Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Yield: 66.5 %

Procedure:
A mixture of 1-fluoro-4-nitro-benzene (500 mg, 3.54 mmol), morpholine (620 mg, 7.08 mmol) and K2CO3 (733 mg, 5.3 mmol) in DMSO (5 mL) was irradiated in a microwave (160 W) for 30 seconds (3×10 seconds). The reaction mixture was cooled to room temperature and poured onto ice. The resulting precipitated was filtered to afford 490 mg (66%) of 4-(4-nitro-phenyl)-morpholine. 1H NMR: (DMSO-d6): δ 8.1 (m, 2H), 7.1 (m, 2H), 3.42 (t, 4H), 3.4 (t, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[C:28](I)[CH:27]=[C:26]([CH3:31])[N:25]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10]([C:28]2[CH:27]=[C:26]([CH3:31])[N:25]=[C:24]([F:23])[CH:29]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Reactant: Cc1cc(I)cc(F)n1
Product: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)cc(F)n1

Procedure:
In analogy to example 74, step 5, from 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 74, step 4) and 2-fluoro-4-iodo-6-picoline (CAS RN: [884494-45-5]) was prepared the title compound as a colorless oil, MS (EI): m/z=411 ([M]+, 1Br).
Reaction SMILES: [F-:1].[K+].[F:3][C:4]([C:12]([F:15])([F:14])[F:13])([C:8]([F:11])([F:10])[F:9])[C:5]([F:7])=O.S([O:21][CH3:22])(OC)(=O)=O>CN(C)C=O>[C:4]([C:5]([O:21][CH3:22])([F:1])[F:7])([C:12]([F:15])([F:14])[F:13])([C:8]([F:11])([F:10])[F:9])[F:3]
Reactant: O=C(F)C(F)(C(F)(F)F)C(F)(F)F
Reactant: COS(=O)(=O)OC
Reactant: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(F)(F)C(F)(C(F)(F)F)C(F)(F)F
Temperature: 40 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
The title compound was prepared essentially as in Example 1 using anhydrous potassium fluoride (31.9 g, 0.55 mole), anhydrous dimethyl formamide (186 g), perfluoroisobutryl fluoride (108 g of 99% purity, 0.5 mole), and dimethyl sulfate (81.9 g, 0.65 mole). The resulting mixture was held at −20° C. for 16 hours, was warmed to 40° C. for 3.5 hours, and was then distilled to yield 109 g of the title compound (83.6% purity by GLC; also containing 11.6% (CF3)2CFCOF). The reaction mixtures from several runs were combined and distilled (b.=60-61° C.).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1([S:19][CH2:20][C:21]([OH:23])=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.FC(F)(F)C([O-])=O.[NH2:31][C@@H:32]1[C:39](=[O:40])[N:38]2[C@@H:33]1[S:34][CH2:35][C:36](/[CH:44]=[C:45]1/[C:46](=[O:68])[N:47]([CH2:50][C:51]3[CH:56]=[CH:55][N+:54]([CH2:57][C:58](=[O:67])[NH:59][C:60]4[CH:65]=[CH:64][C:63]([OH:66])=[CH:62][CH:61]=4)=[CH:53][CH:52]=3)[CH2:48][CH2:49]/1)=[C:37]2[C:41]([OH:43])=[O:42].Cl>CN(C)C(=O)C.O.C(#N)C>[OH:66][C:63]1[CH:62]=[CH:61][C:60]([NH:59][C:58]([CH2:57][N+:54]2[CH:55]=[CH:56][C:51]([CH2:50][N:47]3[CH2:48][CH2:49]/[C:45](=[CH:44]\[C:36]4[CH2:35][S:34][C@H:33]5[N:38]([C:39](=[O:40])[C@H:32]5[NH:31][C:21](=[O:23])[CH2:20][S:19][C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:37]=4[C:41]([O-:43])=[O:42])/[C:46]3=[O:68])=[CH:52][CH:53]=2)=[O:67])=[CH:65][CH:64]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(Cc4cc[n+](CC(=O)Nc5ccc(O)cc5)cc4)C3=O)CS[C@H]12
Reactant: O=C(O)CSc1ccccc1
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(C[n+]1ccc(CN2CC/C(=C\C3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)CSc5ccccc5)[C@H]4SC3)C2=O)cc1)Nc1ccc(O)cc1

