Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:15]([CH2:16][CH2:17][NH2:18])=[C:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27].C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([C:3]1[C:15]([CH2:16][CH2:17][NH:18][C:26](=[O:28])[CH3:27])=[C:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2ccc3oc(C)cc3c2c1CCN
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1nn2ccc3oc(C)cc3c2c1CCNC(C)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.9 %

Procedure:
To a solution of 2-(2-ethyl-8-methylfuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)ethanamine (100 mg, 0.411 mmol) and triethylamine (85.9 μL, 0.616 mmol) in tetrahydrofuran (4 mL) was added acetyl chloride (58.3 μL, 0.617 mmol) under ice-cooling, and the mixture was stirred at room temperature for 10 min. A saturated aqueous sodium hydrogen carbonate solution (100 μL) was added and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) and recrystallization (ethyl acetate/hexane) to give the title compound (59.7 mg, yield 51%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Mg].II.[CH2:12]1[CH:16]2[CH2:17][C:18](=[O:19])[CH:14]([CH2:15]2)[CH2:13]1>C1COCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]2([OH:19])[CH2:17][CH:16]3[CH2:15][CH:14]2[CH2:13][CH2:12]3)=[CH:3][CH:4]=1
Reactant: O=C1CC2CCC1C2
Reactant: Fc1ccc(Br)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccc(F)cc2)CC2CCC1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-bromo-4-fluorobenzene (5.00 ml, 45.5 mmol), magnesium turnings (3.32 g, 137 mmol), and a few iodine crystals in 70 ml dry THF were vigorously stirred for 4 hours under the protection of nitrogen and cooling with ice/water. Norcamphor (5.00 g, 45.5 mmol) dissolved in 10 ml dry THF was added drop-wise, and the reaction was allowed to warm up to room temperature and stirred overnight. The reaction was carefully quenched with water and decanted from the excess magnesium turnings. The reaction mixture in THF and water was adjusted to pH 7 with 2N HCl solution and extracted with chloroform (3×50 ml). The extract was dried over anhydrous sodium sulfate and the solvent was removed by vacuum evaporator. This resulted in an alcohol intermediate (III) appearing as a faintly yellow oil (9.4 g, 99%).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][NH2:14])=[CH:8][CH2:7][CH2:6]2>C(O)(=O)C>[ClH:1].[F:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][NH2:14])[CH2:8][CH2:7][CH2:6]2
Reactant: NCC1=CCCc2cc(F)ccc21
Agent: Cl
Solvent: CC(=O)O
Product: NCC1CCCc2cc(F)ccc21

Procedure:
The product from Example 74 was reduced as in Example 2 but replacing the NH3 with acetic acid and afforded the desired compound, m.p. 236°0 C.-38° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[B:18]1[O:19][C:20]([CH3:26])([CH3:25])[C:21]([CH3:24])([CH3:23])[O:22]1
Reactant: Cc1cccc(CBr)c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1NCc1cccc(C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 2.09 g (19.5 mmol) of 2-methylaniline, 4.00 g (13.0 mmol) of 2-[2-(bromomethyl)-6-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and 1.97 g (14.3 mmol) of K2CO3 in 75 ml of DMF was stirred for 12 h at the 80° C. The resulting mixture was poured into 300 ml of water. The product was extracted with 3×50 ml of ethyl acetate. The combined extract was dried over Na2SO4 and then evaporated to dryness. An excess of 2-methylaniline was distilled off using Kugelrohr apparatus. The residue was re-crystallized from 20 ml of hexane. Yield 2.60 g (59%) of light-yellow powder. Anal. calc. for C21H28BNO2: C, 74.79; H, 8.37; N, 4.15. Found: C, 74.95; H, 8.52; N, 3.95. 1H NMR (CDCl3): δ 7.22 (m, 1H, 3-H in 6-MeC6H3CH2), 7.16 (m, 1H, 3-H in 6-MeC6H3CH2), 7.12 (m, 1H, 5-H in 2-MeC6H4), 7.09 (m, 1H, 5-H in 6-MeC6H3CH2), 7.04 (m, 1H, 3-H in 2-MeC6H4), 6.71 (m, 1H, 6-H in 2-MeC6H4), 6.66 (m, 1H, 4-H in 2-MeC6H4), 4.34 (d, J=25.3 Hz, 1H, CHH′NH), 4.27 (d, J=25.3 Hz, 1H, CHH′NH), 3.85 (br.s, 1H, NH), 2.46 (s, 3H, Me in 6-MeC6H3CH2), 2.11 (s, 3H, Me in 2-MeC6H4), 1.25 (s, 12H, Bpin).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CCO>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Reactant: C1CCNCC1
Solvent: CCO
Product: CS(=O)(=O)c1cc(F)c2c(c1)OC(CN1CCCCC1)OC2

