Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:44])[CH2:3][N:4]([C:26]([C:28]1[N:32]([CH2:33][CH2:34]OS(C)(=O)=O)[C:31]2[CH:40]=[CH:41][CH:42]=[CH:43][C:30]=2[N:29]=1)=[O:27])[C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[CH2:8][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6]1.[NH:45]1[CH:49]=[CH:48][CH:47]=[N:46]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[CH3:44][CH:2]([CH3:1])[CH2:3][N:4]([C:26]([C:28]1[N:32]([CH2:33][CH2:34][N:45]2[CH:49]=[CH:48][CH:47]=[N:46]2)[C:31]2[CH:40]=[CH:41][CH:42]=[CH:43][C:30]=2[N:29]=1)=[O:27])[C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[O:12])[CH2:8][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6]1
Reactant: c1cn[nH]c1
Reactant: CC(C)CN(C(=O)c1nc2ccccc2n1CCOS(C)(=O)=O)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCn1cccn1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 72 h
Yield: 59.3 %

Procedure:
To a solution of tert-butyl (3S,5R)-3-{(2-methylpropyl)[(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-benzimidazol-2-yl)carbonyl]amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (127 mg) and pyrazole (41 mg) in N,N-dimethylacetamide (3 ml) was added cesium carbonate (326 mg), and the mixture was stirred at 60° C. for 3 days. The to reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (72 mg).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]([C:33]([O:35][CH3:36])=[O:34])[C:14]2[NH:15][C:16]3[CH:17]=[C:18]([S:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)(=[O:26])=[O:25])[CH:19]=[CH:20][C:21]=3[C:22]=2[N:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[O:30]1[CH2:31][CH2:32][N:27]([S:24]([C:18]2[CH:19]=[CH:20][C:21]3[C:22]4[N:23]=[C:11]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH:12]=[C:13]([C:33]([O:35][CH3:36])=[O:34])[C:14]=4[NH:15][C:16]=3[CH:17]=2)(=[O:26])=[O:25])[CH2:28][CH2:29]1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(S(=O)(=O)N3CCOCC3)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: COC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(S(=O)(=O)N3CCOCC3)ccc12
Temperature: 70 °C
Yield: 89.8 %

Procedure:
A mixture of phenylboronic acid (41.9 mg, 0.343 mmol),methyl 2-bromo-7-(morpholinosulfonyl)-5H-pyrido[3,2-b]indole-4-carboxylate (120 mg, 0.264 mmol), potassium phosphate tribasic (146 mg, 0.687 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (22 mg, 0.053 mmol), and Pd(OAc)2 (5.9 mg, 0.026 mmol) in a microwave vial was flushed with nitrogen. THF (1.3 mL) was added, the vial was capped and the reaction was heated in a 70° C. for 18 hr. It was partitioned between EtOAc and water and the organic phase was separated and washed with brine. It was dried with sodium sulfate and the solvent were removed. The residue was dissolved in DCM and radial chromatography (step gradient elution with DCM containing 0 to 10% EtOAc) afforded methyl 7-(morpholinosulfonyl)-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxylate (107 mg, 0.237 mmol, 90% yield) as a yellow solid. MS (ESI) m/z 450.0 (M−H). 1H NMR (500 MHz, DMSO-d6) d ppm 12.04 (1H, s), 8.58 (1H, d, J=8.24 Hz), 8.47 (1H, s), 8.26 (2H, d, J=7.32 Hz), 8.19 (1H, d, J=1.22 Hz), 7.67 (1H, dd, J=8.24, 1.53 Hz), 7.58 (2H, t, J=7.63 Hz), 7.46-7.52 (1H, m), 4.11 (3H, s), 3.62-3.72 (4H, m), 2.92-3.00 (4H, m).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH2:11][NH:12][CH2:13][CH2:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:22](I)[CH2:23][CH3:24].O>CN(C)C=O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH2:11][N:12]([CH2:22][CH2:23][CH3:24])[CH2:13][CH2:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(C2=CCCNC2)c1
Reactant: CCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1CCC=C(c2cccc(OC)c2)C1
Reaction time: 16 h