Procedure:
With 70.0 mg (0.43 mmol) 1,1′-carbonyldiimidazole, 71.0 mg (0.43 mmol) 2-(phenylthio)acetic acid and 188.4 mg (0.29 mmol) (E)-(6R,7R)-7-amino-3-[1-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate trifluoroacetate in 4 ml ml N,N-dimethylacetamide. The resulting solid was suspended in 6 ml water:acetonitrile (1:1) and HCl was added until all compound dissolved. After column chromatography on MCI gel (75-150μ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitril (1:0, 4:1, 3:1, 2:1, 1:1) the organic solvent was stripped off at a rotary evaporator and the aqueous phase was freeze-dried.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH:20]([N:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:32](O)=[O:33])=[CH:31][C:26]=2[N:25]=[N:24]1)([CH3:22])[CH3:21]>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:32]([C:30]1[CH:29]=[CH:28][C:27]2[N:23]([CH:20]([CH3:21])[CH3:22])[N:24]=[N:25][C:26]=2[CH:31]=1)=[O:33]
Reactant: CC(C)n1nnc2cc(C(=O)O)ccc21
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc2c(c1)nnn2C(C)C

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 1-isopropyl-1H-benzotriazole-5-carboxylic acid. MS: 447.3 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH3:16])[CH:12]=2)[NH:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:23]([S:26][CH2:27][CH:28]([CH3:32])[C:29](Cl)=[O:30])(=[O:25])[CH3:24]>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH3:16])[CH:12]=2)[N:7]1[C:29](=[O:30])[CH:28]([CH3:32])[CH2:27][S:26][C:23](=[O:25])[CH3:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Cc2cc(OC)ccc2N1
Reactant: CC(=O)SCC(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C1Cc2cc(OC)ccc2N1C(=O)C(C)CSC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the stirred mixture of 4.0 g of 5-methoxyindoline-2-carboxylic acid ethyl ester, 5.0 g of powdered potassium carbonate and 50 ml of methylene chloride, 3.3 g of 3-acetylthio-2-methylpropanoyl chloride in 10 ml of methylene chloride are added during 1 minute. After stirring for 2 hours at reflux the mixture is cooled to room temperature and partitioned between 50 ml of water and 100 ml of diethyl ether. The organic layer is washed with 50 ml of water, 50 ml of 1N hydrochloric acid and 50 ml of saturated aqueous sodium chloride, dried and evaporated, to give the 1-(3-acetylthio-2-methylpropanoyl)-5-methoxyindoline-2-carboxylic acid ethyl ester as an oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.N1CCC[CH2:14]1.CI.O>C1(C)C=CC=CC=1>[CH2:11]([O:10][C:8]([CH:5]1[CH2:6][CH2:7][C:2](=[O:1])[CH:3]([CH3:14])[CH2:4]1)=[O:9])[CH3:12]
Reactant: C1CCNC1
Reactant: CCOC(=O)C1CCC(=O)CC1
Solvent: Cc1ccccc1
Solvent: CI
Solvent: O
Product: CCOC(=O)C1CCC(=O)C(C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 4-oxocyclohexane carboxylate (10.0 g, 58.8 mmol) and pyrrolidine (5.87 g, 82.7 mmol) in toluene (100 mL) and molecular sieves (40 g of 4 Å sieves) are heated to reflux overnight using Dean Stark apparatus. The mixture is filtered and the excess pyrrolidine is removed in vacuo. The resulting mixture is diluted with toluene (50 mL) and treated with methyl iodide (8.96 g, 63.1 mmol). After heating at reflux for 15 hours, the mixture is allowed to cool to RT and silica (3 g) and water (30 mL) are added. The mixture is stirred at RT for 3 hours and partitioned between water and diethyl ether. The organic portion is separated and washed with water, brine, dried (MgSO4) and concentrated in vacuo. Purification by chromatography on silica eluting with iso-hexane:EtOAc (19:1 increasing to 9:1) affords the title compound. 1H NMR (400 MHz, DMSO-d6) δ 4.15 (2H, q), 2.89 (1H, m), 2.51 (1H, m), 2.38 (1H, m), 2.21 (3H, m), 1.89 (1H, m), 1.62 (1H, m), 1.22 (3H, t), 0.95 (3H, d).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]=[N:17][C:18]2[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=2[CH:27]([CH3:29])[CH3:28])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].[BH4-].[Na+].O.C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:9][C:4]1[CH:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][NH:17][C:18]2[C:23]([CH:24]([CH3:25])[CH3:26])=[CH:22][CH:21]=[CH:20][C:19]=2[CH:27]([CH3:29])[CH3:28])[C:2]([CH3:1])=[C:6]([CH3:7])[C:5]=1[CH3:8]
Reactant: CC1=C(C)C(c2ccccc2C=Nc2c(C(C)C)cccc2C(C)C)C(C)=C1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=C(C)C(c2ccccc2CNc2c(C(C)C)cccc2C(C)C)C(C)=C1C
Yield: 82.3 %

