Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:19]([O:23][C:24]([NH:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[C:19]([O:23][C:24]([NH:26][CH:27]1[CH2:31][CH2:30][N:29]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:28]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: ClCc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 70 °C
Reaction time: 15 h
Yield: 80.2 %

Procedure:
4-Chlorobenzyl chloride (4.15 g, 25.8 mmol) and iPr2NEt (6.67 g, 51.6 mmol) were added to a DMF (50 mL) solution of 3-[(tert-butoxycarbonyl)amino]pyrrolidine (4.81 g, 25.8 mmol). The reaction mixture was stirred at 70° C. for 15 hours, and the solvent was removed under reduced pressure. The objective 3-[(tert-butoxycarbonyl)amino]-1-(4-chlorobenzyl)pyrrolidine (6.43 g, 80%) was obtained as an off-white solid by recrystallization (acetonitrile, 50 mL). 1H NMR (CDCl3, 300 MHz) δ 1.37 (s, 9H), 1.5-1.7 (br, 1H), 2.1-2.4 (m, 2H), 2.5-2.7 (m, 2H), 2.83 (br, 1H), 3.57 (s, 2H), 4.1-4.3 (br, 1H), 4.9-5.1 (br, 1H), 7.15-7.35 (br, 4H); the purity was determined by RPLC/MS (98%). ESI/MS m/e 311.0 (M++H, C16H24ClN2O2).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH:18]([OH:28])[C:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[C:12]=1[F:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O>[CH2:1]([O:8][C:9](=[O:30])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[O:28])[C:12]=1[F:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(F)c(C(O)c2c[nH]c3ncccc23)c1F)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(F)c(C(=O)c2c[nH]c3ncccc23)c1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.4 %

Procedure:
Into a round bottom flask was added {2,4-difluoro-3-[hydroxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-carbamic acid benzyl ester (615, 1.01 g, 2.28 mmol) in tetrahydrofuran (5.00 mL, 0.0616 mol). Dess-Martin periodinane (1.20 g, 2.89 mmol) was added in portions. The reaction mixture was stirred at ambient temperature for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel chromatography to give compound 616 (914 mg, 91%). MS (ESI) [M+H+]+=442.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:19])=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=2)[C:13]#[N:14])[CH:8]=1.Cl[C:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)=[O:22].CCN(C(C)C)C(C)C>>[Cl:19][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)=[O:22])=[CH:8][C:7]=1[O:9][C:10]1[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2)cc1
Yield: 45.2 %

Procedure:
Methyl 4-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]phenyl}methyl)amino]carbonyl}benzoate was prepared in a similar manner as described herein from 3-{[5-(aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile (0.05 g, 0.17 mmol), methyl 4-(chlorocarbonyl)benzoate (0.05 g, 0.25 mmol) and DIPEA (0.05 mL, 0.25 mmol). The crude material was purified by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were lyophilized, neutralized and extracted with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound (0.035 g, 45%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 9.22 (s, 1H), 7.98-8.06 (m, 2H), 7.92-7.98 (m, 2H), 7.80 (s, 1H), 7.60 (d, 1H), 7.45 (s, 1H), 7.38 (t, 1H), 7.25 (s, 1H), 7.23 (d, 1H), 4.47 (d, 2H), 3.86 (s, 3H). MS: m/z 455.0 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH:7]=[O:8])[CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:27][C:28]([Si](C)(C)C)([F:30])[F:29]>O1CCCC1>[F:27][C:28]([F:30])([F:29])[CH:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[OH:8]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=CC1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(C1CCOCC1)C(F)(F)F
Yield: 47.1 %

