Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[H-].[Na+].[CH3:26][N:27]([CH3:32])[S:28](Cl)(=[O:30])=[O:29].O>CN(C=O)C>[C:19]([C:12]1[CH:11]=[C:10]2[C:15]([C:16]3[C:17](=[O:18])[C:5]4[CH:4]=[CH:3][C:2]([O:1][S:28](=[O:30])(=[O:29])[N:27]([CH3:32])[CH3:26])=[CH:23][C:6]=4[C:7]([CH3:21])([CH3:22])[C:8]=3[NH:9]2)=[CH:14][CH:13]=1)#[N:20]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)Oc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A6, 50 mg, 0.165 mmol) was dissolved in DMF (1.5 mL), added with sodium hydride (13 mg, 2.0 eq.) and dimethylsulfamoyl chloride (0.02 mL, 1.2 eq.), and then stirred at room temperature for 1 hr. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues were concentrated under reduced pressure to obtain the target compound (yellowish white powder, 62 mg, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N+:21]([O-])=O)[C:18]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:41])[NH:31][C:32]5([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[CH2:34][CH2:33]5)[CH:25]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.C(OCC)(=O)C>CN(C=O)C.[Pd]>[NH2:21][C:19]1[C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:41])[NH:31][C:32]3([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:33][CH2:34]3)[CH:25]=2)=[CH:17][C:11]2[C:12]([C:13]([NH:15][CH3:16])=[O:14])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[CH:20]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3cccc(C(=O)NC4(c5ccccc5)CC4)c3)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3cccc(C(=O)NC4(c5ccccc5)CC4)c3)cc12
Reaction time: 8 h

Procedure:
2-(4-Fluorophenyl)-N-methyl-6-nitro-5-(3-(1-phenylcyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide (83.3 mg, 0.152 mmol) undr N2 at r.t. was dissolved in DMF (2 ml) and then added ethyl acetate (10 mL). The mixture remained as a clear light brown solution. The mixture was added palladium (97 mg, 0.045 mmol, 5%/C), flushed with H2 using a balloon, and the mixture stirred under H2 for about 8 hr. The mixture was diluted with EtOAc, and filtered through a Whatman PTFE 45 uM disk. The filtrate was evaporated. The residue was titurated with 3×1 ml Et2O (the Et2O solution was removed by using a pipette), and the light orange solid product dried (64.4 mg, 82%). 1H NMR (500 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.32 (q, J=4.17, 1H), 7.94-7.89 (overlapping m, 3H), 7.97 (s, 1H), 7.62 (d, J=6.8, 1H), 7.58 (q, 1H), 7.34 (t, J=8.70, 2H), 7.29 (t, 1H), 7.28 (d, J=7.50, 1H), 7.23 (s, 2H), 7.227 (d, J=8.00, 1H), 7.17 (t, J=7.17, 1H,), 6.99 (s, 1H), 5.09 (s, 2H), 2.79 (appeared as d, J=3.97, 3H), 1.29 (appeared as d, 4H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters MICROMASS®. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XTERRA® MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)+=520.39, HPLC Rt=1.497 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:25])=[C:13]([NH:18][C:19](=[O:24])[O:20][CH2:21][CH:22]=[CH2:23])[CH:14]=[CH:15][C:16]=2[F:17])=O)[CH:5]=[CH:4][N:3]=1.[CH3:26][C:27]([CH3:32])([CH3:31])[C:28](=[S:30])[NH2:29]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:30][C:28]([C:27]([CH3:32])([CH3:31])[CH3:26])=[N:29][C:9]=2[C:11]2[C:12]([F:25])=[C:13]([NH:18][C:19](=[O:24])[O:20][CH2:21][CH:22]=[CH2:23])[CH:14]=[CH:15][C:16]=2[F:17])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)C(N)=S
Reactant: C=CCOC(=O)Nc1ccc(F)c(C(=O)Cc2ccnc(Cl)n2)c1F
Product: C=CCOC(=O)Nc1ccc(F)c(-c2nc(C(C)(C)C)sc2-c2ccnc(Cl)n2)c1F
Yield: 17 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 6 using 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2,4-difluorophenyl}carbamate (10 g, 27.2 mmol) NBS (5.08 g, 28.6 mmol) and 2,2-dimethylpropanethioamide (3.51 g, 29.9 mmol) the title compound of Step A was obtained (2.15 g, 17% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.55 (br. s., 1H), 8.67 (d, J=5.3 Hz, 1H), 7.83 (d, J=6.0 Hz, 1H), 7.27 (t, J=8.9 Hz, 1H), 7.16 (d, J=5.3 Hz, 1H), 5.89-6.01 (m, 1H), 5.34 (d, J=17.2 Hz, 1H), 5.22 (d, J=10.4 Hz, 1H), 4.60 (d, J=5.3 Hz, 2H), 1.45 (s, 9H); MS (ESI): 464 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH:36]=[CH:37][C:38]([O:40]CC=C)=[O:39])=[CH:6][CH:5]=1.C1COCC1.N1CCOCC1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:44])[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH:36]=[CH:37][C:38]([OH:40])=[O:39])=[CH:8][CH:9]=1
Reactant: C=CCOC(=O)C=Cc1c(CCOc2ccc(C(=O)OC)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCc2c(C=CC(=O)O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.5 %

