Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:14]=1)([CH2:8][OH:9])[CH2:6][OH:7])(=O)C.[OH-].[Na+].Cl>CO>[NH2:4][C:5]([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:14]=1)([CH2:6][OH:7])[CH2:8][OH:9]
Reactant: CCCCCCCCCCCOc1cccc(CCCC(CO)(CO)NC(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCOc1cccc(CCCC(N)(CO)CO)c1
Temperature: 0 °C
Yield: 71.4 %

Procedure:
2-Acetamido-2-[3-(3-undecyloxyphenyl)propyl]-1,3-propanediol (1.4 g) was dissolved in 50 ml of methanol and 16.6 ml of a 1 N aqueous sodium hydroxide solution was added thereto. The mixture was refluxed under heating for 3 hours. The mixture was poured into ice water and neutralized with dilute hydrochloric acid. The solvent was distilled away and chloroform was added to the residue for extraction. The chloroform layer was washed and dried. The solvent was distilled away and the residue was recrystallized from diisopropyl ether-hexane to give 0.9 g of 2-amino-2-[3-(3-undecyloxyphenyl)propyl]-1,3-propanediol as white crystals.
Reaction SMILES: [CH2:1]([N:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([C:18]([O:20]CC)=O)[NH:15][C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>ClCCl.O>[CH2:23]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([C:18]([NH:30][CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[O:20])[NH:15][C:14]=12)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1cccnc1
Reactant: CCOC(=O)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Solvent: ClCCl
Solvent: O
Product: O=C(NCc1cccnc1)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Temperature: 100 °C
Yield: 49.6 %

Procedure:
A mixture of ethyl 7-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (Reference Example 3) (634 mg, 1.64 mmol) and 3-(aminomethyl)pyridine (3.8 mL, 37 mmol) was heated neat at 100° C. for 72 h under N2. The mixture was cooled to room temperature and diluted with dichloromethane (150 mL) and water (100 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel, gradient 50-70% ethyl acetate/hexanes) to provide 7-(dibenzylamino)-N-(3-pyridinylmethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (364 mg, 49%) as an orange solid: Rf 0.08 (75:25 ethyl acetate/hexanes); mp 105-108° C.; 1H NMR (300 MHz, CDCl3) δ4.60 (2H, d, J=6.0 Hz), 4.89 (4H, s), 6.50 (1H, t, J=5.4 Hz), 6.71 (1H, s), 6.99 (1H, d, J=5.6 Hz), 7.28-7.31 (2H, m), 7.34-7.42 (9H, m), 7.64 (1H, d, J=7.8 Hz), 7.89 (1H, d, J=5.6 Hz), 8.55 (2H, s), 8.97 (1H, s); ESI MS m/z 448 [C28H25N5O+H]+; HPLC (Method A) >99% (AUC), tR=13.02 min.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:13])[CH2:11][NH2:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:12][CH2:11][C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:13])=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: NCC(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(CNCc1ccc(Br)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 63.7 %