Procedure:
According to Reference Example 8-12, by use of tetrahydro-2H-pyran-4-carbaldehyde (300 mg, 2.63 mmol) dissolved in tetrahydrofuran (6 mL), a 1 mol/L solution of tetrabutylammonium fluoride in tetrahydrofuran (0.526 mL, 0.526 mmol) and (trifluoromethyl)trimethylsilane (0.466 mL, 3.16 mmol), the mixture was stirred and reacted at room temperature for 1.7 hours. Then, purification by preparative thin-layer chromatography (hexane/ethyl acetate=4/1) was performed to give 2,2,2-trifluoro-1-(tetrahydro-2H-pyran-4-yl)ethanol (Compound EA) (228 mg, yield: 47%).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].O[C:7]1[CH:12]=[C:11]([CH3:13])[NH:10][C:9](=[O:14])[C:8]=1[C:15]#[N:16].[NH4+].[OH-]>C(Cl)(Cl)Cl>[Cl:3][C:7]1[CH:12]=[C:11]([CH3:13])[NH:10][C:9](=[O:14])[C:8]=1[C:15]#[N:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)c(C#N)c(=O)[nH]1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)c(C#N)c(=O)[nH]1
Reaction time: 0.08 h
Yield: 36 %

Procedure:
Using a 100 ml round bottom with reflux condenser, PCI5 (6.7 g, 32 mmol), POCl3 (3.0 mL, 32 mmol) and 30 ml CHCl3 (dry) were stirred for 5 min (see: Heterocycles, vol. 60, No. 6, 2003, 1461-1468). Added 4-hydroxy-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (4 g, 26.6 mmol) and stirred for 2 h at 80° C. Quenched reaction while hot and poured into 1 L beaker with 100 “g” ice, 24 mL NH4OH, pH by paper was 8-9. Stirred 5 min and filtered. Washed solid with water. Suspended solid in ethanol and filtered and washed with ethanol. Gave: 4-chloro-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (1.7 g, 9.58 mmol, 40% yield)1H NMR (400 MHz, DMSO-d6) δ ppm 12.85 (br. s., 1H) 6.53 (s, 1H) 2.28 (s, 3H) MS(ES) [M+H]+ 168.9.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[CH3:10][C:11]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[C:14]([CH3:27])[C:12]=1[NH2:13]>>[NH2:13][C:12]1[C:14]([CH3:27])=[CH:15][C:16]([C:2]2[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)=[CH:17][C:11]=1[CH3:10]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1N
Reactant: Cn1nc(Cl)ccc1=O
Product: Cc1cc(-c2ccc(=O)n(C)n2)cc(C)c1N
Temperature: 60 °C
Reaction time: 12 h

Procedure:
The title compound is prepared from 6-chloro-2-methylpyridazin-3(2H)-one and 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline following a procedure analogous to that described in Step 2 of Intermediate 62. The mixture is stirred for 12 hours at 60° C. LC (method 9): tR=0.78 min; Mass spectrum (ESI+): m/z=230 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[CH3:10][O:11][C:12]1[CH:29]=[CH:28][C:15]2[CH2:16][NH:17][CH2:18][CH2:19][C@@:20]34[C@@H:25]([O:26][C:13]=1[C:14]=23)[CH2:24][C@@H:23]([OH:27])[CH:22]=[CH:21]4.[OH-].[Na+]>CC(C)=O>[Cl:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([N:17]2[CH2:18][CH2:19][C:20]34[CH:21]=[CH:22][C@H:23]([OH:27])[CH2:24][CH:25]3[O:26][C:13]3=[C:12]([O:11][CH3:10])[CH:29]=[CH:28][C:15](=[C:14]43)[CH2:16]2)[N:3]=1
Reactant: COc1ccc2c3c1O[C@H]1C[C@@H](O)C=C[C@@]31CCNC2
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1ccc2c3c1OC1C[C@@H](O)C=CC31CCN(c1nc(Cl)nc(Cl)n1)C2
Yield: 57.7 %

