Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:6]=[C:7]([CH3:16])[C:8]2[O:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]=2[CH:15]=1)([CH3:3])[CH3:2].[CH2:17]([O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1)[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:17]([O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]2[CH:6]=[C:7]([CH3:16])[C:8]3[O:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=3[CH:15]=2)=[CH:23][CH:22]=1)[CH3:18]
Reactant: Cc1cc(NC(C)C)cc2c1OCC2(C)C
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N(c2cc(C)c3c(c2)C(C)(C)CO3)C(C)C)cc1
Yield: 13.9 %

Procedure:
Following general procedure E and using 5-(isopropyl)amino-3,3,7-trimethyl-2,3-dihydro-benzofuran (Compound 33, 0.43 g, 1.96 mmol), ethyl-4-iodo-benzoate (0.516 g, 2.4 mmol), cesium carbonate (0.92 g, 2.8 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.015 g, 0.015 mmol) and (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.030 g, 0.047 mmol) in 8 mL of anhydrous toluene, the title compound (0.1 g), contaminated with 10% of ethyl-4-iodo-benzoate, was obtained. Some 5-(isopropyl)amino-3,3,7-trimethyl-2,3-dihydro-benzofuran (Compound 33, 0.21 g) was recovered. 1H NMR (300 MHz, CDCl3): δ 7.82 (d, 2H, J=9.1 Hz), 6.68 (d, 1H, J=2.3 Hz), 6.66 (d, 1H, J=2.3 Hz), 6.51 (d, 2H, J=9.1 Hz), 4.35-4.27 (m, 3H), 4.31 (s, 2H), 2.22 (s, 3H), 1.35-1.30 (m, 3H), 1.34 (s, 6H), 1.15 (d, 6H, J=6.5 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:17]2[CH2:22][C:21]([CH3:24])([CH3:23])[O:20][C:19]([CH3:26])([CH3:25])[CH2:18]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:16])[CH:10]=2)=[CH:4][CH:3]=1.[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH:28]=[CH2:29].CCN(CC)CC.CN(C=O)C>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.CCOC(C)=O.O>[F:16][C:11]1[CH:10]=[C:9]([C:8](=[C:17]2[CH2:18][C:19]([CH3:26])([CH3:25])[O:20][C:21]([CH3:23])([CH3:24])[CH2:22]2)[C:5]2[CH:4]=[CH:3][C:2](/[CH:29]=[CH:28]/[C:27]([O:31][CH2:32][CH3:33])=[O:30])=[CH:7][CH:6]=2)[CH:14]=[CH:13][C:12]=1[OH:15]
Reactant: C=CC(=O)OCC
Reactant: CC1(C)CC(=C(c2ccc(Br)cc2)c2ccc(O)c(F)c2)CC(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)c(F)c2)cc1
Temperature: 100 °C
Yield: 74.4 %

Procedure:
To a round-bottomed flask were added 4-[(4-bromophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]-2-fluorophenol (136) (0.40 g, 0.95 mmol), ethyl acrylate (1.05 mL, 9.54 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.067 g, 0.10 mmol), Et3N (0.70 mL, 4.77 mmol) and DMF (12 mL). The stirred reaction mixture was heated overnight at 100° C. under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and transferred to a separatory funnel with the aid of water and EtOAc (100 mL). The layers were separated and the organic phase was washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give brown oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 20% EtOAc:hexanes to give 0.31 g (74%) of the title compound 137 as a light yellow foam. 1H NMR (400 MHz, CDCl3): δ 1.21 (s, 6H), 1.23 (s, 6H), 1.33 (t, J=7.1 Hz, 3H), 2.22 (s, 2H), 2.24 (s, 2H), 4.26 (q, J=7.1 Hz, 2H), 5.44 (br s, 1H), 6.40 (d, J=15.9 Hz, 1H), 6.80-6.90 (m, 2H), 6.93 (t, J=8.5 Hz, 1H), 7.17 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.3 Hz, 2H), 7.65 (d, J=15.9 Hz, 1H). LCMS (ES): m/z, 439 (M+H)+, 437 (M−H)−.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)C[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.Cl.NC1CCN(CCN2CCC([OH:54])CC2)CC1>>[OH:54][CH:4]1[CH2:3][CH2:2][N:1]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:14][CH2:15]2)[CH2:6][CH2:5]1
Reactant: Cc1cccc(Oc2cccc3[nH]c(C(=O)NC4CCN(CCN5CCCCCC5)CC4)cc23)c1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: Cc1cccc(Oc2cccc3[nH]c(C(=O)NC4CCN(CCN5CCC(O)CC5)CC4)cc23)c1

