (100 ml) were added to the reaction mixture, and the resulting mixture was extracted with diethyl ether, then the solvent was removed in vacuo. The residue was dissolved in 1,2-dimethoxyethane (50 ml), and 1 N hydrochloric acid (10 ml) was added to the solution, then the resulting mixture was stirred for 30 minutes at room temperature. Water was added to the reaction mixture, and the resulting mixture was extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/diethyl ether=2/1) gave 4'-benzyloxy-3'-(2-benzyloxyethyl)acetophenone (8.5 g) as an oil.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15][C@H:16]2[O:33][C@H:32]([CH2:34][O:35]C(=O)C)[C@@H:27]([O:28]C(=O)C)[C@H:22]([O:23]C(=O)C)[C@H:17]2[O:18]C(=O)C)[C@@H:8]([CH2:39][O:40]C(=O)C)[O:7][C@H:6]1[O:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([OH:51])[C:46]=1[C:52](=[O:54])[CH3:53])(=O)C.[S:55]1[CH:59]=[CH:58][C:57]2[CH:60]=[C:61]([CH:64]=O)[CH:62]=[CH:63][C:56]1=2>>[C@H:16]1([O:15][C@@H:9]2[C@@H:8]([CH2:39][OH:40])[O:7][C@@H:6]([O:44][C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([OH:51])[C:46]=3[C:52](=[O:54])[CH2:53][CH2:64][C:61]3[CH:62]=[CH:63][C:56]4[S:55][CH:59]=[CH:58][C:57]=4[CH:60]=3)[C@H:5]([OH:4])[C@H:10]2[OH:11])[O:33][C@H:32]([CH2:34][OH:35])[C@@H:27]([OH:28])[C@H:22]([OH:23])[C@H:17]1[OH:18]
Reactant: CC(=O)OC[C@H]1O[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](Oc3cccc(O)c3C(C)=O)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=Cc1ccc2sccc2c1
Product: O=C(CCc1ccc2sccc2c1)c1c(O)cccc1O[C@@H]1O[C@H](CO)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Yield: 51.8 %

Procedure:
2' -[2,3,6-Tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-β-D-glucopyranosyloxy]-6'-hydroxyacetophenone (1541 mg) and benzo[b]thiophene-5-carbaldehyde (389 mg) are treated in the same manner as in Example 1 to give 2'-[4-O-(α-D-glucopyranosyl)-β-D-glucopyranosyloxy]-6'-hydroxy-3-(5-benzo[b]thienyl)propiophenone (645 mg).
Reaction SMILES: [NH2:1][CH:2]([CH3:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C([O-])(O)=O.[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>O.C(#N)C>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH:2]([NH:1][C:17](=[O:19])[CH3:18])[CH3:11])=[CH:5][CH:6]=1
Reactant: CC(N)Cc1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)NC(C)Cc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
1.88 g (10.0 mmol) 4-(2-amino-propyl)-phenol*HCl and 1.80 g (21.0 mmol) NaHCO3 are combined in 50 mL water and cooled down to 0° C. 0.95 mL (10.0 mmol) acetic anhydride, dissolved in 50 mL ACN, are dropped into the mixture over a period of 1.5 h. The reaction mixture is stirred at r.t. for 72 h. The ACN is evaporated in vacuo and the aq. residue is acidified with HCl (1N). The mixture is extracted several times with EtOAc. The organic layers are combined, dried with Na2SO4 and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, DCM/MeOH 95/5).
Reaction SMILES: CN1CCOCC1.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O-:10])=[O:9].[C:18](Cl)(=[O:26])[O:19][CH2:20][O:21][C:22](=[O:25])[CH2:23][CH3:24]>C(Cl)Cl>[C:18](=[O:26])([O:19][CH2:20][O:21][C:22](=[O:25])[CH2:23][CH3:24])[O:17][C:14]1[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCC(=O)OCOC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(=O)OCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 60.7 %