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (7 mg, 0.021 mmol), piperidine (0.5 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 329 (M+, 0.6), 99 (8), 98 (bp), 95 (4), 70 (4), 55 (6).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]2)[C:3]=1[CH3:21].[H-].[Na+].I[CH:25]([CH3:27])[CH3:26]>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([CH:25]([CH3:27])[CH3:26])[C:16](=[O:20])[CH2:15]2)[C:3]=1[CH3:21]
Reactant: CC(C)I
Reactant: Cc1c(N2CCNC(=O)C2)nc2cc(F)cc(F)c2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(N2CCN(C(C)C)C(=O)C2)nc2cc(F)cc(F)c2c1Br
Reaction time: 8 h

Procedure:
The 4-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)piperazin-2-one (89 mg, 0.25 mmol) was dissolved in THF (2.0 mL). To the solution was added sodium hydride (30.0 mg, 1.25 mmol) (60% dispersion) followed by addition of 2-iodopropane (750 μL, 7.50 mmol). The reaction was heated to reflux and stirred overnight. The reaction was quenched with water and the mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (1×25 mL) and dried over magnesium sulfate. The crude product was purified by medium pressure chromatography (silica gel, 0 to 80% EtOAc:hexanes) to give 4-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)-1-isopropylpiperazin-2-one. Mass Spectrum (ESI) m/e=400.1 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[O:10][C:9]3[N:11]=[CH:12][C:13]([CH2:15][N:16]([CH3:18])[CH3:17])=[CH:14][C:8]=3[C:6]=2[N:7]=1.[NH:25]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[C:28]=2[CH:27]=[CH:26]1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>CCOC(C)=O.[Cl-].[Na+].O.O>[NH:25]1[C:33]2[C:28](=[C:29]([C:2]3[N:3]=[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:5]4[O:10][C:9]5[N:11]=[CH:12][C:13]([CH2:15][N:16]([CH3:18])[CH3:17])=[CH:14][C:8]=5[C:6]=4[N:7]=3)[CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: CN(C)Cc1cnc2oc3c(N4CCOCC4)nc(Cl)nc3c2c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CN(C)Cc1cnc2oc3c(N4CCOCC4)nc(-c4cccc5[nH]ccc45)nc3c2c1
Temperature: 88 °C

Procedure:
To a sealed tube was added 9 (5 mg, 0.014 mmol), indole-4-boronic acid (5.8 mg, 0.036 mmol), dichloro-bis(triphenylphosphine)palladium (II) (2.0mg, 0.0029 mmol) and Na2CO3 (3.1 mg, 0.029 mmol) followed by dioxane (2 mL) and water (0.8 mL) under Ar(g). The lid was sealed and the tube was heated to 88° C. for 18 h whereupon it was cooled to rt and diluted with EtOAc (35 mL) and 50% saturated brine (5 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×10 mL). The combined organic layers were then dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 2-5% MeOH/CH2Cl2) furnished H (2 mg, 0.005 mmol, 32%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([NH:11][CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=1>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)=[CH:4][C:3]=1[C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=1)=[O:10]
Reactant: COC(=O)c1ccc(CNC(=O)c2cc(O)ccc2Cl)cc1
Reactant: COc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(CNC(=O)c2cc(OCc3cccc(OC)c3)ccc2Cl)cc1

