Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)[N:9]=[C:8]1[CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:25][CH2:24]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[N:9]=[C:8]([CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])[CH2:25][CH2:24]3)[N:7]([CH2:6][CH:2]=[O:1])[CH:11]=2)=[CH:13][C:14]=1[C:19]([F:20])([F:21])[F:22]
Reactant: O=C(OCc1ccccc1)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CC2OCCO2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: O=CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 50 °C

Procedure:
The reaction mixture of benzyl 4-(1-((1,3-dioxolan-2-yl)methyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (1450.00 mg; 2.72 mmol; 1.00 eq.) and toluene-4-sulfonic acid monohydrate (5169.79 mg; 27.18 mmol; 10.00 eq.) in 30 ml of acetone and 2.5 ml of water was stirred at 50° C. for one week. LC-MS showed some a mixture of the desired product, ˜30% of starting material and some by products. The reaction mixture was concentrated and added 50 ml water, extracted with EA. The combined organic layers were washed with brine, dried and concentrated. The residue was subjected to SNAP column (100 g), eluted with 0-100% EA in hexane, then eluted with 10% methanol in DCM to afford the tile compound as yellow oil (480 mg, yield 36%) with a recovery of some starting material.
Reaction SMILES: [CH2:1]([O:13][CH2:14][CH:15]([OH:37])[CH2:16][O:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H-].[Na+].Br[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50].O>O1CCCC1.C(OCC)C>[CH2:1]([O:13][CH2:14][CH:15]([O:37][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:16][O:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
3-Dodecyloxy-1-triphenylmethoxy-2-propanol (13.5 g, 0.027 mol) was added dropwise to an ice-cooled suspension of sodium hydride (80%, 1.6 g, 0.054 mol) in 150 mL of tetrahydrofuran under nitrogen. After stirring for 2 h at room temperature, heat was applied (55° C.). 1-Bromodecane (6 g, 0.027 mol) was added dropwise, and heating continued for 6 h. After cooling for 3 h, water was added slowly. Diethyl ether (2×100 mL) was added, and the solution washed with 15% sodium thiosulfite, water, and brine. After drying over sodium sulfate, the ether was removed, and the residue chromatographed with a gradient of hexanes:ethyl acetate (100:0 to 20:1) to give 9 g (52%) of a clear liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][C:11]3[N:16]=[N:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[C:6]=2[CH:18]=1.Br[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C([O-])(O)=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]4[N:15]([CH:20]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:17]=4)[N:16]=3)[C:6]=2[CH:18]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ccc(Cn2nnc3ccc(Br)cc32)nn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn2nc(Cn3nnc4ccc(Br)cc43)ccc2n1
Temperature: 60 °C
Yield: 73.7 %

Procedure:
A mixture of 6-((6-bromo-1H-benzo[d][1,2,3]triazol-1-yl)methyl)pyridazin-3-amine 10G (4.8 g, 15.73 mmol), ethyl 3-bromo-2-oxopropanoate (4.60 g, 23.60 mmol) and NaHCO3 (4.0 g) in dioxane was heated at 60° C. for 1 hr. Additional ethyl 3-bromo-2-oxopropanoate (1.5 g, 7.87 mmol, 0.5 eq) was added and stirred at 60° C. for an additional hour. The reaction mixture was filtered and rinsed with dioxane. 4-Methylbenzenesulfonic acid (2.71 g, 15.73 mmol) was added to the filtrate, and the reaction was heated at 75° C. for 2 hrs. The reaction was evaporated to dryness via rotary evaporation and the resulting residue was dissolved in EtOAc. The organic phase was washed with saturated NaHCO3 followed by 0.1 N NaOH (3×150 mL). The solution was dried with MgSO4, filtered, concentrated to dryness and purified by MPLC (10% MeOH/CH2Cl2) to provide the title compound, ethyl 6-((6-bromo-1H-benzo[d][1,2,3]triazol-1-yl)methyl)imidazo[1,2-b]pyridazine-2-carboxylate 13A (4.7 g, 11.6 mmol, 50%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (t, J=7.07 Hz, 3 H) 4.30 (q, J=7.07 Hz, 2 H) 6.26 (s, 2 H) 7.33 (d, J=9.60 Hz, 1 H) 7.59 (dd, J=8.72, 1.64 Hz, 1H) 8.08 (d, J=8.84 Hz, 1 H) 8.23 (d, J=9.60 Hz, 1 H) 8.31 (d, J=1.26 Hz, 1 H) 8.77 (s, 1 H). MS:m/z 401.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24]1([C@@H:30]2[CH2:32][C@H:31]2[C:33](Cl)=[O:34])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:33]([CH:31]5[CH2:32][CH:30]5[C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:34])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)C4CC4c4ccccc4)nc3cc21

