Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[NH:15][C:14]3=[O:22])[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N:30]1[CH:35]=[C:34]([C:36](Cl)=[O:37])[CH:33]=[N:32][CH:31]=1.N>ClCCl>[N:30]1[CH:35]=[C:34]([C:36]([N:4]2[CH2:3][CH2:2][N:1]([C@H:7]3[CH2:12][CH2:11][C@H:10]([N:13]4[C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=5[NH:15][C:14]4=[O:22])[CH2:9][CH2:8]3)[CH2:6][CH2:5]2)=[O:37])[CH:33]=[N:32][CH:31]=1
Reactant: O=C(Cl)c1cncnc1
Reactant: O=c1[nH]c2ccccc2n1[C@H]1CC[C@H](N2CCNCC2)CC1
Agent: N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cncnc1)N1CCN([C@H]2CC[C@H](n3c(=O)[nH]c4ccccc43)CC2)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of 0.044 g of 1,3-dihydro-1-{trans-4-[1-piperazinyl]-1-cyclohexyl}-2H-benzimidazol-2-one and 0.2 mL of triethylamine in 3 mL of dichloromethane was added 0.030 g of pyrimidine-5-carboxylic acid chloride. After 2 h, 5 mL of dilute aqueous ammonia was added and the mixture stirred for an additional 30 min. The organic layer was separated, the aqueous layer extracted with two additional 20 mL portions of chloroform and the combined organic extracts dried over MgSO4 and concentrated under reduced pressure. Chromatography over silica gel eluting with 10% methanol in ethyl acetate gave 0.030 g of 1,3-dihydro-1-{trans-4-[4-(5-pyrimidinecarbonyl)piperazin-1-yl]-1-cyclohexyl}-2H-benzimidazol-2-one as a white solid: 1H NMR (400 MHz, CDCl3) 9.76 (s, 1H), 9.29 (s, 1H), 8.83 (s, 2H), 7.16-7.04 (m, 4H), 4.27 (m, 1H), 3.84 (s, 2H), 3.48 (s, 2H), 2.72 (s, 2H), 2.61 (s, 2H), 2.56 (m, 1H), 2.30 (q, 2H), 2.05 (m, 4H), 1.86 (br s, 1H), 1.5 (q, 2H). The dihydrochloride salt was precipitated from chloroform/ethyl acetate: Analysis calculated for C22H26N6O2.2HCl.0.65 CHCl3C: 48.84, H: 5.18, N: 15.09 found C: 48.85, H: 5.36, N: 14.72.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[N:3]=1.[BH4-].[Na+]>CO>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17]2)[NH:3]1
Reactant: Cc1ccc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1CCc2c(cccc2N2CCN(C(=O)OC(C)(C)C)CC2)N1
Temperature: 0 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
To a cold (0° C.) and stirred mixture of the tert-butyl 4-(2-methylquinolin-5-yl)piperazine-1-carboxylate prepared in example 6 (4.29 g, 13.1 mmol) and NiCl2.6H2O (0.78 g, 3.3 mmol) in MeOH (250 mL) was added portionwise NaBH4 (3.96 g, 104.8 mmol) and then stirring was continued for 3 h. NaBH4 was added when necessary. The solvent was evaporated in vacuo, the residue was treated with water and then extracted with CH2Cl2. After drying over MgSO4, the solvent was evaporated in vacuo and the residue was purified by column chromatography (eluent CH2Cl2) to afford title compound (2.8 g, 51%). Rf 0.85 (CH2Cl2-MeOH 19:1).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10]2)=[CH:5][CH:4]=1)#[N:2].C1C(=O)N([Br:28])C(=O)C1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:28][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)Nc1ccc2ccc(C#N)cc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc2ccc(C#N)cc2c1Br
Temperature: 60 °C
Yield: 99.5 %

Procedure:
