Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH:4]=[CH:3][O:2]1.[C:7]1([SH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>O1CCCC1>[C:7]1([S:13][CH:3]2[CH2:4][O:5][C:1](=[O:6])[O:2]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Sc1ccccc1
Reactant: O=c1occo1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1OCC(Sc2ccccc2)O1

Procedure:
In 70 mL of tetrahydrofuran (THF), 3 g of vinylene carbonate and 5.1 g of benzenethiol were dissolved, and then 4.7 g of triethylamine was added. The mixture was refluxed under an argon atmosphere for 4 hours. When the reaction was finished, the solvent was removed through distillation under reduced pressure, and the resulting material was subjected to the column chromatography on silica gel (eluted with 20% hexane/ethylacetate) and purified to obtain a target product, 4-phenylsulfanyl-[1,3]dioxolan-2-one.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.[CH2:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C)([O-])C.[Na+].O>C1(C)C=CC=CC=1.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH2:17]([N:24]1[CH2:29][CH2:28][N:27]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[CH:5]3)[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Brc1ccc2c(cnn2C2CCCCO2)c1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCN(c3ccc4c(cnn4C4CCCCO4)c3)CC2)cc1
Temperature: 75 °C
Yield: 54.7 %

Procedure:
To a solution of the 5-bromo-1-tetrahydro-2H-pyran-2-yl-1H-indazole (250 mg, 0.889 mmol) obtained in Reference Example 5 in toluene (12 ml) were added 1-benzylpiperazine (0.24 ml, 1.35 mmol) and sodium tert-butoxide (128 mg, 1.33 mmol) at room temperature. After deaeration, bis(tri-o-tolylphosphine)-palladium(II) dichloride (70 mg, 0.0891 mmol) was added thereto and the resulting mixture was stirred at 75° C. for three and a half hours. Then, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/ethyl acetate=5/2) to obtain 5-(4-benzyl-1-piperazinyl)-1-tetrahydro-2H-pyran-2-yl-1H-indazole (183 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22].Br[C:24]1[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:15])[F:16])[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:24]4[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22]
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Reactant: NS(=O)(=O)c1cccc(Br)c1
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C#Cc4cccc(S(N)(=O)=O)c4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-difluoromethyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.16) (159 mg, 0.5 mmol) and commercially available 3-bromo-benzenesulfonamide (118 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (140 mg, 59%). MS (ISP) 473.2 [(M+H)+]; mp 215° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH:4][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1cc([N+](=O)[O-])c(F)cc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Nc2ccccc2)c(F)cc1F
Temperature: 25 °C
Reaction time: 50 h
Yield: 90.9 %

Procedure:
A mixture of 2,4-difluoro-5-nitroaniline (3.00 g, 17.23 mmol) (see EP0379894 A3), phenylboronic acid (6.30 g, 51.69 mmol), copper(II) acetate (3.13 g, 17.23 mmol) and 4 Å molecular sieves (3.0 g) in dichloromethane (170.0 mL) and triethylamine (12.01 mL, 43.08 mmol) was placed in a round bottomed flask. The resulting suspension was stirred under at room temperature under a dry ambient atmosphere 50 h. The mixture was filtered through diatomaceous earth and the solvent was evaporated. Additional phenylboronic acid (6.30 g, 51.69 mmol), copper(II) acetate (3.13 g, 17.23 mmol), molecular sieves (3.00 g) triethylamine (12.01 mL, 43.08 mmol), and dichloromethane (170.00 mL) were added and the slurry was stirred for 12 h. The mixture was again filtered through diatomaceous earth and the solvent was evaporated. The resulting residue was re-dissolved in EtOAc, adsorbed on silica and flash chromatographed (15% EtOAc/hexanes) to give 2,4-difluoro-5-nitro-N-phenylaniline as an orange solid (3.92 g, 91% yield).
Reaction SMILES: C([CH:4]=[CH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([O:16][CH3:17])=[CH:8][CH:7]=1)(O)=O.C(Cl)(Cl)Cl.[Br:22]Br.C(=O)([O-])[O-].[Na+].[Na+]>O.C(Cl)Cl>[Br:22][CH:4]=[CH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([O:16][CH3:17])=[CH:8][CH:7]=1
Reactant: COc1ccc(C=CC(=O)O)c2ccccc12
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1ccc(C=CBr)c2ccccc12