Procedure:
6.12 g of 4-{2-[2-(2-Allyloxycarbonyl-vinyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester (0.098M, 1 eq.) and 1.12 g of tetrakis(triphenylphosphine) palladium (0) (0.001M, 0.1 eq.) were added to 75 mL of THF. To the reaction 8.60 ml of morpholine (0.098M, 1 eq.) was added drop-wise over 20 min. After addition was complete the reaction was stirred at room temperature for 4 hours. The reaction was poured into 250 mL of ethyl acetate and the organic solution was extracted with 1N NaOH (2×75 mL). The aqueous layers were combined and acidified with 1N HCl, the acidic solution was extracted with ethyl acetate (3×75 mL). The organic layers were combined and washed with brine (1×50 mL), dried over magnesium sulfate, filtered and evaporated to yield 4-{2-[1-Benzhydryl-2-(2-carboxy-vinyl)-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester as a yellow oil (5.40 g, 97% yield).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18].[BH4-].[Na+]>C1COCC1>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:18]
Reactant: COCCOc1nc(N)c2ncn(CC(=O)c3ccccc3)c2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1nc(N)c2ncn(CC(O)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of ethanone prepared in step 1 (60 mg, 0.18 mmol) in THF, was added NaBH4 at room temperature. The reaction was complete after stirring at room temperature for 1 h. The solvent was removed under vacuum and the residue was washed with sat. aq. NaHCO3 solution. The aqueous phase was extracted with DCM. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography using a liner gradient of MeOH in DCM as eluent. 1H NMR (CDCl3) δ 3.36 (s, 3H), δ 3.68 (t, 2H), δ 4.07-4.38 (m, 4H), δ 5.12-5.14 (m, 1H), δ 6.36 (bs, 2H), δ 7.26-7.38 (m, 5H), δ 7.51 (s, 1H); MS: 330.1 (M+1).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][CH2:8][CH2:9][SH:10].[C:11]([O:15][C:16](=[O:25])[NH:17][C@H:18]([C:22](F)=[O:23])[CH:19]([CH3:21])[CH3:20])([CH3:14])([CH3:13])[CH3:12]>O.C(Cl)Cl>[C:11]([O:15][C:16](=[O:25])[NH:17][C@H:18]([C:22](=[O:23])[NH:7][CH2:8][CH2:9][SH:10])[CH:19]([CH3:20])[CH3:21])([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)F
Reactant: NCCS
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCCS
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 50 mL round-bottom flask charged with a solution of sodium bicarbonate (158.1 mg, 1.88 mmol) in 9.2 mL water was added 2-aminoethanethiol hydrochloride (114.7 mg, 1.01 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25g (201.3 mg, 0.92 mmol) in 9.2 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo, to afford 222.0 mg (80% from 24g) of clean 26g as a colorless oil. FTIR (neat) 3300, 1681, 1652 cm−1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[CH3:62][N:63]([NH2:74])[C:64]([O:66][CH2:67][C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)=[O:65]>CN(C=O)C>[CH3:62][N:63]([NH:74][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:18][CH:17]=1)[C:64]([O:66][CH2:67][C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)=[O:65]
Reactant: CN(N)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(NC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1)C(=O)OCc1ccccc1
Yield: 100.9 %