Procedure:
To a solution of N-[2-(2,3,4,5-tetramethylcyclopentadienyl)phenylmethylene]-N-(2,6-diisopropylphenyl)amine (10.0 mmol) in acetic acid (7.0 mL) was added sodium borohydride (13.0 mmol). The mixture was reacted at room temperature for 1 hr. Water and toluene were then added to the reaction mixture. The organic layer was dried and concentrated. The obtained oily substance was purified by silica gel column chromatography to give N-[2-(2,3,4,5-tetramethylcyclopentadienyl)phenylmethyl]-N-(2,6-diisopropylphenyl)amine (3.19 g, yield 82.4%) as a yellow oily substance.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:23])[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[CH2:9][C@@H:10]([C:12]1[CH:21]=[CH:20][C:15]2[C:16](=[O:19])[O:17][CH2:18][C:14]=2[C:13]=1[CH3:22])[OH:11].[CH3:24][C:25]1[C:33]2[CH2:32][O:31][C:30](=[O:34])[C:29]=2[CH:28]=[CH:27][C:26]=1[C@@H:35]1[CH2:37][O:36]1>>[CH3:2][C:3]1([CH3:23])[CH2:8][N:7]([CH2:37][C@@H:35]([C:26]2[CH:27]=[CH:28][C:29]3[C:30](=[O:34])[O:31][CH2:32][C:33]=3[C:25]=2[CH3:24])[OH:36])[CH2:6][CH2:5][N:4]1[CH2:9][C@@H:10]([C:12]1[CH:21]=[CH:20][C:15]2[C:16](=[O:19])[O:17][CH2:18][C:14]=2[C:13]=1[CH3:22])[OH:11]
Reactant: Cc1c([C@@H](O)CN2CCNCC2(C)C)ccc2c1COC2=O
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Agent: Cl
Product: Cc1c([C@@H](O)CN2CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)C(C)(C)C2)ccc2c1COC2=O

Procedure:
5,5′-{(2,2-dimethylpiperazine-1,4-diyl)bis[(1R)-1-hydroxyethane-2,1-diyl]}bis(4-methyl-2-benzofuran-1 (3H)-one) was prepared in a similar fashion to that described for the synthesis of EXAMPLE 1 starting from 5-[(R)-2-(2,2-dimethylpiperazin-1-yl)-1-hydroxyethyl]-4-methyl-2-benzofuran-1 (3H)-one hydrochloride (INTERMEDIATE 4) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1 (3H)-one (INTERMEDIATE 2).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH2:12])=[S:11])[CH:5]=[CH:6][C:7]=1[CH3:8].Br[CH2:14][C:15](=O)[CH3:16]>CN(C=O)C>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]2[S:11][CH:14]=[C:15]([CH3:16])[N:12]=2)=[CH:3][C:2]=1[OH:1]
Reactant: Cc1ccc(NC(N)=S)cc1O
Reactant: CC(=O)CBr
Solvent: CN(C)C=O
Product: Cc1csc(Nc2ccc(C)c(O)c2)n1
Yield: 61 %