Procedure:
To a suspension of glycine benzyl ester hydrochloride (2.02 g, 10.0 mmol) and 4-bromobenzaldehyde (1.85 g, 10.0 mmol) in 50 mL DCE, was added acetic acid (2.9 mL, 50 mmol) and TEA (1.4 mL, 10.0 mmol) to give a clear solution. Sodium triacetoxyborohydride (4.24 g, 20.0 mmol) was added. The suspension was stirred at rt for 17 h. The mixture was neutralized with sat. NaHCO3 and extracted with CH2Cl2 (3×). The combined organic extract washed with brine, dried (Na2SO4) and concentrated. The crude product was purified via flash chromatography (0 to 100% EtOAc in hexanes) to afford 80A (2.13 g, 64%). MS (ESI) m/z 334.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][CH3:20])[CH:18]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]1[NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41]>CN(C=O)C>[C:40]([O:39][C:38]([NH:37][C@H:32]1[CH2:33][CH2:34][CH2:35][CH2:36][C@H:31]1[NH:30][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][CH3:20])[CH:18]=2)[N:3]=1)=[O:44])([CH3:43])([CH3:41])[CH3:42]
Reactant: CCn1cc(-c2nc(Cl)cc(C#N)c2C(=O)OC)cn1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc(C#N)c2C(=O)OC)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
To a solution of methyl 6-chloro-4-cyano-2-(1-ethyl-1H-pyrazol-4-yl)nicotinate (201 mg, 0.691 mmol) in DMF (1 mL) was added DIPEA (0.242 mL, 1.383 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (237 mg, 1.106 mmol). The reaction mixture was stirred at 100° C. overnight, after which the solvent was removed, and the resulting crude material was diluted in MeOH (5.0 mL) and purified via reverse phase preparative HPLC. The collected fractions were collected and ACN was removed via rotary evaporation. The resulting aq solution was neutralized with saturated aq NaHCO3 and washed with EtOAc (2×200 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to yield the title compound (62 mg, 19%). [M+H] calc'd for C24H32N6O4, 469. found, 469.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6](O)[CH2:5][CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([C@:50]2([O:68][C@H:67]([CH2:69][O:70][C:71](=[O:73])[CH3:72])[C@@H:62]([O:63][C:64](=[O:66])[CH3:65])[C@H:57]([O:58][C:59](=[O:61])[CH3:60])[C@H:52]2[O:53][C:54](=[O:56])[CH3:55])[OH:51])=[CH:46][C:45]=1[OH:74].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([C@:50]2([O:68][C@H:67]([CH2:69][O:70][C:71](=[O:73])[CH3:72])[C@@H:62]([O:63][C:64](=[O:66])[CH3:65])[C@H:57]([O:58][C:59](=[O:61])[CH3:60])[C@H:52]2[O:53][C:54](=[O:56])[CH3:55])[OH:51])=[CH:46][C:45]=1[O:74][CH:6]1[CH2:7][CH2:8][CH:3]([O:2][CH3:1])[CH2:4][CH2:5]1
Reactant: CC(=O)OC[C@H]1O[C@](O)(c2ccc(Cl)c(O)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COC1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC1CCC(Oc2cc([C@@]3(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
0.08 g 4-methoxycyclohexanol, 0.16 g triphenylphosphine and 0.12 ml diisopropyl azodicarboxylate are added to a solution of 0.25 g 1-chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-hydroxy-benzene in 3 ml of tetrahydrofuran, in the order stated. The solution is stirred for 14 h at ambient temperature and then combined with aqueous potassium carbonate solution. Then it is extracted with ethyl acetate, dried over sodium sulphate and the solvent is removed. The residue is purified on silica gel (cyclohexane/ethyl acetate 7:3->1:1).
Reaction SMILES: C(N(CC)CC)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:29]([NH:36][C@H:37]([C:45]([OH:47])=O)[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].[CH:48]1[C:56]2[C:55]3[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][C:54]=3[O:53][C:52]=2[CH:51]=[CH:50][C:49]=1[NH2:62]>>[CH2:38]([C@H:37]([NH:36][C:29](=[O:30])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[C:45](=[O:47])[NH:62][C:49]1[CH:50]=[CH:51][C:52]2[O:53][C:54]3[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57][C:55]=3[C:56]=2[CH:48]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 39 %

Procedure:
Following the procedure of Example 30, triethylamine (0.43 mL, 3.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.31 g, 1.6 mmol), N-hydroxybenzotriazole (0.22 g, 1.6 mmol), N-Boc-L-phenylalanine (0.36 g, 1.4 mmol), and 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.25 g, 1.2 mmol) provided tert-butyl [(1S)-1-benzyl-2-oxo-2-(7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylamino)ethyl]carbamate (0.21 g). MS (ESI) m/z 449 ([M+H]+); MS (ESI) m/z 447.3 ([M−H]−).
Reaction SMILES: Cl.Cl[C:3]1[S:4][C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][CH:10]=2.[Br:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)C>CC#N>[Br:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:3]2[S:4][C:5]3[C:6]([N:11]=2)=[N:7][CH:8]=[CH:9][CH:10]=3)=[CH:18][CH:17]=1
Reactant: Oc1ccc(OCCBr)cc1
Reactant: Clc1nc2ncccc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOCC
Product: BrCCOc1ccc(Oc2nc3ncccc3s2)cc1
Yield: 87.4 %