Procedure:
A solution of methyl 4-({[(2-chloro-5-hydroxyphenyl)carbonyl]amino}methyl)benzoate (95 mg, 0.3 mol), potassium carbonate (2 eq, 83 mg, 0.6 mmol) and 1-(bromomethyl)-3-(methyloxy)benzene (1.2 eq, 50 ul, 0.36 mmol) in DMF (2 ml) was stirred at room temperature for 2 hours. The mixture was then diluted with ethyl acetate (100 ml) and H2O (80 ml). Layers separated, organic layer washed with brine (80 ml) then dried and evaporated in vacuo. Residue purified by column chromatography (Biotage SP4) eluting with 0-40% ethylacetate in hexanes to give the title compound as a clear oil. MS (ES+) m/z 440 [M+H]+ (C24H2235ClNO5). 1H-NMR (400 MHz, d6-DMSO) δ 3.76 (3H, s), 3.85 (3H, s), 4.51 (2H, d, J 6), 5.12 (2H, s), 6.89-7.96 (11H, m), 7.46 (2H, d, J 8.4), 7.92 (2H, m), 9.05 (1H, J 6).
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[CH3:6][NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1(C)C=CC=CC=1>[CH3:6][N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:1][CH:2]([OH:3])[CH2:4][OH:5]
Reactant: CCCCCCCCCCCCCCCCCCNC
Reactant: OCC1CO1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCN(C)CC(O)CO
Reaction time: 3 h
Yield: 74.6 %

Procedure:
A mixture of glycidol (4 ml, 60 mmol) and N-methyl-octadecylamine (16 g, 60 mmol) in dry toluene (50 ml) was refluxed under stirring for 3 hours. After evaporation of the solvent, the residue was crystallized to yield 16 g (84%) of the title compound. m.p. 59° C. (Hexane).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>C(Cl)Cl.N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:17][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: CCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.4 %

Procedure:
To a solution of pentan-1-ol (9.2 mL, 85 mmol) in CH2Cl2 (70 mL) and pyridine (50 mL) was added DMAP (0.52 g, 4.3 mmol) followed by p-toluenesulfonyl chloride (16.2 g, 85 mmol). This mixture was allowed to stir at ambient temperature for 18 hours then quenched with 5% aqueous HCl (20 mL) and diluted with EtOAc (20 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×7 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 75% hexanes in EtOAc) to give the title compound (13.1 g, 53.9 mmol, 63% yield). MS (DCI/NH3) m/z 260 (M+NH4)−.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.O[CH2:13]/[CH:14]=[C:15](/[CH2:17][CH2:18]/[CH:19]=[C:20](/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])\[CH3:21])\[CH3:16]>ClCCl>[CH2:13]([Cl:1])/[CH:14]=[C:15](/[CH2:17][CH2:18]/[CH:19]=[C:20](/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])\[CH3:21])\[CH3:16]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Reactant: O=C1CCC(=O)N1Cl
Solvent: CSC
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCl
Reaction time: 0.22 h
Yield: 103.8 %

Procedure:
A solution of N-chlorosuccinimide (6.8 g, 50.9 mmol) in dry dichloromethane (338 ml) was cooled to -30° and dimethylsulfide (4.1 ml, 55.3 mmol) was added dropwise over 3 min. After 13 min., the cooling bath was removed and the mixture was stirred for 30 min. The mixture was cooled to -40° and a solution of (E,E)-farnesol (11.3 ml, 44 mmol) in 112 ml dichloromethane was added over 10 min. The cooling bath was removed and the mixture was stirred for 30 min. The temperature of the reaction mixture rose to 0° and a clear solution was obtained. After stirring for two more hours the solvent (about 400 ml) was removed on a rotary evaporator and the material was taken up in hexane (600 ml). The solution was washed with ice cold water (3×90 ml) and cold brine (2×35 ml) and then dried (MgSO4). The solvent was removed under vaccum at ambient temperature and finally dried under pump vaccum to give 11.0 g (100%) of title compound as a pale yellow liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[NH:18][C:12]2=[N:13][CH:14]=[C:15](Br)[CH:16]=[C:11]2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC>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].CO>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[NH:18][C:12]2=[N:13][CH:14]=[C:15]([C:6]([O:5][CH3:1])=[O:19])[CH:16]=[C:11]2[N:10]=1)=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1nc2cc(Br)cnc2[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cnc2[nH]c(CNC(=O)OC(C)(C)C)nc2c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 160.6 %