Procedure:
Following the general procedure for the synthesis of derivatives 6 and 7, a solution of 1-(3-hydroxy-4-methylphenyl)thiourea (100 mg, 0.59 mmol) and bromoacetone (96 mg, 0.71 mmol) in dry DMF (2.4 mL) was heated at 60° C. for 6 h. The title compound was obtained, after purification by flash chromatography on silica gel (hexane:EtOAc 6/4) in 61% yield (79 mg).
Reaction SMILES: C([NH2:4])(C)C.Cl.[C:6]([O:10][C:11]([NH:13][CH:14]([CH2:21][CH:22]([C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[C:27]=1[F:34])[C:23](=O)[CH3:24])[C:15](OC(C)C)=[O:16])=[O:12])([CH3:9])([CH3:8])[CH3:7]>O.CS(C)=O>[CH3:24][C@H:23]1[NH:4][C:15](=[O:16])[CH:14]([NH:13][C:11](=[O:12])[O:10][C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:21][C@H:22]1[C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[C:27]=1[F:34]
Reactant: CC(C)N
Reactant: CC(=O)C(CC(NC(=O)OC(C)(C)C)C(=O)OC(C)C)c1cc(F)cc(F)c1F
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: C[C@H]1NC(=O)C(NC(=O)OC(C)(C)C)C[C@H]1c1cc(F)cc(F)c1F
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a solution of NaBO3.4H2O (1.5 g, 3.9 mmol) in H2O (18.2 g) was charged isopropylamine (1.16 g, 19.6 mmol) dropwise at 20° C. After the mixture was stirred for 30 min, the pH was adjusted to 10.2-10.3 by 6N HCl. PLP (0.042 g, 0.27 mmol) and ATA-412 (1.0 g) was charged to the solution at 20° C. After the above mixture was stirred for 1 h, a solution of 45 (2 g, 4.7 mmoL) in DMSO (10 mL) was added slowly at 20° C. The solution was heated to 55° C. and stirred for 24 h. After the reaction was complete, the reaction was quenched by isopropyl alcohol (10 mL), and then partitioned with water and IPAc. The organic solution was dried over Na2SO4 and concentrated. The crude residual was further purified by flash chromatography on silica gel (5-20% EtOAc/PE) to give 46 (1.45 g, 85% yield). 1H NMR (DMSO-d6, 400 MHz): δ 7.95-7.78 (m, 1H), 6.95 (m, 1H), 3.01 (t, 1H), 1.36 (s, 9H), 1.17-1.10 (br, 4H), 1.12 (m, 3H); MS (ESI) m/e [M+H]+: 359.15.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]([NH2:29])=[O:28])[CH:25]=3)[CH:20]=[N:19][CH:18]=2)[CH2:13][CH2:12]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CO.O>[OH:7][CH2:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]([NH2:29])=[O:28])[CH:25]=3)[CH:20]=[N:19][CH:18]=2)[CH2:13][CH2:12]1
Reactant: NC(=O)c1ccc2cncc(N3CCC(OCCOC4CCCCO4)CC3)c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: NC(=O)c1ccc2cncc(N3CCC(OCCO)CC3)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.1 %

Procedure:
4-{4-[2-(Tetrahydro-2H-pyran-2-yloxy)ethoxy]piperidin-1-yl}isoquinoline-6-carboxamide (330 mg, 0.83 mmol) produced in Example 19 was dissolved in methanol-water (90:10, V/V, 15 mL), to which p-toluenesulfonic acid monohydrate (213 mg, 1.24 mmol) was then added, followed by stirring at room temperature for 24 hours. After addition of triethylamine (300 μL), the solvent was distilled off under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (ethyl acetate:methanol, 100:0-80:20, V/V) to give the desired title compound (160 mg, yield 61%).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:22]3[CH:17]([NH:18][C:19](=[O:26])[C:20]([C:24]#[N:25])=[C:21]3[OH:23])[S:16][CH:15]=2)=[CH:10][CH:9]=1)=O.[C:27]([O-:30])(=[O:29])C.[Na+]>O>[C:24]([C:20]1[C:19](=[O:26])[NH:18][CH:17]2[S:16][CH:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([CH:2]=[N:3][O:4][CH2:5][C:27]([OH:30])=[O:29])=[CH:13][CH:12]=3)[CH:22]2[C:21]=1[OH:23])#[N:25]
Reactant: CNOC
Reactant: N#CC1=C(O)C2C(c3ccc(C=O)cc3)=CSC2NC1=O
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#CC1=C(O)C2C(c3ccc(C=NOCC(=O)O)cc3)=CSC2NC1=O