Procedure:
A mixture of 2-chloro[1,3]thiazolo[4,5-b]pyridine hydrochloride (863 mg, 4.17 mmol), 4-(2-bromo-ethoxy)-phenol (905 mg, 4.17 mmol), and Cs2CO3 (5.88 g, 16.67 mmol) was stirred in CH3CN (42 mL) for 16 h. After filtration through diatomaceous earth, the organic filtrate was partitioned with 1 M NaOH (3×10 mL) and satd. aq. NaCl (1×10 mL). The organic layer was dried and concentrated to yield a red oil. Additional desiccation under high vacuum yielded a brown solid in red oil. Diethyl ether was added, and the mixture was sonicated for 20 min to give a homogenous suspension. The pink solid was filtered and discarded, and the ether solution was concentrated to yield the title compound as a yellow solid (1.28 g, 87%). 1H NMR (500 MHz, CDCl3): 8.58 (dd, J=4.8, 1.7, 1H), 8.02 (dd, J=7.9, 1.67 1H), 7.38-7.34 (m, 2H), 7.21 (dd, J=7.9, 4.8, 1H), 7.01-6.97 (m, 2H), 4.33 (t, J=6.2, 2H), 3.68 (t, J=6.2, 2H). MS (ESI): mass calcd. for C14H11BrN2O2S, 349.97; m/z found, 351.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12]C(C)(C)C)=[O:11].[CH2:18](Cl)Cl>CN(C)C1C=CN=CC=1.C(O)C>[CH3:1][C:2]1([CH3:17])[CH:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH3:18])=[O:8])[CH:3]1[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C
Reactant: ClCCl
Agent: CN(C)c1ccncc1
Solvent: CCO
Product: COC(=O)/C=C\C1C(C(=O)O)C1(C)C
Temperature: 20 °C
Reaction time: 16 h

Procedure:
4 g of the product of Step A, 3.4 g of dicyclohexylcarbodiiumide and 6 mg of 4-dimethylamino-pyridine were added to 30 ml of methylene chloride followed by the addition of 1.5 ml of ethanol and the mixture was stirred at 20° C. for 16 hours. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 9-1 cyclohexane-ethyl acetate mixture to obtain 4.25 g of tert.butyl (1R, cis) 2,2-dimethyl-3-(ethoxycarbonyl-ethynyl)-cyclopropane-carboxylate.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+].Cl[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[N:14])[N:8]=1>O1CCCC1>[C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([S:3][CH2:1][CH3:2])[N:8]=1)#[N:14]
Reactant: N#Cc1cccc(Cl)n1
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
Ethyl mercaptan (0.49 g, 7.9 mmol) was dissolved in tetrahydrofuran (100 ml) and added dropwise to sodium hydride (60% oil, 0.35 g, 8.7 mmol). The reaction mixture was stirred at room temperature for 1 hr. A solution of 2-chloro-6-cyanopyridine (1.00 g, 7.2 mmol) in tetrahydrofuran (10 ml) was added to the mixture, and the mixture was stirred at room temperature for 18 hrs. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure to give the titled compound (1.02 g, 86%) as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:38])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:29]=[C:28]([CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:27]=[CH:26][C:18]=2[C:19]([O:21]C(C)(C)C)=[O:20])=[CH:12][CH:11]=1>>[CH3:38][N:9]([CH3:8])[C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[CH:29]=[C:28]([CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:27]=[CH:26][C:18]=2[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=1
Reactant: CN(C)c1ccc(Nc2cc(CCc3ccccc3)ccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ccc(Nc2cc(CCc3ccccc3)ccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid 5.0 mL was added to tert-butyl 2-((4-(dimethylamino)phenyl)amino)-4-phenethylbenzoate, and it was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, ethyl acetate and water were added to the obtained residue, and it was adjusted to pH6.5 with saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Diisopropyl ether was added to the obtained residue, solid matter was filtrated to give 2-((4-(dimethylamino)phenyl)amino)-4-phenethylbenzoic acid 83 mg of a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:12]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[NH2:1][C:2]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(O)ccc(C#N)c1N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(C#N)c(N)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.5 %