Procedure:
In a similar manner to Example 9, starting material step (a), 4-t-butoxycarbonylaminomethylbenzoic acid (300 mg), HBTU (460 mg), HOBT (190 mg), diisopropylethylamine (0.62 ml), DMF (3 ml) and benzyl 2-methylcarbazate (190 mg) were reacted to give benzyl 2-methyl-3-(4-t-butyoxycarbonylaminomethylbenzoyl)carbazate (440 mg) as a foam; NMR Spectrum (DMSO-d6) 1.39 (9H, s), 3.13 (3H, s), 4.17 (2H, d), 5.08 (2H, s), 7.42 (8H, m), 7.78 (2H, m), 10.73 (1H, br); Mass Spectrum m/Z 414 (M+H)+. In the NMR spectrum, ancillary signals attributable to rotamers were observed.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].[N:19]([CH2:22][CH2:23][CH2:24][N:25]1[CH:33]=[N:32][C:31]2[C:26]1=[N:27][C:28]([NH2:35])=[N:29][C:30]=2Cl)=[N+:20]=[N-:21].FC(F)(F)C(O)=O>CC(N(C)C)=O.O>[NH2:35][C:28]1[N:27]=[C:26]2[C:31]([N:32]=[CH:33][N:25]2[CH2:24][CH2:23][CH2:22][N:19]=[N+:20]=[N-:21])=[C:30]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])=[CH:8][CH:9]=2)[N:29]=1
Reactant: O=C(NCc1ccc(CO)cc1)C(F)(F)F
Reactant: [N-]=[N+]=NCCCn1cnc2c(Cl)nc(N)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: [N-]=[N+]=NCCCn1cnc2c(OCc3ccc(CNC(=O)C(F)(F)F)cc3)nc(N)nc21
Temperature: 90 °C

Procedure:
2,2,2-Trifluoro-N-(4-hydroxymethyl-benzyl)-acetamide (138 mg, 0.59 mmol) is dissolved in 3 mL dry dimethylacetamide under argon atmosphere, and (31 mg, 1.31 mmol) NaH is added. N9-(3-Azidopropyl)-2-amino-6-chloropurine (22, 100 mg, 0.39 mmol) is added and the solution heated to 90° C. for 16 h. After cooling to room temperature, the mixture is poured into 80 mL of water and the pH is adjusted to 6 with trifluoroacetic acid. The aqueous phase is extracted with CH2Cl2 and ethyl acetate. The organic phases are washed with water and brine, dried over MgSO4 and the solvent is evaporated. The crude product is dissolved in methanol, adsorbed on SiO2 (150 mg) and purified by flash column chromatography with dichloromethane:methanol (95:5). Yield: 151 mg (0.0336 mmol, 85%). 1H-NMR (400 MHz, DMSO-d6): δ=10.00 (t, J=5.8, 1H, CF3CONH), 7.90 (s, 1H, H-8), 7.49, (d, J=8.1, 2H, ArH), 7.28 (d, J=8.1, 2H, ArH), 6.47 (s br, 2H, NH2), 5.46 (s, 2H, OCH2), 4.38 (d, J=5.8, 2H, CH2NH), 4.06 (t, J=6.5, 2H, CH2), 3.36 (t, J=6.5, 2H, CH2), 2.00 (m, 2H, CH2) ppm. MS (ESI) m/z 450.0 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25]2)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:9][N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:5]2=[N:6][CH:7]=1.[CH:38]1(B(O)O)[CH2:40][CH2:39]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].P(C1CCCCC1)(C1CCCCC1)C1CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2].CC#N.O.C1(C)C=CC=CC=1>[C:34]([O:33][C:31]([NH:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:3]2[C:2]([CH:38]3[CH2:40][CH2:39]3)=[CH:7][N:6]=[C:5]3[N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:9]=[C:10]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[C:4]=23)[CH2:25]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: OB(O)C1CC1
Reactant: CC(C)C(=O)Nc1cn(C(=O)OC(C)(C)C)c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(C)C(=O)Nc1cn(C(=O)OC(C)(C)C)c2ncc(C3CC3)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 80 °C
Yield: 47.3 %

Procedure:
(R)-tert-Butyl 5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-isobutyramido-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.340 g, 0.586 mmol), cyclopropylboronic acid (0.201 g, 2.34 mmol), K3PO4 (0.435 g, 2.05 mmol), Pd(OAc)2 (0.0131 g, 0.0586 mmol), and P(Cy)3 (0.0197 g, 0.0703 mmol) were placed in 10:1 toluene:water (4.4 mL total volume) and degassed under argon and then heated to 80° C. for 18 hours. The reaction was then cooled to room temperature, poured into water and extracted with DCM. The organic fraction was dried, filtered, and concentrated to give the crude product that was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 5-95% CH3CN/H2O) to give both (R)-tert-butyl 4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-5-cyclopropyl-3-isobutyramido-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.15 g, 47% yield) and a small amount of (R)-tert-butyl 4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-isobutyramido-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.01 g, 3% yield).
Reaction SMILES: [SH2]=N.[CH2:3]([NH:10][C:11](C1C=CC=CC=1C(O)=O)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.CC(C)=O.[Cl:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>O.CC(C)=O.C(N(CC)CC)C>[Cl:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:11]([NH:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:12])=[CH:30][CH:29]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)c1ccccc1C(=O)NCc1ccccc1
Agent: N=[SH2]
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.5 %