Procedure:
To a suspension of 33.3 g. (0.146 mol.) of 1-(2-carboxyethenyl)-4-methoxynaphthalene in 500 ml. of chloroform was added dropwise a solution of 8.05 ml. (0.146 mol.) of bromine in 125 ml. of methylene chloride. The solvent was removed, a solution of 31 g. (0.292 mol.) of sodium carbonate in 300 ml. of water was added to the residue and the mixture was refluxed for 2 hours. After cooling, the mixture was extracted with methylene chloride, the layers were separated and the organic phase was washed with water and saturated sodium chloride solution, dried (MgSO4) and evaporated to dryness to give 1-(2-bromoethenyl)-4-methoxynaphthalene.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:5][C:4]=1[N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15]1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[C:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:5][C:4]=1[N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([OH:25])=[O:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15]1)#[N:2]
Reactant: COC(=O)Cc1ccc(-n2ccc3cc(C(=O)OC(C)(C)C)ccc32)c(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1ccc(-n2ccc3cc(C(=O)O)ccc32)c(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
tert-butyl 1-(2-cyano-4-(2-methoxy-2-oxoethyl)phenyl)-1H-indole-5-carboxylate (0.380 g, 0.973 mmol, in 2 ml of DCM was added 2 mL of TFA and the reaction stirred at ambient temperature under nitrogen. After 2 hours, the reaction was concentrated to give 1-(2-cyano-4-(2-methoxy-2-oxoethyl)phenyl)-1H-indole-5-carboxylic acid (0.320 g, 0.957 mmol, 98%). MS (APCI negative)=333.2 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=2[F:17])=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])=[CH:25][C:21]=1[C:22](O)=[O:23].C1COCC1>CN(C=O)C>[F:17][C:11]1[CH:12]=[CH:13][C:14]([NH:16][C:22](=[O:23])[C:21]2[CH:25]=[C:26]([CH2:29][NH:30][C:31]([C:33]([CH3:34])([CH3:36])[CH3:35])=[O:32])[CH:27]=[CH:28][C:20]=2[Cl:19])=[CH:15][C:10]=1[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:18]
Reactant: Nc1ccc(F)c(C(=O)Nc2ccc(Br)cc2)c1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2ccc(F)c(C(=O)Nc3ccc(Br)cc3)c2)c1

Procedure:
PPA (0.142 mL 50% solution in DMF) was added dropwise to a mixture of N-(4-bromophenyl)-2-fluoro-5-amino-benzoic acid amide (57 mg, 0.19 mmol), 2-chloro-5-(tert-butylcarbonylamino)methyl-benzoic acid (50 mg, 0.19 mmol), 64 μL TEA and 10 mL THF. The reaction was refluxed overnight, additional PPA (0.14 mL) was added and it was refluxed for additional 4.5 h. The crude reaction mixture was concentrated i.vac., EtOAc was added and the organic phase was washed with 2 M aq. HCl, satd. NaHCO3, dried with Na2SO4 and purified via HPLC (Method A) to furnish the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:9]1[CH2:14][CH2:13][CH:12]([C:15](=O)[CH2:16][NH:17][C:18]2[N:19]=[C:20]3[CH:26]=[CH:25][N:24]([S:27]([C:30]4[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:21]3=[N:22][CH:23]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC#N>[CH2:1]([N:8]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:19]3[C:20]4[CH:26]=[CH:25][N:24]([S:27]([C:30]5[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=5)(=[O:29])=[O:28])[C:21]=4[N:22]=[CH:23][C:18]3=[N:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NCC(=O)C4CCC(N(Cc5ccccc5)Cc5ccccc5)CC4)cnc32)cc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2ncc(C4CCC(N(Cc5ccccc5)Cc5ccccc5)CC4)n23)cc1
Temperature: 50 °C
Yield: 200.8 %