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (0.067 g, 0.3 mmol) was added to a room temperature solution of 3-(4-Formyl-phenyl)-4-hydroxy-6-oxo-3a,6,7,7a-tetrahydro-thieno[2,3-b]pyridine-5-carbonitrile (0.1 g, 0.29 mmol) and sodium acetate (0.025 g, 0.3 mmol) in 1:1:1 mixture of methanoldioxane/water (6 mL). The reaction mixture was quenched with 3N HCl after complete reaction, extracted with ethyl acetate (3×20 mL), organic extracts washed with brine, dried (MgSO4) and concentrated to a brown solid. MS (ESI) m/e 369.5 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ ppm 12.30 (br s, 1H), 8.36 (s, 1H), 7.59 (d, J=9, 2H), 7.47 (d, J=9, 2H), 7.03 (s, 1H), 4.66 (s, 2H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][O:14]2)(=O)=O)=CC=1.BrCC1OC(C(F)(F)F)=CC=1.[F:29][C:30]1[C:35]([C:36]#[N:37])=[CH:34][C:33]2[C:38]3([CH2:48][O:49][C:32]=2[CH:31]=1)[C:46]1[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=1)[NH:40][C:39]3=[O:47].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[F:29][C:30]1[C:35]([C:36]#[N:37])=[CH:34][C:33]2[C:38]3([CH2:48][O:49][C:32]=2[CH:31]=1)[C:46]1[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=1)[N:40]([CH2:12][C@H:13]1[CH2:17][CH2:16][CH2:15][O:14]1)[C:39]3=[O:47]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Reactant: N#Cc1cc2c(cc1F)OCC21C(=O)Nc2ccccc21
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: N#Cc1cc2c(cc1F)OCC21C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 6-fluoro-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 6-fluoro-2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile was obtained (34%): 1H NMR (300 MHz, CDCl3) δ 7.37-7.27 (m, 1H), 7.12-7.06 (m, 3H), 7.01-6.92 (m, 1H), 6.79-6.74 (m, 1H), 4.94 (ABq, 2H), 4.31-4.21 (m, 1H), 3.91-3.72 (m, 4H), 2.12-1.84 (m, 4H); MS (ES+) m/z 364.9 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@:5]([C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1)([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)[CH2:6][CH2:7][CH3:8].CCN(CC)CC.Cl[C:37]([O:39][CH3:40])=[O:38].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:15][C:11]1[CH:10]=[C:9]([C@@:5]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:17]2)([O:4][CH2:3][CH2:2][NH:1][C:37]([O:39][CH3:40])=[O:38])[CH2:6][CH2:7][CH3:8])[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)Cl
Reactant: CCC[C@](OCCN)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC[C@](OCCNC(=O)OC)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 98.1 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-1-(2-aminoethoxy)-1-(3-chlorophenyl)butyl)piperidine-1-carboxylate (410 mg, 1 mmol) and DMAP (61 mg, 0.5 mmol) in dry CH2Cl2 (3 mL), Et3N (303 mg, 3 mmol) was added. The resulting mixture was cooled to 0-5° C. using a ice-water bath, a solution of methyl chloroformate (472 mg, 5 mmol) in dry CH2Cl2 (2 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 h at 0-5° C. Upon completion of the reaction water (5 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined organic layers were washed with 10% citric acid (2×10 mL) and brine, then dried over Na2SO4, filtered and concentrated to afford (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-(2-(methoxycarbonylamino)ethoxy)butyl)piperidine-1-carboxylate (460 mg, 98%), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41].C(N1C=CC(N)=N1)CCCCC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:41][CH2:35][CH2:36][CH2:37][CH3:38])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cc1cccc(C)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: CCCCCCn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCCCCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 174 mg, 0.53 mmol) was dissolved in methylene chloride and a 2.0 M solution of oxalyl chloride in methylene chloride (191 mg, 0.58 mmol) was added. The reaction stirred at 25° C. for 1 h. The reaction was chilled to 0° C. under nitrogen and 2,6-lutidine (140 μL, 1.21 mmol) was added dropwise. The reaction became golden brown, the ice bath was removed and the reaction continued to stir at 25° C. for 30 min. 1-Hexyl-1H-pyrazol-3-ylamine (88 mg, 0.53 mmol) was dissolved in methylene chloride and added dropwise to the reaction. The solution continued to stir at 25° C. for 16 h. The reaction was diluted with methylene chloride, washed with water and saturated aqueous brine solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 10% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) to afford 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-hexyl-1H-pyrazol-3-yl)-propionamide as a white powder (171 mg, 68%) ESI-LRMS m/e calcd for C24H34ClN3O3S [M+] 479.2, found 480.5 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.88 (t, J=6.7 Hz, 3H, CH3), 1.08-1.21 (m, 2H, CH2), 1.24-1.37 (m, 6H, 3×CH2), 1.45-1.94 (m, 10H, 5×CH2), 2.09-2.31 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.53 (t, J=7.6 Hz, 1H, CH), 3.96 (t, J=7.1 Hz, 2H, NCH2), 6.63 (d, J=2.3 Hz, 1H, Ar), 7.24 (d, J=2.3 Hz, 1H, Ar), 7.45 (dd, Jo=8.1, Jm=1.8 Hz. 1H, Ar), 7.59 (d, Jm=1.8 Hz, 1H, Ar), 7.82 (s, 1H, NH), 8.09 (d, Jo=8.1 Hz, 1H, Ar).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=O)=[CH:27][CH:26]=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=1)[NH2:40].CN(C=O)C>O>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([NH:40][C:32](=[O:34])[CH2:31][C:28]2[CH:27]=[CH:26][C:25]([O:24][C:15]3[C:14]4[C:19](=[CH:20][C:21]([O:22][CH3:23])=[C:12]([O:11][CH3:10])[CH:13]=4)[N:18]=[CH:17][N:16]=3)=[CH:30][CH:29]=2)[CH:41]=[CH:42][CH:43]=1
Reactant: COc1cccc(N)c1
Reactant: COc1cc2ncnc(Oc3ccc(CC(=O)O)cc3)c2cc1OC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(NC(=O)Cc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2)c1