Procedure:
A mixture of compound 76 (12 g, 0.08 mol), K2CO3 (11 g, 0.08 mol) in dry DMF (200 mL) was stirred for 15 min at RT. To this was added MeI (13.6 g, 0.096 mol) and the mixture was stirred for 4 h at RT. The reaction mixture was diluted with water (800 mL), extracted with 30% ethyl acetate in pet. ether (3×300 mL). The combined organic layers were washed with water and brine, dried and concentrated to give a crude product. The crude product was washed with pet. ether to give pure title compound (12 g, 93%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.C(=NO)C1C=CC=CC=1>>[C:5]1([C:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][O:10][N:9]=2)[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: COC(=O)c1conc1-c1ccc(F)cc1
Agent: ON=Cc1ccccc1
Product: COC(=O)c1conc1-c1ccccc1
Yield: 35 %

Procedure:
This compound was synthesised following the procedure described for Compound 8C but using benzaldoxime instead of 4-fluorobenzaldoxime as a starting material. The crude was purified twice by flash chromatography (toluene-acetone 96:4 followed by toluene) to give the title compound as an oil (35%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.C(Cl)(=O)C(Cl)=O>CS(C)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[C:4]([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1
Reactant: OCc1ccc(I)cc1OCCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Product: O=Cc1ccc(I)cc1OCCc1ccccc1

Procedure:
The procedure is the same as that described above, using 6.6 g, that is 18.8 mmol, of (4-iodo-2-phenethyloxyphenyl)methanol, 1.8 ml of oxalyl chloride and 3 ml of DMSO. After evaporation of the solvents, 6.4 g (96%) of the expected compound are recovered in the form of a yellow solid.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[OH:9][C:10]1[CH:11]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH:12]2[N:13]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:14](=[O:33])[C:15]=1[C:16]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=2[S:18](=[O:32])(=[O:31])[N:17]=1>CN(C)C=O>[OH:9][C:10]1[CH:11]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH:12]2[N:13]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:14](=[O:33])[C:15]=1[C:16]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([N:26]([CH3:1])[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=2[S:18](=[O:31])(=[O:32])[N:17]=1
Reactant: CC(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)C2CCCCCC21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(N(C)S(C)(=O)=O)ccc3N2)=C(O)C2CCCCCC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.4 %

Procedure:
Potassium carbonate (0.067 g, 0.488 mmol) and iodomethane (0.017 mL, 0.268 mmol) were added sequentially to a solution of N-{3-[4-hydroxy-1-(3-methyl-butyl)-2-oxo-2,4a,5,6,7,8,9,9a-octahydro-1H-cyclohepta[b]pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (prepared as described in Example 33b, 0.128 g, 0.244 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 2 h, and then was partitioned between ethyl acetate (30 mL) and water (2×20 mL). The organic layers were washed with saturated aqueous brine solution (50 mL), dried over sodium sulfate, filtered, and were concentrated in vacuo. The residue was purified by flash column chromatography (Analogix SuperFlash Column; 30-80% ethyl acetate in hexanes) to afford the desired product, N-{3-[4-hydroxy-1-(3-methyl-butyl)-2-oxo-2,4a,5,6,7,8,9,9a-octahydro-1H-cyclohepta[b]pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-N-methyl-methanesulfonamide (0.045 g, 0.084 mmol, 34%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 1.00 (d, 6H, J=7.1 Hz), 1.40-2.24 (m, 14H), 2.88 (d, 3H, J=2.1 Hz), 2.94-3.09 (m, 1H), 3.30-3.53 (m, 2H), 3.37 (d, 3H, J=3.1 Hz), 3.95-4.09 (m, 1H), 7.17-7.23 (m, 1H), 7.67-7.73 (m, 1H), 7.77-7.80 (m, 1H). LC-MS (ESI) calcd for C24H34N4O6S2 538.19, found 539.4 [M+H+].
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20](Cl)=[O:21]>C(Cl)Cl>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)=[O:21]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(NC(=O)c3c(F)cccc3F)cc2)OC1(C)C
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a stirred solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (a) (5.2 g, 24 mmol), TEA (5 mL) in dry DCM (50 mL) at 0° C. was added 2,6-difluoro-benzoyl chloride (b) (3.0 mL, 24 mmol) dropwise. The mixture was allowed to warm to room temperature over 2 h before it was washed with water (2×100 mL) and dried. Removal of solvents gave 2,6-difluoro-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (c) (8.4 g, 23 mmol) as white solid.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:30](OCC)=[O:31])[N:18]([CH2:28][CH3:29])[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])=[CH:11][CH:10]=1>>[CH2:1]([NH:7][C:30]([C:17]1[N:18]([CH2:28][CH3:29])[C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=2)[N:16]=1)=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1CC
Product: CCCCCCNC(=O)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1CC