Procedure:
4-Methylmorpholine (0.67 mL, 6.0 mmol) is added to a suspension of 4-nitrophenol (0.83 g, 6.0 mmol) in CH2Cl2 (10 mL) with stirring. A solution of 7c (1.27 g, 95% purity, 7.2 mmol) in CH2Cl2 (3 mL) is added during 20 min followed by stirring at 0° C. (30 min) and overnight at room temperature. After filtration the filtrate is evaporated and the residue partitioned between ice-cold Et2O (25 mL) and H2O (25 mL). The organic phase is extracted with ice-cold 0.5N NaOH (10 mL), H2O (3×15 mL), dried (MgSO4) and evaporated. The residue (1.50 g) is extracted with hexane (2×10 mL) to leave the title compound (0.98 g, 61%), mp 35°-36° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([O:20][CH3:21])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)([O-])[O-].[K+].[K+].F[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N+:35]([O-:37])=[O:36]>CN(C)C=O.CCOCC>[C:1]([NH:8][C@H:9]([C:18]([O:20][CH3:21])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N+:35]([O-:37])=[O:36])=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(Oc2ccccc2[N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of N-Boc-(L)tyrosine, methyl ester (500 mg) and potassium carbonate (467 mg) in dimethylformamide (5 mL) was added dropwise 1-fluoro-2-nitrobenzene (189 μL). The yellow solution was stirred for 3 days at room temperature. The mixture was diluted with ether which was subsequently washed with 1N hydrochloric acid, water, saturated salt solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed by rotoevaporation to yield the title compound (700 mg) which was used in the subsequent reaction without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[Br:23]Br>C(Cl)(Cl)Cl.O>[F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]2[C:10]([Br:23])=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1
Reactant: COc1c(F)cnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1c(F)cnc2c1c(Br)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cold (0° C.) solution of 5-fluoro-4-methoxy-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 68b, (0.79 g, 2.45 mmol) in chloroform (50 mL) was added bromine (0.13 mL, 2.45 mmol). The reaction mixture was stirred at 0° C. for 3 hours and then slowly warmed to ambient temperature. The mixture was diluted with deionized water and quenched with aqueous sodium bicarbonate. The aqueous phase was extracted with methylene chloride and dried over sodium sulfate. The resulting solid was purified via silica gel chromatography (15-30% EtOAc/Hexanes) to give 170 mg of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:12][C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:16]=[CH:15][CH:14]=2)=[C:7]([CH:11]=1)[C:8](O)=[O:9].Cl.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[CH2:25]([NH:32][C:8](=[O:9])[C:7]1[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[NH:12][C:13]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:16]=[CH:15][CH:14]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(Nc2ccnn2-c2ccccc2)c(C(=O)O)c1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2ccnn2-c2ccccc2)c(C(=O)NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.9 %

Procedure:
A mixture of 5-methoxy-2-[(1-phenyl-1H-pyrazol-5-yl)amino]benzoic acid (made by Ullmann reaction as described in Example 1, 42.0 mg, 0.14 mmol), benzylamine hydrochloride (23.4 mg, 0.16 mmol), EDCI (31.2 mg, 0.16 mmol), HOBT (22.0 mg, 0.16 mmol), and triethylamine (0.066 mL, 0.48 mmol) in DMF (3 mL) was stirred at rt for 16 h. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Flash chromatography of the residue over silica gel, using 20% ethyl acetate/hexane, gave the title compound (16.1 mg, 30%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.72 (s, 1H), 9.14 (t, 1H), 7.57 (d, 1H), 7.38-7.51 (m, 4H), 7.16-7.36 (m, 7H), 6.96-7.06 (m, 2H), 6.15 (s, 1H), 4.37 (d, 2H), 3.70 (s, 3H); ES-MS m/z 399.1 (MH+), HPLC RT (min) 3.72.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[CH2:12][CH2:11][C:10]2[C:9]([C:13]([NH2:15])=[O:14])=[C:8]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:7]=[CH:6][C:5]=2[C@H:4]1[OH:24].[CH2:25]([CH2:32][C:33](=O)[CH3:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([BH3-])#N.[Na+]>CO.O>[ClH:1].[CH2:17]([O:16][C:8]1[CH:7]=[CH:6][C:5]2[C@@H:4]([OH:24])[C@H:3]([NH:2][CH:33]([CH3:34])[CH2:32][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:12][CH2:11][C:10]=2[C:9]=1[C:13]([NH2:15])=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(=O)c1c(OCc2ccccc2)ccc2c1CC[C@@H](N)[C@@H]2O
Reactant: CC(=O)CCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(CCc1ccccc1)N[C@@H]1CCc2c(ccc(OCc3ccccc3)c2C(N)=O)[C@H]1O
Reaction time: 8 h
Yield: 60.9 %