Procedure:
This compound is synthesized analogously to Example 1 from 4-m-tolyloxy-1H-indole-2-carboxylic acid 133 (see example 112) and amine 21.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15]([CH3:16])=[C:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=2)[C:13]([O:28][C@@H:29]2[O:37][C@H:36]([CH2:38][OH:39])[C@@H:34]([OH:35])[C@H:32]([OH:33])[C@H:30]2[OH:31])=[N:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:41]([O:43][CH2:44][CH3:45])=[O:42].O.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC1C=C(C)C=C(C)N=1>[CH2:1]([O:8][C:9]([N:11]1[C:15]([CH3:16])=[C:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:23]=2)[C:13]([O:28][C@@H:29]2[O:37][C@H:36]([CH2:38][O:39][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C@@H:34]([OH:35])[C@H:32]([OH:33])[C@H:30]2[OH:31])=[N:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1c(Cc2ccc(OC(C)C)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1C(=O)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)OC[C@H]1O[C@@H](Oc2nn(C(=O)OCc3ccccc3)c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1-(benzyloxycarbonyl)-3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methylpyrazole (0.20 g) in 2,4,6-trimethylpyridine (4 mL) was added ethyl chloroformate (0.092 mL), and the mixture was stirred at room temperature for 1 day. To the reaction mixture were added water and citric acid monohydrate, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 1-(benzyloxycarbonyl)-3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methylpyrazole (0.17 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH3:13])[CH:5]=[N:6][CH:7]=1.[C:14]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:19]=CC=C[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>[Pd].[Cu]I.O>[C:15]([C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH3:13])[CH:5]=[N:6][CH:7]=1)#[C:14][CH3:19]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CN1CCCC1c1cncc(Br)c1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC#Cc1cncc(C2CCCN2C)c1
Temperature: 90 °C
Yield: 312.1 %

Procedure:
A Parr hydrogenation vessel was charged with 5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine (1 g, 4.15 mmol), 10% palladium on charcoal (106 mg, 0.1 mmol), copper(I)iodide (38 mg, 0.2 mmol), triphenylphosphine (104 mg, 0.4 mmol) and potassium carbonate (1.38 g, 10 mmol), DME (10 mL) and water (10 mL). The vessel was evacuated and propyne gas was introduced to a pressure of 20 p.s.i. The mixture was agitated and heated at 90° C. for 6 days, readmitting propyne gas as necessary. Analysis by GC at this stage indicated about 40% completion and the cooled mixture was filtered through celite and the filtrate concentrated in vacuo. The mixture was then acidified with 1M HCl (50 mL) and extracted with toluene (50 mL). The aqueous layer was made basic with solid potassium carbonate and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate extracts were washed with water (50 mL), dried (MgSO4) and concentrated to afford an oil. The crude product was purified by silica gel column chromatography with ethyl acetate:hexane (1:1) as eluant to afford 5-propynyl-3-(1-methyl-2-pyrrolidinyl)pyridine (250 mg, 30%). A portion (225 mg) of this material was converted to the title compound by the addition of one equivalent of fumaric acid to a methanol (10 mL) solution of the free amine at 25° C. After 30 minutes the solvent was removed in vacuo and the residue pumped under high vacuum. Trituration with diethyl ether followed by recrystallization from ethyl acetate afforded 5-[1-(1-propynl)]-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate, 180 mg, 50%. M.p. 188°-189° C. (EtOAc); 1H NMR (DMSO-d6, 300 MHz): δ 8.49 (s, 1H), 8.47 (s, 1H), 7.77 (s, 1H), 6.60 (s, 2H), 3.34 (t, J=9 Hz, 1H), 3.25 (app. t, J=9 Hz, 1H), 2.41 (dd, J=9, 9 Hz, 1H), 2.22 (m, 1H), 2.16 (s, 3H), 2.08 (s, 3H), 1.85 (m, 2H), 1.69 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4](Br)[CH2:5][CH2:6][CH2:7][CH3:8].[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[CH3:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:10])[CH:4]([O:18][C:15]1[CH:16]=[CH:17][C:12]([F:11])=[C:13]([CH3:19])[CH:14]=1)[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Cc1cc(O)ccc1F
Reactant: CCCCC(Br)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(Oc1ccc(F)c(C)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 88 h
Yield: 76.4 %