Procedure:
A mixture of a solution of 5 g of the product of Step D of Example 3 in 50 ml of dimethylformamide, 7 g of sodium carbonate and 2.3 ml of n-propyl iodide was stirred for 16 hours under an inert atmosphere and was then poured into 250 ml of iced water. The mixture was extracted with ethyl acetate and the organic phase was washed with aqueous saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-1-1 cyclohexane-chloroform-triethylamine mixture. The eluate was distilled to dryness under reduced pressure to obtain 4.84 g of 3-(3-methoxyphenyl)-1-propyl-1,2,5,6-tetrahydropyridine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15](C=O)=[N:14][N:13]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[C:10]3=[N:11][CH:12]=2)[CH:2]=1.FC1C=C(C2C(N)=C(N)C=NC=2)C=CC=1.[S]>C(O)CCC>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[CH:15]=[N:14][N:13]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[C:10]3=[N:11][CH:12]=2)[CH:2]=1
Reactant: O=Cc1nn(C2CCCCO2)c2ncc(-c3cccnc3)cc12
Agent: Nc1cncc(-c2cccc(F)c2)c1N
Agent: [S]
Solvent: CCCCO
Product: c1cncc(-c2cnc3c(cnn3C3CCCCO3)c2)c1
Temperature: 25 °C

Procedure:
A solution of 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (CXXXI) (65 mg, 0.21 mmol), 5-(3-fluorophenyl)pyridine-3,4-diamine (LXXV) (45 mg, 0.22 mmol) and sulfur (7 mg, 0.22 mmol) in n-butanol (10 mL) was heated at reflux overnight. The solution was cooled to room temperature, filtered and the solvent was evaporated under reduced pressure to give crude 3-(743-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (CXXXII). CXXXII was dissolved in dry DCM (5 mL) before adding triethylsilane (84 μL, 0.52 mmol) and TFA (2.5 mL). The reaction was stirred at room temperature for 2 h under argon. The solvent was evaporated under reduced pressure; the residue was taken up water (10 mL), and basified with 5N NH4OH. The precipitates were filtered, washed by cold water and dried under vacuum at room temperature. The crude product was suspended in DCM (10 mL), sonicated briefly and then heated to boiling for 5 min. The solution was cooled to room temperature and the solids were filtered, washed with DCM and dried under vacuum at room temperature to produce 3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine (3) as a yellow solid (53 mg, 0.13 mmol, 62% yield). 1H NMR (DMSO-d6) δ ppm 7.25-7.34 (m, 1H), 7.54-7.65 (m, 2H), 8.11-8.21 (m, 1H), 8.23-8.30 (m, 1H), 8.37-8.50 (m, 1H), 8.63-8.70 (m, 1H), 8.70-8.80 (m, 1H), 9.02-9.09 (m, 2H), 9.09-9.15 (m, 1H), 13.94 (brs, 1H), 14.59 (s, 1H); ESIMS found for C23H14FN7 m/z 408.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[O:17])=[CH:11][C:10]=2[N+:23]([O-])=O)=[CH:4][CH:3]=1.[NH4+].[Cl-]>[Fe]>[NH2:23][C:10]1[CH:11]=[C:12]([NH:15][C:16]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[O:17])[CH:13]=[CH:14][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: O=C(Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1cccs1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: Nc1cc(NC(=O)c2cccs2)ccc1Sc1ccc(O)cc1
Yield: 52 %

Procedure:
The product from Example 240b was reduced with Fe and NH4Cl following the procedure from Example 9E to provide the title compound (800 mg, 52%).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:6]=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([CH:11]=1)[NH2:10]>O1CCOCC1>[CH3:1][O:2][C:5]1[CH:6]=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([CH:11]=1)[NH2:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc([N+](=O)[O-])c(N)c1

Procedure:
70 ml of a 28% w/v methanolic solution of sodium methoxide were added at room temperature to a solution of 25 g of 5-chloro-2-nitroaniline in 500 ml of 1,4-dioxane, and the resulting mixture was heated under reflux for 4 hours, after which the solvent was removed by distillation under reduced pressure. The resulting residue was diluted with water, and the resulting aqueous mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel using a gradient elution method, with mixtures of ethyl acetate and hexane in ratios ranging from 1:4 to 1:2 by volume as the eluent, to give 16.3 g of the title compound, melting at 124-128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[N:12]1[CH2:17][C:16]2[CH:18]=[N:19][C:20]([N:22](OC)[CH3:23])=[CH:21][C:15]=2[N:14]([CH3:26])[C:13]1=[O:27]>CO.[Pd]>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Cl:1])=[C:3]([N:12]2[CH2:17][C:16]3[CH:18]=[N:19][C:20]([NH:22][CH3:23])=[CH:21][C:15]=3[N:14]([CH3:26])[C:13]2=[O:27])[CH:4]=1
Reactant: CON(C)c1cc2c(cn1)CN(c1cc([N+](=O)[O-])c(F)cc1Cl)C(=O)N2C
Agent: [Pd]
Solvent: CO
Product: CNc1cc2c(cn1)CN(c1cc(N)c(F)cc1Cl)C(=O)N2C
Reaction time: 96 h
Yield: 71.5 %