Procedure:
A mixture of 1-(4-(dibenzylamino)cyclohexyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone (5.8 g, 9.54 mmol) and PFPAA (23.7 g, 76 mmol) in MeCN (70 mL) was heated at about 50° C. for about 17 h. PFPAA (4.73 g, 15.2 mmol) was added and the reaction mixture was heated at about 60° C. for about 7 h and at ambient temperature for about 72 h. The solvent was removed under reduced pressure to yield N,N-dibenzyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclohexanamine (11.3 g crude, but assumed 5.6 g, 100%) as a foam: LC/MS (Table 1, Method b) Rt=3.03 and 3.09 min; MS m/z 590 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:28]3=[N:29][CH:30]=[CH:31][CH:32]=[C:27]3[N:26]([CH2:33][CH3:34])[C:25]2=[O:35])=[CH:20][CH:19]=1.[H-].[Na+].[Cl-].[Cl-].[Ca+2]>CN(C=O)C.CO>[CH2:33]([N:26]1[C:27]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[N:24]([C:21]2[CH:20]=[CH:19][C:18]([O:17][C:9]3[N:8]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[N:10]=3)=[CH:23][CH:22]=2)[C:25]1=[O:35])[CH3:34]
Reactant: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4[nH]3)cc2)c2ncccc21
Reactant: CCOC(=O)CBr
Agent: [Ca+2]
Agent: [Cl-]
Agent: [H-]
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(Oc2ccc(-n3c(=O)n(CC)c4cccnc43)cc2)nc2ccccc21

Procedure:
Ethyl bromoacetate (0.240 mL) was added to a solution of 3-[4-(1H-benzimidazol-2-yloxy)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (400 mg) and sodium hydride (86 mg) in DMF (2 mL) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 2 h. The reaction mixture was diluted with MeOH (5 mL), and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 0%-50% EtOAc in hexane) to give ethyl {2-[4-(1-ethyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy]-1H-benzimidazol-1-yl}acetate (480 mg) as off-white crystals.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[C:16]4[CH:17]=[CH:18][C:19]([B:21]5[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]5)=[CH:20][C:15]=4[S:14][C:13]=3[CH:30]=2)O1.Br[C:33]1[CH:34]=[CH:35][C:36]2[N:40]=[C:39]([C@@H:41]3[CH2:45][CH2:44][CH2:43][N:42]3[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[NH:38][C:37]=2[CH:53]=1.C(=O)([O-])[O-].[K+].[K+].ClC(Cl)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.C1(C)C=CC=CC=1.C(COC)OC>[CH3:27][C:24]1([CH3:26])[C:23]([CH3:28])([CH3:29])[O:22][B:21]([C:19]2[CH:18]=[CH:17][C:16]3[C:12]4[CH:11]=[CH:10][C:9]([C:33]5[CH:34]=[CH:35][C:36]6[N:40]=[C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46]([O:48][C:49]([CH3:51])([CH3:50])[CH3:52])=[O:47])[NH:38][C:37]=6[CH:53]=5)=[CH:30][C:13]=4[S:14][C:15]=3[CH:20]=2)[O:25]1
Reactant: CC1(C)OB(c2ccc3c(c2)sc2cc(B4OC(C)(C)C(C)(C)O4)ccc23)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(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: COCCOC
Solvent: Cc1ccccc1
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc4c(c3)sc3cc(B5OC(C)(C)C(C)(C)O5)ccc34)cc2[nH]1
Temperature: 85 °C
Yield: 62.2 %

Procedure:
A mixture of 3,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-dibenzo[b,d]thiophene (3.6 g, 8.2 mmol), (S)-tert-butyl 2-(6-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.0 g, 2.7 mmol), tetrakis(triphenylphosphine)palladium(0) (0.31 mg, 0.27 mmol), 2M aqueous potassium carbonate solution (5 mL, 10 mmol), dimethoxyethane (25 mL), toluene (5 mL) and dichloroethane (2.5 mL) was degassed under a stream of argon for 15 minutes. The reaction was heated to 85° C. for 2 hours. Upon completion, the reaction was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water and brine, dried (MgSO4) and concentrated. The resulting crude material was purified by flash column chromatography to yield (S)-tert-butyl 2-(6-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dibenzo[b,d]thiophen-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.0 g, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][NH:14][CH:13]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=4[CH3:32])[CH2:21][CH2:20]3)=[O:18])[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:40][CH2:41][CH3:42].O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:40][CH2:41][CH3:42])[CH:13]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=4[CH3:32])[CH2:21][CH2:20]3)=[O:18])[CH2:12]2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4cccc(Cl)c4)CCN3)CC2)c1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: CCCN1CCN(S(=O)(=O)c2cccc(Cl)c2)CC1C(=O)N1CCN(c2cc(C)ccc2C)CC1