A mixture of 193 (1.90 g, 7.09 mmol), NBS (1.41 g, 7.20 mmol) and K2CO3 (1.11 g, 8.50 mmol) in MeCN (20 mL) was heated at 60° C. under N2 for 30 min. The solvent was removed under reduced pressure and the residue was partitioned between CH2Cl2 and water. The organic layer was washed with water (×2), brine and dried. Filtration through silica gel gave tert-butyl 1-bromo-7-cyano-2-naphthylcarbamate (194) (2.45 g, 100%) as a colorless powder. A sample was recrystallised (petroleum ether) to give colorless needles: mp 139-141° C.; 1H NMR (CDCl3) δ 8.58 (d, J=9.1 Hz, 1H), 8.54 (d, J=1.0 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.83 (d, J=9.1 Hz, 1H), 7.56 (dd; J=8.3, 1.4 Hz, 1H), 7.36 (br s, 1H), 1.57 (s, 9H); 13C NMR δ 152.3, 136.7, 132.5, 132.0, 131.4, 129.4, 128.3, 125.6, 122.4, 119.0, 111.3, 109.4, 81.9, 28.3. Anal. (C16H15BrN2O2) C, H, N, Br.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]3[C:17]4[CH2:22][CH2:21][NH:20][C:19]([CH2:24][NH:25][C:26](=[O:30])[CH:27](C)C)([CH3:23])[C:18]=4[O:31][C:13]=3[CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.CC(C)C(OC(=O)C(C)C)=O>>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]3[C:17]4[CH2:22][CH2:21][NH:20][C:19]([CH2:24][NH:25][C:26](=[O:30])[CH3:27])([CH3:23])[C:18]=4[O:31][C:13]=3[CH:12]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)NCC1(C)NCCc2c1oc1cc(S(=O)(=O)c3cccc(F)c3)ccc21
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC(C)C(=O)OC(=O)C(C)C
Product: CC(=O)NCC1(C)NCCc2c1oc1cc(S(=O)(=O)c3cccc(F)c3)ccc21

Procedure:
Prepared as described for N-[7-(3-Fluoro-benzenesulfonyl)-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-c]pyridin-1-ylmethyl]isobutyramide using acetic anhhydride instead of 2-methylpropanoic anhydride. mp 140-155° C. dec.; MS m/z 417 [M+H]+.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:18]=[CH:17][C:7]([C:8]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1.[C:19](Cl)([Cl:21])=[S:20]>O.C(Cl)(Cl)Cl>[Cl:21][C:19]([O:3][C:4]1[CH:18]=[CH:17][C:7]([C:8]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1)=[S:20]
Reactant: S=C(Cl)Cl
Reactant: O=C(Sc1ccccc1)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(Sc1ccccc1)c1ccc(OC(=S)Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of sodium hydroxide (1.55 g in 150 ml of water was added dropwise with vigorous stirring to a solution of 8.8 g of S-phenyl 4-(hydroxy)thiobenzoate and 3.70 ml of thiophosgene in 250 ml of chloroform, the temperature being kept below 10° C. The mixture was stirred at room temperature for 2 hours and the organic layer separated. The organic layer was washed successively with water and brine, dried over calcium chloride, and evaporated to dryness in vacuo to give 11.57 g of the title compound.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:9]=3[N:10]([CH2:18][CH2:19]4)[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[OH-].[Na+]>C1COCC1>[CH:1]1([CH:7]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]3[CH2:18][CH2:19][C:20]4=[CH:21][CH:22]=[CH:23][C:8]2=[C:9]34)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1ccc2c(c1)N=C(C1CCCCC1)c1cccc3c1N2CC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: c1ccc2c(c1)NC(C1CCCCC1)c1cccc3c1N2CC3
Temperature: 0 °C

Procedure:
A solution of 8.81 g of 6-cyclohexyl-1,2-dihydroindolo[1,7-ab][1,5]benzodiazepine in 50 ml dry THF is added dropwise to an ice cold solution of BH3 in THF (90 ml of 1 M solution; 0.090 mole) under N2. The resulting solution is refluxed for 15 minutes, cooled to 0° C., treated dropwise with 6 M HCl, and gently refluxed for 1 hour. The resulting clear solution is cooled to 0° C. and made basic with solid NaOH. The aqueous phase is extracted with ether and the combined organic layers are washed with brine, dried over K2CO3, and concentrated to give an oil. Two crystallizations from ether/heptane yield 6-cyclohexyl-1,2,6,7-tetrahydroindolo[1,7-ab][1,5]benzodiazepine, m.p. 136°-137.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:35]C)=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:16]=2[NH:24][C:25](=[O:34])[CH2:26][C:27]2[N:31]([CH2:32][CH3:33])[N:30]=[N:29][N:28]=2)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[Cl-].[Li+].Cl.C(OCC)(=O)C.C[N:47](C)C=O>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:35])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:17][C:16]=2[NH:24][C:25](=[O:34])[CH2:26][C:27]2[N:31]([CH2:32][CH3:33])[N:30]=[N:29][N:28]=2)(=[O:10])=[O:11])[CH:8]=1)(=[NH:47])[NH2:2]