Procedure:
3-(2-chloro-4-fluoro-5-nitrophenyl)-7-(methoxy(methyl)amino)-1-methyl-3,4-dihydro pyrido[4,3-d]pyrimidin-2(1H)-one (1 g, 2.5 mmol), Pd/C (0.3 g) were combined in MeOH (30 mL) and hydrogenated (45 psi) at 50° C. for 4 days. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residual solid was washed with ethyl acetate and dried in vacuo to give 3-(5-amino-2-chloro-4-fluorophenyl)-1-methyl-7-(methylamino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (0.6 g, 71% yield). 1H-NMR (400 MHz, DMSO-d6): δ 7.71 (s, 1 H), 7.26 (d, J==10.8 Hz, 1 H), 6.78 (d, J=8.8 Hz, 1 H), 6.41 (m, 1 H), 5.94 (s, 1 H), 5.43 (s, 2 H), 4.50 (d, J=13.6 Hz, 1 H), 4.40 (d, J=13.6 Hz, 1 H), 3.16 (s, 3 H), 2.76 (d, J=5.2 Hz, 3 H); MS (ESI) m/z: 336.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:34]I)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:34][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1ccc(-c2ncc(Cl)cn2)cc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(F)cc2)C1
Product: CCOC(=O)C1(COc2ccc(-c3ncc(Cl)cn3)cc2)CCN(C(=O)c2ccc(F)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4-(5-chloro-pyrimidin-2-yl)-phenol (Preparation 19) and 1-(4-fluoro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 12) to afford the racemate as a pale yellow solid (103 mg, 43.1%)
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][O:32][CH2:31]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH2:29][CH:30]3[CH2:34][CH2:33][O:32][CH2:31]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Reactant: BrCCCC1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCCC1CCOC1

Procedure:
Prepared similarly to Intermediate 216 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(3-bromopropyl)tetrahydrofuran.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[S:12](Cl)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[S:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
A solution of 1H-indole-3-carboxaldehyde (7.26 g, 50.0 mmol) in methylene chloride (100 mL) was added with tosyl chloride (11.4 g, 60.0 mmol) and diisopropylethylamine (7.75 g, 60.0 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate to terminate the reaction, and then extracted three times with methylene chloride, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 1-tosyl-1H-indole-3-carboxaldehyde (11.8 g, 78%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][C:10]=1[N:11]1[C:15](=[O:16])[NH:14][C:13]([CH:17]([C:31]2[CH:40]=[C:39]([O:41][CH3:42])[C:34]3[O:35][CH2:36][CH2:37][O:38][C:33]=3[C:32]=2[F:43])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[N:29]=C(C)O[N:26]=3)=[CH:21][CH:20]=2)=[N:12]1)=[O:5])[CH3:2].O.C(O)(=O)C>CO.[Fe]>[C:4]([OH:5])(=[O:3])[CH3:6].[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][C:10]=1[N:11]1[C:15](=[O:16])[NH:14][C:13]([CH:17]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH2:29])=[CH:23][CH:24]=2)[C:31]2[CH:40]=[C:39]([O:41][CH3:42])[C:34]3[O:35][CH2:36][CH2:37][O:38][C:33]=3[C:32]=2[F:43])=[N:12]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(-c3noc(C)n3)cc2)c2cc(OC)c3c(c2F)OCCO3)[nH]c1=O
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(C(=N)N)cc2)c2cc(OC)c3c(c2F)OCCO3)[nH]c1=O
Temperature: 62.5 °C
Reaction time: 40 h
Yield: 45.5 %

Procedure:
To a solution of 68 mg of 5-(3-{(5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-1H-pyrazole-4-carboxylic acid ethyl ester in 6 ml of a methanol:water:acetic acid=1:1:1 mixed solvent there was added 68 mg of iron powder, and the mixture was stirred at 62.5° C. for 40 hours under a nitrogen atmosphere. After cooling, the reaction mixture was filtered through celite and purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid). The title compound (16.0 mg) was obtained as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:6][CH:5]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][C@@H:31]2[CH2:33][C@H:28]1[CH2:29][NH:30]2)=[O:26])([CH3:23])([CH3:22])[CH3:21].CCN(CC)CC>CC#N>[C:20]([O:24][C:25]([N:27]1[CH2:32][C@@H:31]2[CH2:33][C@H:28]1[CH2:29][N:30]2[CH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:6][CH:5]=1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: BrCCc1ccc(Oc2nc3ccccc3s2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2CCc1ccc(Oc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.1 %