Procedure:
2-Phenyl-cyclopropanecarboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and trans-2-phenyl cyclopropan-1-carbonyl chloride (137 μl, 0.89 mmol). The title compound was obtained as yellow powder (216 mg, 59%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(Cl)(=O)C(Cl)=O.[C:21]1([O-])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Na+].Cl>ClCCl.O1CCCC1.CN(C)C=O>[C:21]1([O:5][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=[C:10]([CH3:11])[C:2]=2[CH3:1])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C(=O)O)c1C
Reactant: [O-]c1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cc(C(=O)Oc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a solution of 2,3-dimethyl-5-nitrobenzoic acid (1.7 g) in dichloromethane (20 ml) was added oxalylchloride (1.0 ml) and dimethylformamide (0.05 ml). After the solution was stirred for 1 hour at room temperature, the solvent was removed in vacuo. The residue was dissolved in tetrahydrofuran (20 ml). To the solution was added a solution of sodium phenolate (20 mmol) in tetrahydrofuran (20 ml) at 0° C. The mixture was stirred for 30 minutes and poured into diluted hydrochloric acid (110 ml). The organic layer was extracted with ethyl acetate (50 ml) and washed with water (50 ml×3). The solution was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by a column of silica gel to give a yellow solid of 2,3-dimethyl-5-nitrobenzoic acid phenyl ester (1.50 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[CH:4]=[C:5]([C:7]#[N:8])[CH:6]=1.[C:18]([CH2:21][C:22](=O)[CH3:23])(=O)[CH3:19].Cl>C(O)C>[CH:9]1([N:3]2[C:2]3=[N:1][C:18]([CH3:19])=[CH:21][C:22]([CH3:23])=[C:6]3[C:5]([C:7]#[N:8])=[CH:4]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: CC(=O)CC(C)=O
Reactant: N#Cc1cc(N)n(C2CCc3ccccc32)c1
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)c2c(C#N)cn(C3CCc4ccccc43)c2n1
Yield: 45.7 %

Procedure:
To a solution of 2-amino-1-(indan-1-yl)pyrrole-4-carbonitrile (19.4 g), acetylacetone (9.6 g) and ethanol (375 ml) was added concentrated hydrochloric acid (3 ml), and the mixture was heated under reflux for 3 hours. The reaction solution was concentrated under reduced pressure and an aqueous sodium hydrogen carbonate solution was added to the residue, which was extracted with ethyl acetate. After the organic layer was washed with water and dried (MgSO4), the solvent was distilled off under reduced pressure and the crystal was collected by filtration to give 1-(indan-1-yl)-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (11.4 g, 46%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][CH2:12][CH2:13][O:14][C:15]1[C:24]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:23][CH:22]=[CH:21][C:16]=1[C:17](OC)=[O:18].[OH-].[Na+].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][N:11]1[C:17](=[O:18])[C:16]2[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH:26]([CH3:28])[CH3:27])[C:15]=2[O:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1cccc(OC(C)C)c1OCCNCc1c(C)cc(C)[nH]c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cc(C)c(CN2CCOc3c(OC(C)C)cccc3C2=O)c(=O)[nH]1
Reaction time: 25 h
Yield: 15.7 %