Procedure:
A solution of 2,4,6-trichloro-1,3,5-triazine (0.66 g, 3.7 mmol) in acetone (16 ml) was poured onto ice water (35 ml) and added in small portions at 0° C. to (+/−)-norgalanthamine (1.0 g, 3.7 mmol). After the addition of 2N-sodium hydroxide (2 ml), the reaction mixture was refluxed for 40 hours. The aqueous phase was extracted with EtOAc (3×30 ml). The combined, organic phases were washed with common salt solution (30 ml), dried (Na2SO4) and concentrated by evaporation, to produce 0.90 g (59.5%) of compound 4e: 1H-NMR (CDCl3) δ 6.82 (d, J=10.0 Hz, 1H), 6.63 (d, J=10.0 Hz, 1H), 6.02 (b, 2H), 5.30 (d, J=11.0 Hz, 1H), 4.75 (d, J=16.0, 1H), 4.50 (b, 1H), 4.22 (d, J=11.0 Hz, 1H), 4.11 (b, 1H), 3.78 (s, 3H), 3.59 (m, 1H), 3.06 (m, 1H), 2.61 (d, J=16.0 Hz, 1H), 1.90 (m, 3H); 13C-NMR (CDCl3) δ 207.0 (s) 171.2 (s), 163.7 (s), 146.2 (s), 143.9 (s), 132.3 (d), 129.5 (s), 127.6 (s), 126.7 (d), 121.5 (d), 110.8 (d), 88.0 (d), 61.7 (d), 55.7 (q), 51.8 (t), 48.2 (5), 43.4 (t), 35.9 (t), 29.7 (t).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]=[O:12])=[C:8]([CH3:13])[C:7]=2[CH:14]=1.[CH2:15]([Mg]Br)[CH:16]([CH3:18])[CH3:17].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([OH:12])[CH2:15][CH:16]([CH3:18])[CH3:17])=[C:8]([CH3:13])[C:7]=2[CH:14]=1
Reactant: CC(C)C[Mg]Br
Reactant: COc1ccc2oc(C=O)c(C)c2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc2oc(C(O)CC(C)C)c(C)c2c1
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution (4.0 mL) of 5-methoxy-3-methyl-1-benzofuran-2-carbaldehyde (1.91 g) synthesized in Example A27(2) in tetrahydrofuran was added a solution (15.0 mL) of 1.0M isobutylmagnesium bromide in tetrahydrofuran at 0° C., and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, tetrahydrofuran was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title object compound (1.53 g, 62%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25]C)=[O:24].[OH-].[Na+]>CO.C(O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Temperature: 25 °C
Yield: 56 %

Procedure:
To a solution of methyl [2-methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate (0.100 g; 0.245 mmol) in methanol (5 mL) and ethanol (2.5 mL) was added a 5% sodium hydroxide solution (6.6 mL; 8.250 mmol). The reaction mixture was heated under reflux for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water, acidified with 1N HCl (pH˜2) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.054 g (56%) of the title compound as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[CH3:25][O:26][C:27](=[O:39])[C:28]([C:31]1[CH:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][CH:32]=1)([CH3:30])[CH3:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:37][C:34]2[CH:33]=[CH:32][C:31]([C:28]([CH3:30])([CH3:29])[C:27]([O:26][CH3:25])=[O:39])=[CH:36][CH:35]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: COC(=O)C(C)(C)c1ccc(C=O)cc1
Product: COC(=O)C(C)(C)c1ccc(CNc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)cc1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 2-(4-formyl-phenyl)-2-methyl-propionic acid methyl ester according to the procedure of Step 5 Example 6. MS (ES) m/z 522.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C.Cl>CCOCC.O>[CH3:9][Si:8]([CH3:11])([CH3:10])[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:20]=[O:21]
Reactant: C[Si](C)(C)c1cccc(Br)c1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: C[Si](C)(C)c1cccc(C=O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
To a solution of 5 g (21.89 mmol) of 1-bromo-3-trimethylsilylbenzene prepared according to the protocol described in the preceding step, in 40 mL of anhydrous Et2O, cooled to 0° C. and maintained under a nitrogen atmosphere, are added dropwise, with stirring and over 30 minutes, 16.36 mL (26.18 mmol) of BuLi (1.6M/hexane). Stirring is continued at 0° C. for a further 30 minutes, and the mixture is then maintained at room temperature for 90 minutes. 2.69 mL (34.91 mmol) of DMF, diluted with 17 mL of anhydrous Et2O, are then introduced into the reaction mixture. After stirring for 3 hours at room temperature, the reaction mixture is hydrolysed at 0° C. by successive addition of 10 mL of concentrated HCl solution and 100 mL of water. The product is extracted with 3×50 mL of CH2Cl2. The combined organic phases are washed with 100 mL of water, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude reaction product is purified by flash chromatography on a column of silica gel, eluting with a gradient of from 10 to 20% of CH2Cl2 in heptane to give 1.82 g of the expected 3-trimethylsilylbenzaldehyde in the form of a yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10]C)(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].Br[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[O:24][CH3:25]>C1COCC1>[CH3:25][O:24][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:14]=1[CH2:13][CH:4]([C:3]([O:9][CH3:10])=[O:8])[C:5](=[O:6])[CH3:7])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(C(C)=O)C(=O)OC)c(OC)c1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
NaH (60% in mineral oil, 1.5 g) was added portion-wise over 10 mins to a solution of ethyl acetoacetate (4.4 mL) in THF (60 mL) at 0° C. The mixture was then stirred for 10 mins. Then, a solution of methyl 4-(bromomethyl)-3-methoxybenzoate (7.5 g) in THF (40 mL) was added and the mixture was warmed to 70° C. and stirred for 15 h. The mixture was then poured into ice/water (300 mL) and stirred for 30 mins. The resulting aqueous mixture was extracted with EtOAc. The organic extracts were combined, dried and concentrated in vacuo to provide crude product. The reaction was repeated on the same scale. The two batches of crude product were combined and purified by flash column chromatography on silica gel to give the sub-title compound (15 g) as a colourless oil; 1H NMR (300 MHz, CDCl3) δ=7.48 (1H, dd), 7.45 (1H, d), 7.24 (1H, d), 4.05 (2H, q), 3.95 (1H, dd), 3.86 (3H, s), 3.84 (3H, s), 3.10 (1H, dd), 3.00 (1H, dd), 2.17 (3H, s), 1.09 (3H, t).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[N:16]([C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)=[O:12])[CH2:15][CH2:14]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]ccc2c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 51 %