Procedure:
6.32 g benzylcarbamoyl-benzoic acid sulfimide was suspended in 40 ml of a 1:1 mixture of water and aceton. 2.55 g p-chloroaniline was added to the suspension, then a solution of 2.8 ml triethylamine with 10 ml of a 1:1 water-aceton mixture was added dropwise at ambient temperature during a half hour. The reaction mixture was stirred for 5 hours at room temperature, the obtained product was evacuated, washed with a 1:1 mixture of water and aceton and dried. 4.3 g 1-(4-chlorophenyl)-3-benzylurea was obtained, which melted at 206°-208° C.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:14]3[NH:13][C:12]4[CH:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:18][CH2:19][C:11]=4[C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].[Br-].[CH:33]1([Zn+])[CH2:35][CH2:34]1>O1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:33]1([C:2]2[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]3[CH:16]=[CH:15][C:14]4[NH:13][C:12]5[CH:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:18][CH2:19][C:11]=5[C:10]=4[CH:9]=3)=[CH:4][C:3]=2[C:28]([F:31])([F:30])[F:29])[CH2:35][CH2:34]1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(Cl)c(C(F)(F)F)c3)cc21
Reactant: [Zn+]C1CC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CC4)c(C(F)(F)F)c3)cc21
Temperature: 90 °C

Procedure:
To a solution of ethyl 2-(7-(4-chloro-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (200.5 mg, 0.444 mmol) in tetrahydrofuran (1 mL) was added 0.5 M cyclopropylzinc(II) bromide solution in tetrahydrofuran (8.87 mL, 4.44 mmol) and bis(tri-t-butylphosphine)palladium (46.3 mg, 0.089 mmol) at room temperature. The mixture was heated at 90° C. for 63 h. The mixture was then quenched with 1 N aqueous HCl solution and filtered through Celite®. The filtrate was extracted with ethyl acetate. The organic layer was washed with brine solution to remove excess HCl and concentrated under reduced pressure. The residue was purified by HPLC. The combined fractions were triturated with saturated aqueous sodium bicarbonate solution to basic solution and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and acidified to pH 4. The organic layer was washed with water until the aqueous layer was neutral. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the title compound as a light brown solid (36.6 mg). LCMS m/z=430.5 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.74-0.88 (m, 2H), 0.98-1.07 (m, 2H), 2.02-2.12 (m, 2H), 2.34 (dd, J=15.98, 9.03 Hz, 1H), 2.59-2.76 (m, 4H), 3.39-3.52 (m, 1H), 5.10 (s, 2H), 6.69 (dd, J=8.72, 2.53 Hz, 1H), 6.91 (d, J=2.40 Hz, 1H), 7.10-7.26 (m, 2H), 7.61 (d, J=8.34 Hz, 1H), 7.72 (d, J=1.14 Hz, 1H), 10.45 (s, 1H), 12.20 (bs, 1H).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:6])([CH3:5])[CH3:4].[CH2:20]([O:22][C:23](=[O:28])[CH2:24][C:25](O)=[O:26])[CH3:21].C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C)C=O>[C:3]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:19][CH2:18][N:17]([C:25](=[O:26])[CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:28])[CH2:16][CH2:15]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CC(=O)O
Reactant: CC(C)(C)c1cc(Cl)ccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)N1CCN(c2ccc(Cl)cc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
A mixture of 1-(2-tert-butyl-4-chlorophenyl)piperazine dihydrochloride (Reference Example 20, 0.40 g, 1.23 mmol), 3-ethoxy-3-oxopropanoic acid (0.19 g, 1.47 mmol), triethylamine (514 μL, 3.69 mmol), EDCI (0.23 g, 1.47 mmol) and HOBt (0.23 g, 1.47 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 h. The reaction mixture was added to saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with saturated NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 80:20 to 20:80) to give the title compound (0.39 g, 87%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][C:13](=[O:16])[CH2:14][O:15][C:7]3=[CH:6][C:5]=2[CH2:4][CH2:3]1.[CH3:17][CH:18](C)CCC1C=CC2OCC(=O)COC=2C=1>>[CH2:4]([C:5]1[CH:10]=[CH:9][C:8]2[O:11][CH2:12][C:13](=[O:16])[CH2:14][O:15][C:7]=2[CH:6]=1)[CH2:3][CH2:2][CH2:1][CH2:17][CH3:18]
Reactant: CC(C)CCc1ccc2c(c1)OCC(=O)CO2
Reactant: CC1CCc2cc3c(cc21)OCC(=O)CO3
Product: CCCCCCc1ccc2c(c1)OCC(=O)CO2