Procedure:
To a MeOH 25 mL solution of tert-butyl[(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)methyl]carbamate (Priepke, H.; Pfau, R; Gerlach, K.; Gillard, J.; Bauer, E.; Wienen, E.; Wolfgang, H.; Sandra N. H. WO 2004056784, 2004.) (1.2 g, 3.66 mmol) were added Et3N (1.11 g, 11 mmol), Pd(dppf)Cl2 (263 mg, 0.366 mmol). The reaction mixture was stirred at 80° C. under CO atmosphere (50 psi) for 24 hr. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated, chromatographed on silica gel eluting with DCM: MeOH: TEA (50:1:0.01, v/v/v) to give the title compound (0.9 g, 82%).
Reaction SMILES: C[CH:2]1[C:7]2([CH2:18][NH:17][CH2:16][C:9]3([CH2:14][CH2:13][CH2:12][CH2:11][CH:10]3C)[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C1C2(C(=O)NC(=O)C3(CCCCC3)N2)CCCC1.CC1C2(C(=O)NC(=O)C3(CCCCC3C)N2)CCCC1>>[CH2:2]1[C:7]2([CH2:18][NH:17][CH2:16][C:9]3([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1CCCCC12CNCC1(CCCCC1C)N2
Agent: CC1CCCCC12NC1(CCCCC1C)C(=O)NC2=O
Agent: O=C1NC(=O)C2(CCCCC2)NC12CCCCC2
Product: C1CCC2(CC1)CNCC1(CCCCC1)N2

Procedure:
In a similar manner, 1,9-dimethyl-7,15-diazadispiro[5,1,5,3]hexadecane is prepared by substituting for 7,15-diazadispiro[5,1,5,3]hexadecane-14,16-dione an equivalent amount of 1,9-dimethyl-7,15-diazadispiro[5,1,5,3]hexadecane-14,16-dione.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:20][CH3:21])=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]3[CH2:16][CH2:17][CH2:18][C:11]=3[C:10]=2[CH:19]=1.Cl.Cl.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1.C(O)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O>[CH3:21][O:20][C:7]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:35]2[CH2:34][CH2:33][N:32]([C:29]3[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=3)[CH2:37][CH2:36]2)=[CH:19][C:10]2[C:11]3[CH2:18][CH2:17][CH2:16][C:12]=3[C:13](=[O:15])[O:14][C:9]=2[CH:8]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCl)CCC3
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Solvent: CC(C)=O
Product: COc1ccc(N2CCN(CCCOc3cc4c5c(c(=O)oc4cc3OC)CCC5)CC2)cc1
Yield: 45 %

Procedure:
Method A (60 h at 40° C.); starting materials: 8-(3-chloropropoxy)-2,3-dihydro-7-methoxy-cyclopenta[c][1]benzopyran-4(1H)-one (example 83) and 1-(4-methoxyphenyl)piperazine dihydrochloride; yield 45%; fusion point 155°-156° C. (from ethanol). Fumarate: method E; yield 96%; fusion point 207°-210° C. (from acetone).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:15]=2[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[C:35]1[NH:39][C:38]2[CH:40]=[C:41](B3OC(C)(C)C(C)(C)O3)[CH:42]=[CH:43][C:37]=2[N:36]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:41]3[CH:42]=[CH:43][C:37]4[N:36]=[C:35]([CH:31]5[CH2:32][CH2:33][CH2:34][N:30]5[C:28]([O:27][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:29])[NH:39][C:38]=4[CH:40]=3)[CH:20]=[CH:21][C:15]=2[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(Br)cc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(-c3ccc4nc(C5CCCN5C(=O)OC(C)(C)C)[nH]c4c3)cc2[nH]1
Temperature: 110 °C
Yield: 15.1 %

Procedure:
A mixture of 2-(6-bromo-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (64 mg, 0.174 mmol), 2-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (72 mg, 0.174 mmol), tetrakis(triphenylphosphine)palladium (30 mg, 0.026 mmol) and potassium carbonate (48 mg, 0.35 mmol) in 2 ml 1,2-dimethoxyethane and 1 mL water was heated to 110° C. in microwave for 15 minutes. The reaction mixture was cooled and dissolved in ethyl acetate and washed with 5% lithium chloride aqueous solution. The organic layer dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 10% methanol/ethyl acetate) to give 2-[2′-(1-Boc-pyrrolidin-2-yl)-3H,3′H-[5,5]bibenzoimidazolyl-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (15 mg, yield 15%). LCMS-ESI−: calc'd for C32H40N6O4: 572.70. Found: 573.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:23]=[CH:24][CH:25]=3)[O:17][CH:18]([CH3:22])[C:19](O)=[O:20])=[N:9]2)=[CH:4][CH:3]=1.C([N:28](CC)CC)C.ClC(OCC)=O.N>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:23]=[CH:24][CH:25]=3)[O:17][CH:18]([CH3:22])[C:19]([NH2:28])=[O:20])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: CC(Oc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1)C(=O)O
Agent: CCOC(=O)Cl
Agent: N
Solvent: ClCCl
Product: CC(Oc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1)C(N)=O
Temperature: 0 °C