Procedure:
The title compound is prepared from 1H-indole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 51% of theory; LC (method 4): tR=1.99 min; Mass spectrum (ESI+): m/z=331 [M+H]+.
Reaction SMILES: C(OCC)C.[H-].[Na+].[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[CH2:16][N:17]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:19][C:20]=2[CH:21]=1)=[O:12])[CH3:9].[C:25]([O:29][C:30](=O)[O:31]C(C)(C)C)([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O>[C:25]([O:29][C:30]([N:14]1[C:15]2[CH2:16][N:17]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:19][C:20]=2[CH:21]=[C:13]1[C:11]([O:10][CH2:8][CH3:9])=[O:12])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)c1cc2c([nH]1)CN(C(C)=O)CC2
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1cc2c(n1C(=O)OC(C)(C)C)CN(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49 %

Procedure:
A suspension of diethyl ether washed sodium hydride (0.28 g, 0.009 mole) in dry dimethylformamide (8 ml) at 0° C. was treated with a solution of 2-ethoxycarbonyl-6-acetyl-4,5,6,7-tetrahydro-6-azaindole from Example 2 (2 g, 0.0085 mole) in dry dimethylformamide (2 ml) and stirred for 20 minutes. The mixture was warmed to room temperature and stirred for 1 hour by which time solution was complete. The solution was cooled to 0° C., a solution of di-tert-butylcarbonate (1.85 g, 0.0085 mole) in dry dimethylformamide (2 ml) added dropwise over 10 minutes, and the solution stirred at room temperature for 4 hours. The mixture was quenched with water (200 ml), extracted with ethyl acetate (4×100 ml) the organic extracts washed with brine (3×100 ml), dried over sodium sulphate, and evaporated to give a yellow oil which was chromatographed on silica gel (20 g) eluting with dichloromethane:hexane (9:1) to give the title product as a pale yellow oil (1.4 g, 49%). Found: C, 60.12; H, 7.32; N, 8.15. C17H24N2O5 requires C, 60.70; H, 7.19; N, 8.33%.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14](Br)([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:15]>[N+](C)([O-])=O.C1(C)C=CC=CC=1.[Cl-].[Cl-].[Zn+2]>[CH3:19][C:18]([CH3:21])([CH2:17][CH:14]([CH3:16])[CH3:15])[CH2:20][C:3]1[CH:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][C:8]([CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:10]=3
Reactant: CC(C)(C)CC(C)(C)Br
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)CC(C)(C)Cc1ccc2[nH]c3ccc(CC(C)(C)CC(C)C)cc3c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
ZnCl2 (36.8 g, 276 mmol) and carbazole (21.0 g, 126 mmol) are suspended in 600 mL nitromethane in a 1 qt jar in a glove-box. The t-octyl bromide (53.4 g, 276 mmol) is added dropwise to the gray-green suspension via addition funnel. The mixture turns into a black solution during the addition. The solution is allowed to stir at room temperature for two hours and then poured into 500 mL ice water. The product is extracted out of the mixture with 500 mL and 250 mL CH2Cl2. The combined organic portions are dried with MgSO4, filtered and rotovapped to yield a dark residue. This residue is taken up in 200 mL toluene, passed through a plug of silica, and washed through with 150 mL toluene. The yellow solution is reduced to a solid on the rotovap. This material is recrystallized from 100 mL hexane at −13° C. 27 g (55%) of white crystals are collected. The crystallization only moderately improved the purity of the product. 1H NMR (CDCl3): δ 8.02 (d, JH-H=1.6 Hz, 2H), 7.80 (br s, 1H, NH), 7.42 (dd, JH-H=8.6, 1.8 Hz, 2H), 7.29 (d, JH-H=8.5 Hz, 2H), 1.83 (s, 4H, CH2), 1.49 (s, 12H, CMe2), 0.72 (s, 18H, CMe3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].C(Cl)Cl.[C:15](Cl)(=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:24])[C:5]([OH:7])=[O:6]
Reactant: CCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1Cl
Yield: 26.1 %