Procedure:
Odor: Marine, aquatic.—IR (film): ν=1502/1435/1580 cm−1 (ν C═C, Ar), 1265/1304/1201 cm−1 (ν ring), 1051 cm−1 (ν C—O—C), 1741 cm−1 (ν C═O).—1H-NMR (CDCl3): δ=0.88 (t, J=6.8 Hz, 3H, 6′-H2), 1.27–1.35 (m, 6H, 3′-H2-5′-H2), 1.57 (br. quint, J=8.0 Hz, 2H, 2′-H2), 2.51 (t, J=7.8 Hz, 2H, 1′-H2), 4.68 (d, J=8.0 Hz, 4H, 2-, 4-H2), 6.77 (dd, J=8.0, 4.0 Hz, 1H, 8-H), 6.81 (d, J=4.0 Hz, 1H, 6-H), 6.90 (d, J=8.0 Hz, 1H, 9-H).—13C-NMR (CDCl3): δ=13.96 (q, C-6′), 22.46 (t, C-5′), 28.77 (t, C-3′), 31.19/31.56 (2t,C-2′,-4′), 34.89 (t, C-1′), 75.35/75.63 (2t, C-2,-4), 120.31/120.47 (2d, C-6,-9), 123.50 (d, C-8), 138.85 (s, C-7), 146.03/147.83 (2s, C-5a,-9a), 204.73 (s, C-3).—MS (EI): m/z (%)=77 (16) [C8H6+], 91 (9) [C7H7+], 135 (9) [M+-C5H11—C2H2O], 149 (21) [M+-C5H11—CO], 177 (100) [M+-C5H11], 191 (2) [M+-C4H9], 205 (3) [M+-C3H7], 248 (43) [M+].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[NH:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:15][CH:14]=3)=[N:12][C:3]=12.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[NH:28]([C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[NH:10][C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]([CH2:27][CH2:26][O:25][CH3:24])[CH3:23])=[CH:17][CH:18]=3)=[N:12][C:3]=12)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1ccccc1
Reactant: N#Cc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Product: COCCN(C)CCOc1ccc(-c2nc3c(Nc4ccccc4)c(C#N)cnc3[nH]2)cc1
Temperature: 180 °C
Yield: 2 %

Procedure:
7-Chloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine-6-carbonitrile (Example 243) (0.050 g, 0.13 mmol) was dissolved in aniline (2 ml) and heated at 180° C. for 3 h in a sealed vial. The excess aniline was evaporated and the crude product was purified by HPLC-C18, giving the title product (0.001 g, 2%).
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([OH:17])=[C:10]([C:14]([NH2:16])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].Br[CH2:22][CH2:23][CH2:24][F:25]>>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:17][CH2:22][CH2:23][CH2:24][F:25])=[C:10]([C:14]([NH2:16])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:19][CH3:20]
Reactant: FCCCBr
Reactant: CCCN(CCC)C1Cc2cc(O)c(C(N)=O)cc2C1
Product: CCCN(CCC)C1Cc2cc(OCCCF)c(C(N)=O)cc2C1

Procedure:
Using procedure 44, 2-(Dipropylamino)-2,3-dihydro-6-hydroxy-1H-indene-5-carboxamide (87, 0.19 g, 0.7 mmol) was treated with 1-bromo-3-fluoropropane (0.296 g, 2.1 mmol). Chromatographic purification yielded pure product 89 as a oil which was converted into the HCl salt and crystallized from EtOAc/MeOH to give a white solid (m.p. 219-220° C.).
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:31]=[CH:30][C:20]([O:21][C:22]2[CH:23]=[C:24]([OH:29])[CH:25]=[C:26]([CH3:28])[CH:27]=2)=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[C:37]([O:41][CH2:42][CH3:43])(=[O:40])[CH2:38]O>>[F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:31]=[CH:30][C:20]([O:21][C:22]2[CH:23]=[C:24]([CH:25]=[C:26]([CH3:28])[CH:27]=2)[O:29][CH2:38][C:37]([O:41][CH2:42][CH3:43])=[O:40])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: CCOC(=O)CO
Reactant: Cc1cc(O)cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)c1
Product: CCOC(=O)COc1cc(C)cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 89E and ethyl glycolate were processed as described in Example 62A to provide the title compound.