Reactant: CCn1nnnc1CC(=O)Nc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Reactant: CN(C)C=O
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CCn1nnnc1CC(=O)Nc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C(=N)N)ccc1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 0.112 g of N-[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenyl]-2-(1-ethyl-1H-tetrazol-5-yl)acetamide and 28 mg of lithium chloride in 0.65 mL of N,N-dimethylformamide was stirred at 140° C. for 4 hours. To the reaction mixture were added 1 mol/L hydrochloric acid and ethyl acetate, and the mixture was separated. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined. After the organic layer was washed with water, and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in 2.5 mL of 39% hydrogen chloride-ethanol solution, and the solution was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 1.0 mL of ethanol. To the solution was added 66 mg of ammonium acetate, and the mixture was stirred at room temperature for 14 hours. To the reaction mixture were added water, ethyl acetate, and hexane, and the precipitate was collected by filtration to give 42 mg of N-[2-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenyl]-2-(1-ethyl-1H-tetrazol-5-yl)acetamide.
Reaction SMILES: [CH2:1]([C:6](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[CH2:7]Br)[CH2:2][CH2:3][CH2:4][CH3:5].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)(Cl)Cl>[CH2:1]([C:6](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[CH2:7][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC(=Cc1ccc(Cl)cc1Cl)CBr
Reactant: C1CCNC1
Solvent: ClC(Cl)Cl
Product: CCCCCC(=Cc1ccc(Cl)cc1Cl)CN1CCCC1
Temperature: 150 °C
Yield: 39.1 %

Procedure:
A mixture of 50 g of (III) and 31.7 g of pyrrolidine was heated for 5 hours at 150° C. in an oil bath. The crude product was cooled, and dissolved in CHCl3, and the solution was washed with dilute NaOH and then several times with water. The organic phase was dried over Na2SO4 and concentrated. Distillation of the residue gave 19 g of (IV) of boiling point 148°-150° C./0.1 mbar.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1I.[NH:10]1[C:18]2[C:13](=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:10]1[C:18]2[C:13](=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: Fc1ccc(I)c(F)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3ccc(F)cc3F)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 2,4-difluoro-1-iodobenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 488.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[S:12]([CH:15]1[S:19][C:18](=[O:20])[NH:17][C:16]1=[O:21])(=[O:14])=[O:13].S1CC(=O)NC1=O.C([Li])CCC.[Br:34]C1C=CC=C2C=1C=CC=C2S(Cl)(=O)=O.S(=O)(=O)(O)O>O1CCCC1>[Br:34][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][CH:2]=[C:3]2[S:12]([CH:15]1[S:19][C:18](=[O:20])[NH:17][C:16]1=[O:21])(=[O:14])=[O:13]
Reactant: O=C1NC(=O)C(S(=O)(=O)c2c(Br)ccc3ccccc23)S1
Reactant: O=S(=O)(Cl)c1cccc2c(Br)cccc12
Agent: O=C1CSC(=O)N1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1NC(=O)C(S(=O)(=O)c2cccc3c(Br)cccc23)S1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