Procedure:
Using essentially the same procedure as Example 42, Step C, but using neat hexylamine (2 mL), ethyl 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1-ethylimidazole-2-carboxylate (25 mg, 0.060 mmol) from Example 42, Step B was converted to the title compound after purification by Prep TLC (25% ethyl acetate in hexanes). HPLC/MS: 478 (M+1), 480 (M+3); Rt=5.23 min.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([OH:22])=[N:11][CH:10]=1.[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl.C(=O)([O-])[O-].[Ag+2]>[CH2:34]([O:22][C:12]1[CH:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:9]([C:8]([N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:32])([F:1])[F:33])[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=2)[CH3:24])=[O:23])=[CH:10][N:11]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1ccccc1-c1cc(O)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(OCc2ccccc2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 39.1 %

Procedure:
A mixture of 50 mg (0.11 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-hydroxy-N-methyl-4-o-tolyl-nicotinamide (Example 111), 0.014 ml (0.12 mmol) benzyl bromide and 59 mg (0.21 mmol) silver carbonate in 2 ml dichloromethane was heated at reflux for 2 h. Cooling to room temperature was followed by dilution with dichloromethane and filtration. The filtrate was washed with water. The aqueous layer was extracted with three portions of dichloromethane. The combined organic layers were dried with sodium sulfate, concentrated and dried in high vacuo. Column chromatography afforded 24 mg (41%) of the title compound as a viscous light yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[N:13](CCC)CCC)([O-])=O.Cl.[Sn](Cl)Cl.[OH-].[K+]>C(O)C>[CH2:5]([C:7]1[CH:6]=[C:5]([NH2:13])[C:4]([NH2:1])=[C:9]([CH2:6][CH2:7][CH3:8])[C:8]=1[NH2:10])[CH2:4][CH3:9]
Reactant: CCCN(CCC)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [K+]
Solvent: CCO
Product: CCCc1cc(N)c(N)c(CCC)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 157.5 %

Procedure:
(2,4-Dinitro-phenyl)-dipropyl-amine (13.1 g, 49 mmol) was dissolved in 200 ml ethanol and cooled in an icebath. In succession, ION HCl (60 ml, 600 mmol) and tin(II)chloride (112.5, 499 mmol), were added. The solution was stirred at room temperature 16 h. The reaction mixture was poured into a separatory funnel containing 100 ml ice-cold water followed by the addition of 20% KOH (ice-cold, 1L). The mixture was extracted with ether (3×150 ml). The combined organic phases were washed with water (3×100 ml) and brine, dried with solid MgSO4 and concentrated. Distillation (Krugel Rohr, 90°-100° C. at 0.2 mm Hg) followed by treatment with decolorizing charcoal and recrystallization from 15% ethyl acetate in hexane gave 8.0 g product >99% pure by HPLC.
Reaction SMILES: [CH2:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])[CH2:2][CH3:3].C([O-])(O)=O.[Na+].[I:16]I>CO.O>[I:16][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:1][CH2:2][CH3:3])[CH:10]=1
Reactant: II
Reactant: CCCc1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCc1cc(I)ccc1N
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 2-n-propylaniline in MeOH (25 mL) was added a solution of NaHCO3 (5.0 g, 59.5 mmol) in H2O (25 mL). Iodine (8.4 g, 33.3 mmol) was added portionwise over 70 min. while maintaining the temp. at 10° C., then the mixture was allowed to stir at 10° C. for 30 min. The resulting mixture was diluted with H2O (30 mL) and extracted with EtOAc (4×40 mL). The combined organic layers were sequentially washed with a 5% Na2S2O3 solution (30 mL) and a saturated NaHCO3 solution (30 mL), dried (Na2SO4), and concentrated under reduced pressure to give 4-iodo-2-n-propylaniline (9.4 g, 98%): TLC (20% EtOAc/hex) Rf0.43. This material was used in the next step without further purification.