Procedure:
To a solution of 2-bromo-hexanoic acid methyl ester (0.500 g, 2.404 mmol) and 4-fluoro-3-methylphenol (0.303 g, 2.404 mmol) in 15 mL of DMF, was added K2CO3 (1.661 g, 12.020 mmol). After stirring at room temperature under N2 for 88 h, the reaction mixture was diluted with 60 mL of water and extracted with dichloromethane (60 mL×3). The organic extracts were combined and dried over anhydrous Na2SO4. After removing the solvent under reduced pressure, the product was isolated by Flash chromatography (silica gel) eluting with 0-20% ethyl acetate/hexanes to give the title compound as yellow oil (0.467 g, 76% yield). LC-MS: tR=10.5 min; m/z 255 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[Br:35][CH2:36][CH2:37][CH2:38][C:39](Cl)=[O:40].C(N(CC)CC)C.ClCC(NC1N=C2C(C3C=CC=C(C(F)(F)F)C=3)=C(C)C(C3N(C4C=CC(C#N)=CC=4)N=CC=3)=CN2N=1)=O>>[Br:35][CH2:36][CH2:37][CH2:38][C:39]([NH:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1)=[O:40]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)CCCBr
Agent: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCl)nc2c1-c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCCBr)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 4-{5-[2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 400 mg, 1.0 mmol), 4-bromo-butyryl chloride (0.5 mL, 4.32 mmol) and triethylamine (0.84 mL, 6.02 mmol) instead of DIPEA using a similar method to that employed for Intermediate 17 (362 mg).
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].[CH:5]1[CH2:9][CH:8]=[CH:7][CH:6]=1>>[CH:6]12[CH2:5][CH:9]([CH:3]([CH:1]=[O:2])[CH2:4]1)[CH:8]=[CH:7]2
Reactant: C1=CCC=C1
Reactant: C=CC=O
Product: O=CC1CC2C=CC1C2

Procedure:
The exo,exo-2,5-norbornanedicarboxaldehyde; exo,exo-2,6-norbornanedicarboxaldehyde; exo,endo-2,5-norbornanedicarboxaldehyde; exo,endo-2,6-norbornanedicarboxaldehyde; endo,endo-2,5-norbornanedicarboxaldehyde; and endo,endo-2,6-norbornanedicarboxaldehyde product (endo and exo mixture) can be prepared by a process comprising reacting acrolein and cyclopentadiene in a Diels-Alder reaction to give a 2-norbornene-5-carboxaldehyde, and hydroformylating the 2-norbornene-5-carboxaldehyde.
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:29])=[N:26][CH:27]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1oc(-c2ccc(F)cc2)cc1C(Nc1ccc(C(=O)O)nc1)C1CCCCC1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(-c3ccc(F)cc3)oc2C)C2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.4 %