5-[(Bromo-1-naphthalenyl)sulfonyl]-2,4-thiazolidinedione. To a stirred solution of 2,4-thiazolidinedione (5.5 g, 47 mmol) in tetrahydrofuran (THF) (275 mL) at -78° C. under nitrogen was added n-butyllithium (62 mL, 99 mmol) portionwise over 15 minutes. The mixture was maintained at -78° C. for 15 minutes and then warmed to 0° C. for 30 minutes to complete the dianion formation. Upon recooling to -78° C., 5-bromo-1-naphthalene-sulfonyl chloride (16 g, 52 mmol) was added as a solid, all at once. After 30 minutes the solution was allowed to warm to 25° C. After 1.5 hours the reaction mixture was treated with 5% aqueous sulfuric acid. The aqueous phase was washed with chloroform (3×), and the combined organic extracts were concentrated to an oil which was taken up in 5% aqueous sodium bicarbonate and extracted with chloroform (3×). The combined organic extracts of the acidified aqueous phase were dried (magnesium sulfate) and then concentrated to give an oil, which was purified by chromatography (acid-washed silica gel, 10:1 chloroform/acetonitrile) to give 5-[(5-Bromo-1-naphthalenyl)sulfonyl]-2,4-thiazolidinedione (7.6 g, 42% yield): mp 189°-190° C. (acetonitrile/chloroform): 1H NMR (DMSO-d6, 200 MHz) δ 6.60 (s, 1 H, CH, exchanges with D2O), 7,7-8.7 (m, 6 H, ArH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]([F:13])([F:12])[F:11])=[CH2:9])[CH:5]=[C:4]([F:14])[C:3]=1[F:15].[OH:16][N:17]=[C:18](Cl)[C:19]1[CH:30]=[CH:29][C:22]2[B:23]([OH:28])[O:24][C:25]([CH3:27])([CH3:26])[C:21]=2[CH:20]=1>CN(C=O)C>[CH3:26][C:25]1([CH3:27])[O:24][B:23]([OH:28])[C:22]2[CH:29]=[CH:30][C:19]([C:18]3[CH2:9][C:8]([C:10]([F:12])([F:13])[F:11])([C:6]4[CH:7]=[C:2]([F:1])[C:3]([F:15])=[C:4]([F:14])[CH:5]=4)[O:16][N:17]=3)=[CH:20][C:21]1=2
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Reactant: C=C(c1cc(F)c(F)c(F)c1)C(F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(F)c(F)c(F)c4)(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,2,3-trifluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene in DMF were added TEA (0.86 g, 1.18 mL, 8.52 mmol, 3 eq) and N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (545 mg, 2.27 mmol, 0.8 eq) at 0° C. The reaction mixture was stirred for 12 h at rt, poured into ice-water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica column and prep-HPLC to give 105 mg pure product. 1H NMR (400 MHz, DMSO-d6): δ 9.23 (s, 1H), 7.76-7.59 (m, 5H), 4.43 (d, J=18.4 Hz, 1H), 4.28 (d, J=18.4 Hz, 1H), 1.48 (s, 3H), 1.47 (s, 3H) ppm; HPLC purity: 99.6% at 254 nm; MS: m/z=430 (M+1, ESI+).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[C:6]([CH3:32])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]3[O:22][C:23]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=4[C:25]=3[CH3:26])=[O:20])=[CH:14][CH:13]=2)[C:9]=1[CH3:10].[OH-].[Na+].Cl>O1CCOCC1.O.O>[F:31][C:28]1[CH:29]=[CH:30][C:23]2[O:22][C:21]([C:19]([NH:18][C:15]3[CH:16]=[CH:17][C:12]([CH2:11][N:8]4[C:9]([CH3:10])=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[C:6]([CH3:32])=[N:7]4)=[CH:13][CH:14]=3)=[O:20])=[C:25]([CH3:26])[C:24]=2[CH:27]=1
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(NC(=O)c3oc4ccc(F)cc4c3C)cc2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nn(Cc2ccc(NC(=O)c3oc4ccc(F)cc4c3C)cc2)c(C)c1CC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.3 %

Procedure:
To a solution of [1-(4-aminobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]acetic acid methyl ester (400 mg, 1.46 mmol) in 5 mL dichloromethane are added diisopropylethylamine (1.5 mL, 8.8 mmol) and 5-fluoro-3-methyl-1-benzofuran-2-carboxylic acid (369 mg, 1.9 mmol). After stiffing at room temperature for 10 minutes a 50% solution of 1-propylphosphonic acid cyclic anhydride in ethyl acetate (1.725 mL, 2.93 mmol) is added with cooling and the mixture is stirred at room temperature for 12 hours. The solvent is evaporated in vacuo and the residue is purified by MPLC (dichloromethane/methanol 98:2) to yield 410 mg of (1-{4-[(5-fluoro-3-methylbenzofuran-2-carbonyl)amino]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (ESI mass spectrum: [M+H]+=450; TLC: Rf=0.56 (dichloromethane/methanol 95:5, silicagel 60 F254)). b) To a solution of (1-{4-[(5-fluoro-3-methylbenzofuran-2-carbonyl)amino]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (410 mg, 0.91 mmol) in dioxane/water (10 mL/10 mL) is added 1 M NaOH (2.3 mL) and the mixture is stirred at room temperature for 24 hours. The mixture is diluted with water and acidified with hydrochloric acid (1 M, 3.25 mL). The precipitate is filtered, washed with water and dried to yield 338 mg of the title compound (ESI mass spectrum: [M+H]+=436; Retention time HPLC: 0.85 min (method D).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:12])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10].[OH:13][C:14]1[CH:23]=[CH:22][C:17]2[CH:18]([CH3:21])[CH2:19][O:20][C:16]=2[CH:15]=1>>[CH3:12][C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10])=[CH:3][CH2:2][O:13][C:14]1[CH:23]=[CH:22][C:17]2[CH:18]([CH3:21])[CH2:19][O:20][C:16]=2[CH:15]=1
Reactant: CC1COc2cc(O)ccc21
Reactant: CCC(C)=CCCC(C)=CCBr
Product: CCC(C)=CCCC(C)=CCOc1ccc2c(c1)OCC2C

Procedure:
1-bromo-3,7-dimethyl-2,6-nonadiene and 6-hydroxy-3-methyl-2,3-dihydrobenzofuran are reacted to form 6-[(3,7-dimethyl-2,6-nonadienyl)-oxy]-3-methyl-2,3-dihydrobenzofuran of boiling point 147° C./0.001 mmHg; nD20 = 1.5312; and
Reaction SMILES: C(N)(=O)CCC(N)=O.[C:9]1([NH:15][C:16](=[O:21])[CH2:17][C:18](O)=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.NC1C=CC=CC=1.ClCC(=O)C[C:33]([O:35]C)=[O:34].[OH-].[Li+]>>[C:9]1([NH:15][C:16](=[O:21])[CH2:17][CH2:18][C:33]([OH:35])=[O:34])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: O=C(O)CC(=O)Nc1ccccc1
Agent: NC(=O)CCC(N)=O
Agent: [Li+]
Agent: [OH-]
Solvent: Nc1ccccc1
Product: O=C(O)CCC(=O)Nc1ccccc1

Procedure:
The synthesis of the succinamide analogs 29, 30, 31, 32, and 33 are described in Schemes 12, 13, and 14. N-Phenyl-succinamic acid was prepared via a two step reaction sequence analogous to the preparation of the N-phenyl-malonamic acid: 1) reaction of aniline with methyl 4-chloro-3-oxobutyrate followed by 2) treatment with lithium hydroxide. Coupling of N-phenyl-succinamic acid with 1-(2-methylamino-(S)-2-phenyl-ethyl)-pyrrolidin-(S)-3-ol, 1-(3-methyl-(S)-2-methylamino-butyl)-pyrrolidin-(S)-3-ol or 1-piperidin-(S)-2-ylmethyl-pyrrolidin-(S)-3-ol afforded 29, 30 and 31, respectively.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[CH2:11][CH2:12][CH2:13][CH:4]([C:5]=23)[C:3]1=[O:14].[H-].[Na+].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.C(OC(C)C)(C)C>CN(C)C=O.O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][C:4]12[CH2:13][CH2:12][CH2:11][C:6]3[C:5]1=[C:10]([CH:9]=[CH:8][CH:7]=3)[N:2]([CH3:1])[C:3]2=[O:14]
Reactant: BrCCCCBr
Reactant: CN1C(=O)C2CCCc3cccc1c32
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: CN1C(=O)C2(CCCCBr)CCCc3cccc1c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