Procedure:
A solution of methyl 2-(2-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-amino}ethoxy)-3-(propan-2-yloxy)benzoate (123e, 76.2 mg, 0.196 mmol) in methanol (5.0 mL) was stirred with sodium hydroxide (1.0 M aq., 0.800 mL, 0.800 mmol) for 28 hours at room temperature, then 4.0 M aqueous sodium hydroxide solution (0.5 mL, 2.0 mmol) was added and stirring continued for 25 hours at room temperature. LCMS showed that a portion of the material had spontaneously cyclized, while some uncyclized material remained. The solvents were concentrated under vacuum and the residue acidified to pH˜2 with 1N aqueous hydrochloric acid solution. The resulting white precipitate was collected by suction filtration. The mother liquor was extracted with ethyl acetate (2×10 mL), and the combined extracts dried over magnesium sulfate, filtered, concentrated under vacuum, and combined with precipitate. The aqueous layer was lyophilized and the residue suspended in N,N-dimethylformamide (6.0 mL), passed through a 0.2 micron syringe filter to remove inorganic salts, and then treated with triethylamine (0.08 m L) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 87.0 mg, 0.23 mmol) for 20 hours at room temperature. This mixture was partitioned between deionized water (5 mL) and ethyl acetate (3×15 mL); and the combined organics were dried, filtered, and concentrated under vacuum. This batch was combined with the first batch of product and purified by reverse-phase HPLC to give the title compound 4-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-9-(propan-2-yloxy)-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (Example 123, 11 mg, 16% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.58 (br. s., 1H), 7.05-7.18 (m, 3H), 5.93 (s, 1H), 4.60 (s, 2H), 4.51 (spt, J=6.03 Hz, 1H), 4.01 (t, J=5.38 Hz, 2H), 3.43 (t, J=5.38 Hz, 2H), 2.19 (s, 3H), 2.14 (s, 3H), 1.23 (d, J=6.11 Hz, 6H). MS: 357 [M+H].
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:14][C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([O:13][CH:10]2[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Oc1ccc(F)cc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(F)cc2)C1
Yield: 95.2 %

Procedure:
The title compound (D36) (1.43 g) was prepared according to the experimental procedure described in Description 34 starting from 1-Boc-3-pyrrolidinol (1 g, 5.34 mmol) and 4-Fluorophenol (598 mg, 5.34 mmol).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][CH2:24][C:25]2[NH:34][C:28]3=[N:29][CH:30]=[C:31](I)[CH:32]=[C:27]3[N:26]=2)[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][CH2:24][C:25]2[NH:34][C:28]3=[N:29][CH:30]=[C:31]([C:2]4[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=4)[CH:32]=[C:27]3[N:26]=2)[CH:18]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(C#N)cc4)cnc3[nH]2)c1
Yield: 46.9 %

Procedure:
A mixture of 0.364 g of 4-bromobenzonitrile, 0.56 g of bis-(pinacolato)-diboron, 0.034 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.044 g of [1,1′-bis(diphenylphosphino)ferrocene]palladium-di-chloride 0.588 g of potassium acetate in 20 ml of degassed dioxane are heated to reflux under N2 for 16 hours. To the resulting mixture 13 ml of degassed dioxane, 0.456 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (example 7), 0.139 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.332 g of potassium carbonate and 0.102 g of lithium chloride in 10 ml of degassed water are added under N2. The mixture is heated to reflux under N2 for 30 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 25–20:1). Concentration of the chromatographically pure fractions and crystallisation from ethyl acetate gives 0.2 g of the title compound as a solid of m.p. 241–242° C. The mass spectrum shows the molecular peak MH+ at 356.4 Da.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C@H:7]2[NH:12]C(=O)COC>Cl.CCO>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C@H:7]2[NH2:12]
Reactant: COCC(=O)N[C@@H]1CCOc2c(F)cccc21
Agent: Cl
Solvent: CCO
Product: N[C@@H]1CCOc2c(F)cccc21
Yield: 88.1 %