Procedure:
A mixture of 3-[chloro(cyclohexyl)methyl]-5-(4-fluorophenyl)-2-methylfuran (1.3 g), methy 5-aminopyridine-2-carboxylate (0.7 g), sodium carbonate (0.5 g) and sodium iodide (1.4 g) in N,N-dimethylacetamide (20 mL) was stirred at 80° C. for 10 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL). 2N Lithium hydroxide (5 mL) was added, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-({cyclohexyl[5-(4-fluorophenyl)-2-methylfuran-3-yl]methyl}amino)pyridine-2-carboxylic acid. To the obtained 5-({cyclohexyl[5-(4-fluorophenyl)-2-methylfuran-3-yl]methyl}amino)pyridine-2-carboxylic acid (694 mg) were added ethyl β-alaninate hydrochloride (261 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (326 mg), hydroxybenzotriazole monohydrate (260 mg), triethylamine (237 μl) and N,N-dimethylformamide (10 mL), and the obtained mixture was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (5% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound (521 mg, 60%) as an amorphous compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11](O)[CH:10]([CH2:14][N:15]=[N+:16]=[N-:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH:11]([Cl:21])[CH:10]([CH2:14][N:15]=[N+:16]=[N-:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCC1CN(Cc2ccccc2)CC1O
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: [N-]=[N+]=NCC1CN(Cc2ccccc2)CC1Cl
Yield: 40.3 %

Procedure:
1-Benzyl-4-hydroxy-3-azidomethylpyrrolidine (59.7 g) is added to chloroform (100 ml), and the mixture is saturated with dry hydrogen chloride gas. A solution of thionyl chloride (61.2 g) in chloroform (100 ml) is added dropwise to the mixture under reflux. After refluxing for 2 hours, the mixture is concentrated. To the residue is added ethanol and the excess thionyl chloride is removed, and then, the mixture is again concentrated. After neutralizing the concentrate with an aqueous sodium hydrogen carbonate, the mixture is extracted with dichloromethane. The dichloromethane layer is washed with water, dried and concentrated, and the resulting residue is then purified by silica gel column chromatography (solvent, ethyl acetate-n-hexane) to give 1-benzyl-3-azidomethyl-4-chloropyrrolidine (26.0 g) as an yellow oil.
Reaction SMILES: F[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([N+:15]([O-])=O)[C:3]=1[NH2:18]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[CH:14]1([N:11]2[CH2:12][CH2:13][N:8]([C:7]3[CH:2]=[C:3]([NH2:18])[C:4]([NH2:15])=[CH:5][CH:6]=3)[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2][CH2:7]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: Nc1ccc(N2CCN(C3CCCC3)CC2)cc1N

Procedure:
A reaction tube was charged with a suspension of 1 (270 mg, 0.9 mmol) and Lindlar catalyst (192 mg, 10 mol %) in methanol (5 mL), and was then placed on a Parr shaker. The was reaction pressurized with H2 (60 psi) and maintained for 1 h. The reaction was filtered through Celite and the remained solids were washed with methanol. The combined organics were concentrated to give 2 as a brown semi-solid which was carried forward without further purification LCMS m/z 273.3 (MH+), tR=1.56 min.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH:13]([CH3:14])[CH2:12][N:11](C(=O)C(F)(F)F)[CH2:10][CH2:9][C:8]=2[N:21]=1.C([O-])([O-])=O.[K+].[K+].CO>O>[F:22][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH:13]([CH3:14])[CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[N:21]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2nc(OC(F)F)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC1CNCCc2nc(OC(F)F)ccc21
Yield: 35.7 %

Procedure:
To a mixture of 5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (77.0 mg, 281 μmol), K2CO3 (19.0 mg, 141 μmol) and DMF (1.4 ml) was added F2ClCCO2Na (47.0 mg, 310 μmol). The mixture was heated at 90° C. for 2 h. The reaction mixture was parted between sat. aq. NaHCO3 and EtOAc. The organic layer was dried, concentrated in vacuo and purified by means of column chromatography to give 49.0 mg (54%) of 2-(difluoromethoxy)-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. MS (ESI) m/z 325.2. A mixture of 2-(difluoromethoxy)-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (28.0 mg, 86.0 μmol), K2CO3 (30 mg), MeOH (1 ml) and H2O (200 μl) was heated to reflux for 10 min. The reaction mixture was concentrated in vacuo and the resulting residue was purified by column chromatography to yield 7.0 mg (36%) of 2-(difluoromethoxy)-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 7.46 (d, 1H), 6.66 (d, 1H), 3.09 (m, 2H), 3.40-2.90 (m, 4H), 2.74, (dd, 1H), 1.31 (d, 3H) ppm.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>>[CH3:21][C:18]1([CH3:22])[CH2:19][CH2:20][N:15]([C:13](=[O:14])[CH2:12][N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3](=[O:4])[CH2:2][NH:1][C:31]([NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[CH:25]=2)=[O:32])[CH2:16][CH2:17]1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC1(C)CCN(C(=O)CN(C(=O)CN)c2ccccc2)CC1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N2CCC(C)(C)CC2)c2ccccc2)c1
Yield: 48.6 %