Procedure:
To a solution of 2.0 g (1.1×10-2 mol) of 3-chloro-4-hydroxy benzoic acid in 40 ml of dried methylene chloride containing 3.0 g (9.2×10-3 mol) of pyridine was added dropwise 3.0 g (9.2×10-3 mol) of nonanoic acid chloride, which were stirred under reflux for 7 hours. After the completion of the reaction, the solution was washed with an aqueous solution of 1 normal hydrochloric acid and further with water and dried on anhydrous magnesium sulfate. After magnesium sulfate was filtered off, the resulting product was purified through a silica gel column chromatography using methylene chloride and ethanol at 9:1 (v/v) as a developing solution and then recrystallized with 5 ml of ethanol to obtain 750 mg (yield: 25%) of a white solid.
Reaction SMILES: [C:1]([C:9]1[O:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[O:13][C:9]([C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)o1
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(C(=O)c3ccccc3)o2)c1

Procedure:
Acid (9) (48 mg, 0.22 mmol) was coupled to aniline (2) (43 mg, 0.22 mmol) using Method B, except that DIPEA (57 mg, 0.44 mmol) and DMF (0.5 mL) were used. The crude product was purified by preparative HPLC to give the title compound. Yield: 28 mg; LC-MS tr 41.54 min; MS (ES+) m/z 389 (M+H)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:12]([OH:14])=[O:13].[CH:15]1C=CC=CC=1.[Si](C=[N+]=[N-])(C)(C)C>CO>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: c1ccccc1
Reactant: Nc1ccc2ncccc2c1C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1c(N)ccc2ncccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of Example 96A (0.43 g, 2.3 mmol), benzene (10 mL), and methanol (4 mL) was treated with TMSCHN2 (2.0 mL, 4.0 mmol, 2.0M solution in hexanes), stirred at room temperature for 90 minutes, quenched with glacial acetic acid, and concentrated. The residue was diluted with ethyl acetate, washed with saturated Na2CO3, dried (MgSO4), filtered, and concentrated to provide the desired product (0.401 g). MS (DCI) m/e 220 (M+NH4)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH2:15]([C:22]1[S:26][N:25]=[C:24]([C:27](O)=[O:28])[N:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:15]([C:22]1[S:26][N:25]=[C:24]([C:27]([NH:14][CH2:13][CH2:12][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([Cl:2])[CH:4]=3)[NH:8][CH:7]=2)=[O:28])[N:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)c1nsc(Cc2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1nsc(Cc2ccccc2)n1

Procedure:
The 5-benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1,2,4-thiadiazole-3-carboxamide is prepared following method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride, 5-benzyl-1,2,4-thiadiazole-3-carboxylic acid (which can be prepared by procedures known to the skilled in the art), HATU and N,N-diisopropylethylamine in DMF.