Procedure:
Resolution of 8-fluorochroman-4-amine. (Procedure based on US published application 2004/0157739). A mixture of 8-fluorochroman-4-amine (3.40 g), methyl 2-methoxyacetate (2.44 g) and Novozyme 435 (Aldrich, 0.68 g) in anhydrous tert-butyl methyl ether (75 mL) was heated at reflux under argon for 2 hours (at which time the ratio of acylated to unacylated product was 1:1 by HPLC). The solid that formed upon cooling was collected via filtration and dissolved in EtOAc. The mixture was filtered to remove the biocatalyst and washed once with 0.5M HCl to remove any lingering (S)-amine. The solvent was evaporated and the product was recrystallized from tert-butyl methyl ether to yield (R)—N-(8-fluorochroman-4-yl)-2-methoxyacetamide (0.78 g). The reaction solvent and recrystallization mother liquor was washed 3 times with 0.5 M HCl and concentrated to yield additional (R)—N-(8-fluorochroman-4-yl)-2-methoxyacetamide (0.83 g). The combined acidic aqueous layers were made basic by NaOH and extracted with DCM to yield (S)-8-fluorochroman-4-amine (1.6 g). A solution of (R)—N-(8-fluorochroman-4-yl)-2-methoxyacetamide (0.78 g) in 8M HCl in EtOH (50 mL) was heated at reflux for 4 hours. The solvents were removed from the cooled reaction mixture, the resulting solid was taken up in 50 mL of 0.5M NaOH, salted out with NaCl(S), and extracted 4 times with DCM to yield (R)-8-fluorochroman-4-amine (0.48 g (87%)). The % ee was checked via chiral HPLC: Chiralcel OD-H (0.46×25 cm analytical column, Daicel Chemical Industries) method: isocratic 5% (0.05% TFA/EtOH) 95% (0.05% TFA/Hex), Rt=7.2 min (S)-enantiomer, Rt=9.2 min (R)-enantiomer.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[CH:10]1([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12][CH2:11]1>CN(C=O)C>[CH:10]1([N:15]2[CH2:16][CH2:17][N:18]([C:2]3[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=3)[C:8]#[N:9])[CH2:19][CH2:20]2)[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: C1CCC(N2CCNCC2)C1
Solvent: CN(C)C=O
Product: N#Cc1ccnc(N2CCN(C3CCCC3)CC2)c1
Temperature: 80 °C
Yield: 94.7 %

Procedure:
A mixture of 2 g (14 mmol) 2-chloro-4-cyanopyridine and 2.34 g (15 mmol) 1-cyclopentylpiperazine in 5 ml DMF was heated to 80° C. for 16 h. The mixture was evaporated under reduced pressure and the residue was treated with 100 ml 1M NaHCO3 aq. and extracted with two times 100 ml ethyl acetate. The combined organic phases were dried with MgSO4 and evaporated under reduced pressure to yield 3.4 g (92%) of the title compound as grey solid. (m/e): 257.3 (MH+; 100%).
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.C1(CN2CCC(C[CH2:23][C:24]3[C:28]4[CH:29]=[C:30]5[CH2:35][C:34](=[O:36])[NH:33][C:31]5=[CH:32][C:27]=4[O:26][N:25]=3)CC2)C=CC=CC=1.N1C=CC=CC=1.O>CN(C)C=O>[CH3:23][C:24]1[C:28]2[CH:29]=[C:30]3[CH2:35][C:34](=[O:36])[NH:33][C:31]3=[CH:32][C:27]=2[O:26][N:25]=1
Reactant: O=C1Cc2cc3c(CCC4CCN(Cc5ccccc5)CC4)noc3cc2N1
Agent: O=C(O)/C=C\C(=O)O
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1noc2cc3c(cc12)CC(=O)N3
Temperature: 127.5 °C
Yield: 64.9 %