Procedure:
The procedure is analogous to that described in Example 1, but 1.0 g of 2-amino-N-[2-(4,4-dimethylpiperidino)-2-oxoethyl]-N-phenylacetamide and 0.44 g of 3-methylphenyl isocyanate are used as the starting material. After recrystallization from an ethyl acetate/acetonitrile mixture (50-50 by volume), 0.7 g of N-[2-(4,4-dimethylpiperidino)-2-oxoethyl]-2-[3-(3-methylphenyl)ureido]-N-phenylacetamide melting at 205° C is obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([S:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22])(=[O:17])=[O:16])[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][S:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22])(=[O:16])=[O:17]
Reactant: NNS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNS(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 100 °C
Yield: 71 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 3-(hydrazinosulfonyl)benzoic acid. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 131 mg of the title compound (71%) as a yellow solid in 87.8% purity by HPLC (Rt: 4.71, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:9][C:7]=2[CH:8]=1.[O:18]([C:25]1[CH:30]=[CH:29][C:28](O)=[C:27]([CH2:32][CH2:33][CH3:34])[CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:30]=[CH:29][C:28]([O:1][CH2:2][CH2:3][C:4]2[O:5][C:6]3[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][C:7]=3[CH:8]=2)=[C:27]([CH2:32][CH2:33][CH3:34])[CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCCc1cc(Oc2ccccc2)ccc1O
Reactant: COC(=O)Cc1ccc2oc(CCO)cc2c1
Product: CCCc1cc(Oc2ccccc2)ccc1OCCc1cc2cc(CC(=O)O)ccc2o1

Procedure:
Using the procedure from Example 1, steps F and G, the title compound was prepared from methyl 2-(2-hydroxyethyl)benzofuran-5-acetate and 4-phenoxy-2-propylphenol as a colorless solid.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:11]1[C:15]2([CH2:20][CH2:19][N:18]([C:21]#N)[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[C:4]1([C:3]2[N:10]=[C:21]([N:18]3[CH2:19][CH2:20][C:15]4([O:11][CH2:12][CH2:13][O:14]4)[CH2:16][CH2:17]3)[O:1][N:2]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N=C(NO)c1ccccc1
Reactant: N#CN1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc(-c2noc(N3CCC4(CC3)OCCO4)n2)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A 0.5 M solution of zinc chloride in tetrahydrofuran (18.00 mL) is added dropwise at room temperature to a mixture of N-hydroxy-benzamidine (817 mg) and 1,4-dioxa-8-aza-spiro[4.5]decane-8-carbonitrile (1.00 g) in ethyl acetate (20 mL). The reaction mixture is stirred at 50° C. for 3 h and cooled to room temperature. The precipitate is filtered off and heated to 100° C. for 1 h in a mixture of ethanol (10 mL) and glacial acetic acid (5 mL). The solvents are evaporated and the crude product is purified by HPLC. TLC: rf=0.88 (silica gel, CH2Cl2/MeOH 9:1); Mass spectrum (ESI+): m/z=288 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].C(O)(=O)C.[NH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:5]=1[C:10](=[O:11])[N:19]([CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[C:7]2=[O:9])([O-:3])=[O:2]
Reactant: NCc1cccnc1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1Cc1cccnc1
Yield: 93.6 %

Procedure:
To a mixture of 15.0 g of 3-nitrophthalic acid anhydride, 233 ml of acetic acid and 80 ml of toluene was added 10.1 g of 3-aminomethylpyridine, and the resultant mixture was refluxed for 1.5 hours under heating. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, washed with 1N aqueous sodium hydroxide and water in order, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 20.6 g of the titled compound.