1-Methyl-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H) -one (3.7 g, 20 mmol) was dissolved in anhydrous N,N-dimethylformamide (50 ml). Thereto was added sodium hydride (60% content, 800 mg, 20 mmol), and the resulting solution was stirred at a room temperature for 30 minutes. The reaction solution was cooled in an ice bath of −10° C., mixed with 1,4-dibromobutane (7.0 ml) and then 1 hour of the reaction was carried out while temperature of the reaction solution was increased to a room temperature. The reaction solution was mixed with diisopropyl ether (150 ml) and water (100 ml), and the reaction product was extracted. Then the resulting organic layer was washed three times with water and dried with anhydrous sodium sulfate. Diisopropyl ether was evaporated under a reduced pressure, and the thus obtained oily residue was separated and purified by a silica gel column chromatography (developing system: diisopropyl ether) to obtain 4.8 g of the title compound (15 mmol, 75% in yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH:10]([OH:12])[CH3:11])=[N:6][CH:7]=1.[H][H]>CCOC(C)=O.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][CH:10]([OH:12])[CH3:11])=[N:6][CH:7]=1
Reactant: CC(O)C#Cc1ccc(Br)cn1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Product: CC(O)C=Cc1ccc(Br)cn1
Yield: 49.1 %

Procedure:
The 4-(5-bromo-pyridin-2-yl)-but-3-yn-2-ol prepared in Step 1 (2.26 g, 0.010 mol) was dissolved in EtOAc (50 mL). Lindlar's catalyst (1.13 g) was added and the mixture was shaken on a Parr shaker under 55 psi hydrogen for 16 h. The mixture was filtered and concentrated. The residue was chromatographed (SiO2, 9/1 to 4/1 hexane/EtOAc) to afford 4-(5-bromo-pyridin-2-yl)-but-3-en-2-ol as a clear oil (1.12 g, 49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.[CH2:36](Br)[CH:37]=[CH2:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[N:23]([CH2:38][CH:37]=[CH2:36])[C:22]2=[O:35])[CH2:17][CH2:16]1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Reactant: C=CCBr
Product: C=CCn1c(=O)n(C2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)c(=O)c2cc([N+](=O)[O-])ccc21
Yield: 53 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 334.6 mg (0.7 mmol) of Compound 24 was used and allyl bromide was used in place of methyl iodide. As a result, 192.8 mg (yield: 53%) of Compound 5 was obtained as pale yellow crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[C:14]([O:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[S:30](Cl)(=[O:32])=[O:31])=[O:20])([CH3:17])([CH3:16])[CH3:15]>ClCCCl.CN(C1C=CN=CC=1)C>[C:14]([O:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[S:30](=[O:32])(=[O:31])[NH:11][C:10]1[CH:12]=[CH:13][C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:8][CH:9]=1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: Nc1ccc(-c2ccncc2)cc1
Reactant: CC(C)(C)OC(=O)n1c(S(=O)(=O)Cl)cc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)n1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2)cc2ccccc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 49.1 %

Procedure:
To a solution of (4-pyridine-4-yl)aniline (CAS: 13296-04-3, 0.054 g) and 2-chlorosulfonyl-indole-1-carboxylic acid tert-butyl ester (0.120 g; cf. Shankar, Bandarpalle B.; Gilbert, Eric; Rizvi, Razia K.; Huang, Chunli; Kozlowski, Joseph A.; McCombie, Stuart; Shih, Neng-Yang. WO 2006002133) in 1,2-dichlorethane (5.0 ml) was added DMAP (0.047 g). The reaction mixture was stirred at 50° C. for 3 h and chromatographed on silica gel using dichloromethanelethyl acetate as eluent to obtain the desired compound (0.070 g) as a colorless powder. MS (ISP): 450.4 (M+H)+