Procedure:
(+)-2-(3-(2-(7-Chloroquinolin-2-yl)ethenyl)phenoxy)propanoic acid from Example 72 (2.372 g, 6.71 mmol) was dissolved in methylene chloride (40 mL) containing triethylamine (1.87 mL, 12.5 mmol), and ethyl chloroformate (710 μL, 7.38 mmol) in methylene chloride (20 mL) was added dropwise at -15° C. with stirring. The mixture was stirred for a further 20 minutes at -15° C., and then it was poured into methylene chloride (125 mL) that had been saturated with ammonia at 0° C. The reaction mixture was stirred for a few minutes, and then poured into ice-water The mixture was filtered, and the filtrate was separated. Evaporation of the methylene chloride layer gave more solid, and the two fractions were combined and recrystallized from acetonitrile to give the title product, mp 195°-197° C., [α]D -9.8° (c 0.515 in dimethylformamide).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](O)=[O:39])=[CH:33][CH:32]=1)([CH3:30])[CH3:29].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C([O-])(O)=O.[Na+]>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([C:38](=[O:39])[CH2:37][C:34]2[CH:35]=[CH:36][C:31]([CH:28]([CH3:29])[CH3:30])=[CH:32][CH:33]=2)[CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCOC(=O)c1ccc2c(c1)CCC2N[C@H]1CC[C@H](C(C)(C)C)CC1
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCCCOC(=O)c1ccc2c(c1)CCC2N(C(=O)Cc1ccc(C(C)C)cc1)[C@H]1CC[C@H](C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of enantiomer A of butyl 1-[(trans-4-tert-butylcyclohexyl)amino]indane-5-carboxylate, (41 mg, 0.11 mmol) in CH2CL2 (3 mL) was added (4-isopropylphenyl)acetic acid (98 mg, 0.55 mmol), EDC (105 mg, 0.55 mmol), HOBt (74 mg, 0.55 mmol) and DIEA (200 μL, 1.10 mmol). After stirring at room temperature for 18 h, the reaction mixture was poured into saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine (2×10 mL), dried over Na2SO4, filtered and concentrated. Chromatography (10% EtOAc in Hexane) gave butyl 1-{(trans-4-tert-butylcyclohexyl)[(4-isopropylphenyl)acetyl]amino}indane-5-carboxylate. HPLC/MS: m/z=532.3 (M+1), Rt=3.15 min.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[O-:11][CH2:12][CH3:13].[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][CH2:12][CH3:13])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(Cl)ccc1C#N
Yield: 57.4 %

Procedure:
To a solution of 4-chloro-2-fluoro-benzonitrile (1.0 g, 6.428 mmol) in ethanol (10 mL) were added sodium ethoxide solution (4.8 mL, 12.86 mmol, 21% wt in ethanol). The reaction mixture was heated at gently reflux for 12 h. The solvent was removed and the residue was partitioned between water (10 mL) and diethyl ether (20 mL). The layers were separated and the product was extracted with diethyl ether (20 mL). The organic layers were washed with brine (5 mL) and dried over anhydrous sodium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 5% ethyl acetate in hexanes yielded 4-chloro-2-ethoxy-benzonitrile (0.67 g, 57%).
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].Br[CH2:14][CH2:15][Cl:16].C(N(CC)CC)C>CN(C=O)C>[Cl:16][CH2:15][CH2:14][O:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12]
Reactant: ClCCBr
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1OCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A 1 L round-bottomed flask was charged 2-hydroxyisoindoline-1,3-dione (16.6 g, 98.71 mmol), followed by DMF (100 mL), then 1-bromo-2-chloroethane (25.2 mL, 296.1 mmol), and then triethylamine (42.1 mL, 296.1 mmol). After stirring at ambient temperature overnight, the reaction mixture was filtered (GF/F) and rinsed with DMF. The filtrate (250 mL) was poured into ice-water (2 L) while stirring, and the resulting precipitate was filtered, rinsed with water, and dried, yielding the crude product as a white solid (21 g). The crude product was triturated with heptane (3×400 mL), filtered and air-dried, giving the product as white solid (17.6 g, 79%).