Procedure:
In 30 ml of methanol was dissolved 1 g of trans-6-amino-2-benzyloxy-5-hydroxy-5,6,7,8-tetrahydro-1-naphthalenecarboxamide hydrochloride, followed by addition of 5 g of benzylacetone. Then, under ice-cooling, 1 g of sodium cyanoborohydride was added and the mixture was allowed to stand at room temperature overnight. The reaction mixture was diluted with 300 ml of water and extracted 3 times with 30 ml of CHCl3. The CHCl3 layers were combined, washed with water, dried and concentrated under reduced pressure. The residue was dissolved in 50 ml of ethyl ether, followed by addition of 5 ml of 20% ethanolic hydrochloric acid, whereby 0.84 g of trans-2-benzyloxy-5-hydroxy-6-(1-methyl-3-phenylpropylamino)-5,6,7,8-tetrahydro-1-naphthalenecarboxamide hydrochloride was obtained as colorless crystals, m.p. 215°-218° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:9]=1)=[O:4].C(N(CC)C(C)C)(C)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][CH:32]=O)[CH:27]=[CH:28][CH:29]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH:13][CH2:32][CH2:31][CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[CH:25]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: O=CCCc1cccc(Cl)c1
Reactant: COC(=O)c1ccc(CCCN)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CCCNCCCc2cccc(Cl)c2)s1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97.2 %

Procedure:
A solution of 5-(3-amino-propyl)-thiophene-2-carboxylic acid methyl ester (from Preparation 5, Step C, 0.118 g, 0.5 mmol) and N,N-diisopropylethylamine (0.071 g, 0.55 mmol) in 10 mL MeOH was stirred at room temperature for 30 minutes and 3-(3-chloro-phenyl)-propionaldehyde (from Preparations 3, 0.093 g, 0.55 mmol) was added. The mixture was stirred for 90 minutes. The reaction was cooled to 0° C., NaBH4 (30.3 mg, 0.801 mmol) was added and the mixture was stirred for 30 minutes. The reaction was quenched with 1:1 NaHCO3:H2O and was washed with CH2Cl2. The CH2Cl2 extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound as an oil (171 mg). MS 352 (M+1).
Reaction SMILES: CS(O[CH2:6][C:7]([F:19])([F:18])[CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)=O.CN(C=O)C.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K]>O>[CH2:11]([O:10][CH2:9][CH2:8][C:7]([F:19])([F:18])[CH2:6][N:29]1[C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]2[C:25]1=[O:35])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OCC(F)(F)CCOCc1ccccc1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC(F)(F)CCOCc1ccccc1
Temperature: 120 °C

Procedure:
The compound 1-methanesulfonyloxy-2,2-difluoro-4-benzyloxybutane (21.8 g, 74.1 mM), dry DMF (100 mL), and potassium phthalimide (15.26 g, 10% excess) are stirred and heated under nitrogen, at 120° C. for 5 days. Following the addition of water (500 mL), the mixture is extracted with ether. The organic phase is washed with 1N CCl followed by water (twice), dried (Na2SO4) and concentrated to a volume of about 100 mL. Upon addition of petroleum ether, crystallization occurs. After chilling for 3 hours at 5° C., beige crystals of the compound N-(4-benzyloxy-2,2-difluorobutyl)phthalimide are obtained, filtered and washed with petroleum ether: 18 g (70%).