Procedure:
Diisopropylethylamine (0.073 ml) and 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.16 g) were added in turn to a stirred mixture of 2-[4-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]acetic acid (0.12 g), 3-methoxyaniline (0.047 ml) and DMF (3 ml) and the resultant mixture was stirred at ambient temperature for 2 hours. Water was added and the precipitate was recovered by filtration and purified by column chromatography on silica using a 19:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound as a solid (0.122 g); 1H NMR: (DMSOd6) 3.69 (s, 2H), 3.73 (s, 3H), 3.97 (s, 3H), 3.99 (s, 3H), 6.63 (m, 1H), 7.15 (d, 1H), 7.21 (m, 1H), 7.26 (d, 2H), 7.34 (m, 1H), 7.39 (s, 1H), 7.43 (d, 2H), 7.55 (s, 1H), 8.54 (s, 1H), 10.21 (s, 1H); Mass Spectrum: M+H+ 446.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)=[O:17].F[C:26]1[C:31]([CH:32]2[CH2:38][CH2:37][CH2:36][C:35](=[O:39])[CH2:34][CH2:33]2)=[CH:30][CH:29]=[CH:28][N:27]=1>CN1C(=O)CCC1>[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:26]2[C:31]([CH:32]3[CH2:38][CH2:37][CH2:36][C:35](=[O:39])[CH2:34][CH2:33]3)=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:20][CH:19]=1)=[O:17]
Reactant: O=C1CCCC(c2cccnc2F)CC1
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C1CCCC(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 140 °C

Procedure:
A mixture of cesium carbonate (0.34 g, 1.03 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.25 g, 1.03 mmol), and 4-(2-fluoropyridin-3-yl)cycloheptanone (0.071 g, 0.343 mmol) in NMP (0.3 mL) under argon was heated to 140° C. for 36 h, then cooled to room temperature. The resulting mixture was partitioned between ethyl acetate and water, the layers were separated, and the organic layer was washed 1N aqueous sodium hydroxide (2×), saturated aqueous sodium chloride (1×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The oil was purified by silica gel chromatography to give 4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)cycloheptanone. MS (ESI, pos. ion) m/z: 426.1 (M+1). IC50 (uM) +++++.