Procedure:
A mixture of the oxime acetate formed in step c (4.48 g, 18.0 mmol) and pyridine (14.6 mL, 180 mmol) in dimethylformamide (DMF) (660 mL) was heated at 125-130° C. for 4 hours. The cooled reaction mixture was poured over water and extracted with EtOAc (4 times). The combined organic layer was washed with water and brine and dried (MgSO4), filtered, and concentrated. Purification by silica gel flash chromatography (50% EtOAc/hexanes→100% EtOAc) gave the title compound (2.20 g, 65%) as a pale yellow-orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH2:12])=[CH2:10])=[CH:5][CH:4]=1.[C:21]1(=[O:27])[O:26][C:24](=[O:25])[CH:23]=[CH:22]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[CH2:12][CH:23]3[CH:22]([CH2:10][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:21](=[O:27])[O:26][C:24]3=[O:25])=[CH:18][CH:17]=1
Reactant: O=C1C=CC(=O)O1
Reactant: C=C(C(=C)c1ccc(OC)cc1)c1ccc(OC)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(C2=C(c3ccc(OC)cc3)CC3C(=O)OC(=O)C3C2)cc1

Procedure:
To the solution of 2,3-di(4-methoxyphenyl)-1,3-butadiene (2.1 g) in toluene (30 mL) was added maleic anhydride (3.8 g, 5.0 eq.) and the reaction mixture refluxed for 6 h. The reaction mixture was then diluted with ethyl acetate (500 mL) and was washed with water (3×200 mL). The organic layer was dried and concentrated to yield 5,6-bis-(4-methoxy-phenyl)-3a,4,7,7a-tetrahydro-isobenzofuran-1,3-dione.
Reaction SMILES: [F:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[F:1][C@H:2]1[C@H:7]([O:8][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(F)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)[C@H](F)C1
Temperature: 0 °C
Reaction time: 14 h
Yield: 10.1 %

Procedure:
A solution of tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (52.76 g, 241 mmol) dissolved in anhydrous methylene chloride (1 L) was cooled to 0° C. and treated with triethylamine (43.6 mL, 313 mmol) followed by methanesulfonyl chloride (20.5 mL, 265 mmol). The solution was allowed to warm slowly to ambient temperature and stirred for 14 hours. The mixture was partitioned between saturated NaHCO3 (400 mL) and methylene chloride (400 mL). The aqueous layer was extracted with methylene chloride. The combined organic phases were washed with 1N HCl and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with hexanes:EtOAc to provide the desired product (7.24 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.[NH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:7]=[N:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:9]=1
Reactant: NCC1CCNCC1
Reactant: O=Cc1cc(Br)ccc1O
Solvent: CCO
Product: Oc1ccc(Br)cc1C=NCC1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.2 %

Procedure:
A mixture of 5-bromo-2-hydroxybenzaldehyde (170 g) and 4-(aminomethyl)piperidine (96.9 g) in ethanol (2.5 L) was stirred at ambient temperature for 3 hours. The solvent was removed in vacuo to give 4-bromo-2-[N-(4-piperidylmethyl)iminomethyl]phenol (267 g) as a yellow solid m.p 35-38° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][N:9]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:40])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](O)=[O:36])=[CH:30][C:29]=1[O:38][CH3:39].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:40])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][N:9]=2)=[O:36])=[CH:30][C:29]=1[O:38][CH3:39]
Reactant: COC(=O)c1ccc(OCC2CCCN2)nc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3Cl)c(OC)c2)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.1 %

Procedure:
To a stirred mixture of methyl 2-(2-pyrrolidinyl)methoxypyridine-5-carboxylate (370 mg, 1.57 mmol), 4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid (525 mg, 1.57 mmol), 4-DMAP (230 mg, 1.88 mmol) in DMF (10 ml) was added EDC.HCl (360 mg, 1.88 mmol) at room temperature. The resulting mixture was stirred at room temperature for 20 hr. The mixture was pored into ice-water. The solid was collected, washed with water and air-dried. The crude solid was purified by silica-gel (30 ml) column chromatography with CHCl3—EtOH (98:2, v/v) as eluent and crystallized with Et2O to give methyl 2-[1-[4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenyl acetyl]-2-pyrrolidinylmethoxy]pyridine-5-carboxylate (600 mg, 69%) as an amorphous solid. 1H-NMR (CDCl3) δ0.21 and 2.01 (each m, 4 H), 3.45-4.50 (series of s and m, 13H which contains amide-isomers), 6.58-8.83 (series of s and m, 12 H which contains amide-isomers)