Procedure:
To a solution of [4-(3-chloro-benzenesulfonyl)-piperazin-2-yl]-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (100 mg) in acetone (4 mL) was added cesium carbonate (82 mg), followed by 1-bromopropane (21 μL). The reaction mixture was stirred at reflux overnight. Water was added and the reaction mixture was extracted with ethyl acetate (×2). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. Purification by chromatography (SiO2, n-heptane/ethyl acetate 3:1) yielded [4-(3-chloro-benzenesulfonyl)-1-propyl-piperazin-2-yl]-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone as a white foam (75 mg), MS: 519.3 ([M+H, 1Cl]+).
Reaction SMILES: [F:1][CH2:2][C:3](=[CH2:14])[CH2:4][N:5]([CH2:11][CH:12]=O)[C:6](=[O:10])[O:7][CH2:8][CH3:9].O.[NH:16]([CH2:18]C(O)=O)[CH3:17]>C1(C)C=CC=CC=1>[F:1][CH2:2][C:3]12[CH2:4][N:5]([C:6]([O:7][CH2:8][CH3:9])=[O:10])[CH2:11][CH:12]1[N:16]([CH3:18])[CH2:17][CH2:14]2
Reactant: CNCC(=O)O
Reactant: C=C(CF)CN(CC=O)C(=O)OCC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2N(C)CCC2(CF)C1

Procedure:
9.1 g (43 mmol) of ethyl N-(2-fluoromethylallyl)-N-(2-oxoethyl)-carbamate are heated under reflux overnight in a water separator with 3.9 g (43 mmol) of powdered sarcosine in 170 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:11][OH:12])=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:9]=[C:6]([CH2:7][OH:8])[C:5]([F:10])=[CH:4][C:3]=1[CH2:11][OH:12]
Reactant: O=Cc1cc(Br)c(CO)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc(Br)c(CO)cc1F
Reaction time: 0.17 h
Yield: 40.6 %

Procedure:
5-Bromo-2-fluoro-4-hydroxymethyl-benzaldehyde (604.3 mg, 2.59 mmol) was dissolved in methanol (5 mL). To the resultant solution was added sodium borohydride (98.1 mg, 2.59 mmol) at 0° C. After stirring for 10 minutes, about 3 mL of methanol was removed by distillation. Water was added to the solution, and the resultant mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography (developing solution methanol:dichloromethane (3:100)), to thereby obtain the titled compound (247.3 mg, 43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:8](=[O:15])[C:9]3[CH2:10][CH2:11][CH2:12][NH:13][C:14]=3[C:5]=2[CH:4]=1.[H-].[Na+].I[CH3:30]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:8](=[O:15])[C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH3:30])[C:14]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc(Cn2c(=O)c3c(c4cc(OC)ccc42)NCCC3)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3c(c4cc(OC)ccc42)N(C)CCC3)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
9-methoxy-6-(4-methoxybenzyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-5(6H)-one (500 mg, 1.36 mmol) was dissolved in N,N-dimethylformamide (10 ml), added with sodium hydride (140 mg, 2.04 mmol) at 0° C. After stirring for 30 minutes, iodomethane (0.13 ml, 2.04 mmol) was added and the resulting mixture was stirred for 3 hours at 0° C. After completion, the mixture was poured into ice water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was then purified by flash column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (445 mg, yield: 90%, white solid).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[CH2:10][CH2:11][NH:12][C:13](=[O:27])[CH:14]([O:23][C:24](=[O:26])[CH3:25])[C:15]([CH3:22])([CH3:21])[CH2:16][O:17][C:18](=[O:20])[CH3:19])=[CH:4][CH:3]=1.[C:29](Cl)(=[O:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>>[C:29]([O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[CH2:10][CH2:11][NH:12][C:13](=[O:27])[CH:14]([O:23][C:24](=[O:26])[CH3:25])[C:15]([CH3:22])([CH3:21])[CH2:16][O:17][C:18](=[O:20])[CH3:19])=[CH:6][CH:7]=1)(=[O:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CC(=O)OCC(C)(C)C(OC(C)=O)C(=O)NCCC(=O)Nc1ccc(O)cc1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Oc1ccc(NC(=O)CCNC(=O)C(OC(C)=O)C(C)(C)COC(C)=O)cc1
Yield: 80.5 %

Procedure:
N-(4-hydroxyphenyl)-3-[N-(2,4-diacetoxy-3,3 -dimethyl-1-oxobutyl)amino]propanamide (394 mg) and 301 mg of oleoyl chloride were reacted in the same manner as in Example 6 to obtain 530 mg of the title compound (yield 81%)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=3)=[O:14])=[C:10]([NH:23][C:24]([C@H:26]3[CH2:31][CH2:30][C@H:29]([N:32]4[CH2:36][CH2:35][CH2:34][C:33]4=[O:37])[CH2:28][CH2:27]3)=[O:25])[C:9]=2[CH:38]=1)=[O:4].[OH-].[Na+]>O1CCCC1CO>[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=3)=[O:14])=[C:10]([NH:23][C:24]([C@H:26]3[CH2:27][CH2:28][C@H:29]([N:32]4[CH2:36][CH2:35][CH2:34][C:33]4=[O:37])[CH2:30][CH2:31]3)=[O:25])[C:9]=2[CH:38]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4=O)CC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: O=C(O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4=O)CC3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Trans-5-methoxycarbonyl-3-[4-(2-oxopyrrolidin-1-yl)-cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (710 mg) obtained in Example 1 is suspended in tetrahydrofuran-methanol (1:1, 10 ml), and thereto is added 4N aqueous sodium hydroxide solution (2 ml) under ice-cooling. The mixture is warmed to room temperature, and stirred for 18 hours. The reaction solution is concentrated under reduced pressure, and thereto is poured ice-water, and the mixture is neutralized with 10% hydrochloric acid. The precipitates are collected by filtration, washed with water, and dried to give the title compound (655 mg).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8][CH2:9][CH3:10])=[CH2:7])CCC.Br[C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])=[CH:22][C:21]=1[CH3:31]>O1CCOCC1.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>[CH2:9]([O:8][C:6]([C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])=[CH:22][C:21]=1[CH3:31])=[CH2:7])[CH3:10]
Reactant: CC(=O)N(C)c1ccc(Br)c(C)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=C(OCC)c1ccc(N(C)C(C)=O)cc1C
Temperature: 90 °C
Reaction time: 12 h
Yield: 176.3 %

Procedure:
Tributyl(1-ethoxyvinyl)tin (1.07 mmol, 3.18 mmol) and dichlorobis(triphenylphosphine)palladium(II) (101 mg, 0.145 mmol) were added to a solution of N-(4-bromo-3-methylphenyl)-N-methylacetamide (700 mg, 2.89 mmol) in 1,4-dioxane (7 mL), and the mixture was heated with stirring at 90° C. for 12 hours in a nitrogen stream. The reaction mixture was cooled and then filtered through celite. The solution was concentrated under reduced pressure, and the residue was then silica gel column chromatography (hexane-ethyl acetate) to give N-[4-(1-ethoxy-vinyl)-3-methyl-phenyl]-N-methyl-acetamide (440 mg, 65%).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][C@@H](O)S([O-])(=O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+].CO.Cl.CO[CH:26]([O:29][CH3:30])[O:27][CH3:28]>O1CCOCC1>[CH3:19][O:18][C:16](=[O:17])[C@@H:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH2:9][CH:26]([O:27][CH3:28])[O:29][CH3:30]
Reactant: COC(OC)OC
Reactant: COC(=O)C(CC1CCCCC1)C[C@@H](O)S(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)[C@@H](CC1CCCCC1)CC(OC)OC
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 64.8 %

Procedure:
To a slurry of sodium (S)-4-cyclohexyl-1-hydroxy-3-methoxycarbonyl-butane-1-sulfonate (400.0 g, 1.26 mol) and methanol (2 L) was added 4.0 M HCl in 1,4-dioxane (400 mL) and the reaction mixture was stirred for 15 min. Trimethoxymethane (340 mL, 3.11 mol) was added and reaction mixture was heated at 50° C. overnight, and then cooled to room temperature. White solids were filtered off and discarded. Most of the solvent was removed from the filtrate by rotary evaporation. Ethyl acetate (800 mL) was added resulting in more precipitation. The white precipitate was removed by filtration. Solvent was removed from the filtrate by rotary evaporation and then under high vacuum at room temperature overnight to yield the title compound (211 g) as a thick oil. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 4.25 (t, 1H), 3.57 (s, 3H), 3.18 (s, 6H), 2.43 (m, 1H), 1.55-1.81 (m, 2H), 1.50-1.72 (m, 5H), 1.20-1.48 (m, 2H), 1.05-1.21 (m, 4H), 0.71-0.92 (m, 2H).