Procedure:
To a stirred solution of 2-[4-(2-bromo-ethyl)-phenoxy]-benzothiazole (1.5 g, 4.5 mmol) and (S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (980 mg, 4.9 mmol) in CH3CN (20 mL) at rt was added Et3N (900 μL, 6.3 mmol). The resulting suspension was stirred at rt for 24 h and then partitioned between CH2Cl2 (200 mL) and satd. aq. NaHCO3 (80 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated. Purification by silica gel flash chromatography (EtOAc) afforded the title compound as a white foam (1.1 g, 56%). MS (ESI): mass calcd. for C25H29N3O3S, 451.19; m/z found, 452.2 [M+H]+. 1H NMR (500 MHz, CDCl3, mixture of rotamers): 7.73 (d, J=8.4 Hz, 1H), 7.66 (d, J=7.5 Hz, 1H), 7.38 (m, 1H), 7.30-7.24 (m, 5H), 4.38 (br m, 0.5H), 4.24 (br m, 0.5H), 3.53 (br m, 2H), 3.16 (t, J=10.4 Hz, 1H), 3.03 (d, J=8.4 Hz, 0.5H), 2.98 (d, J=9.8 Hz, 0.5H), 2.86-2.74 (br m, 4H), 2.69 (br d, J=9.8 Hz, 0.5H), 2.52 (br d, J=9.4 Hz, 0.5H), 1.84 (br d, J=9.2 Hz, 1H), 1.73 (br d, J=10.0 Hz, 0.5H), 1.69 (br d, J=9.2 Hz, 0.5H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.C(N(CC)CC)C.[CH2:23](Br)[CH:24]=[CH2:25]>C(#N)C>[CH2:25]([N:9]1[CH2:10][CH2:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:13]([O:14][CH3:15])=[CH:12][C:6]=2[CH2:7][CH2:8]1)[CH:24]=[CH2:23]
Reactant: COc1cc2c(cc1OC)CCNCC2
Reactant: C=CCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCN1CCc2cc(OC)c(OC)cc2CC1

Procedure:
To a mixture of 7 g. (0.0337 mole) of 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine dissolved in 170 ml. of acetonitrile and 5 ml. of triethylamine, cooled in an ice bath, was added 4.25 g. (0.035 mole) of allyl bromide in 30 ml. of acetonitrile, dropwise with stirring. The mixture was brought to room temperature and refluxed for 11/2 hours. The reaction mixture was evaporated to dryness, partitioned between ethyl acetate and 5% sodium bicarbonate solution, and the separated ethyl acetate dried and evaporated to give 3-allyl-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([C:23](O)=[O:24])=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[N:15]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].C(Cl)Cl.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:51]([CH2:53][NH2:54])[OH:52]>>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([C:23]([NH:54][CH2:53][CH2:51][OH:52])=[O:24])=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[N:15]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(-c2nc(-c3ccccc3Cl)c(C(=O)O)s2)ccn1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2nc(-c3ccccc3Cl)c(C(=O)NCCO)s2)ccn1
Reaction time: 1 h
Yield: 55.4 %

Procedure:
To a stirred solution of 2-[2-(acetylamino)pyridin-4-yl]-4-(2-chlorophenyl)-1,3-thiazole-5-carboxylic acid (0.050 g, 0.130 mmol) in methylene chloride (3.00 mL, 46.80 mmol) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.056 g, 0.294 mmol) followed by 1-hydroxybenzotriazole (0.040 g, 0.294 mmol) and the resulting solution was stirred for 1 h. Ethanolamine (0.081 mL, 1.340 mmol) was added and the reaction mixture was continued to stir for 18 h. The mixture was quenched by the addition of water (5.0 mL) and extracted with EtOAc (10.0 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, elution with 0-75% EtOAc in hexanes) to provide 0.0300 g of product as a clear colorless oil (54% 2 steps). LC/MS (AA) ES+ 417, 419. 1H NMR (400 MHz, d1 CDCl3) δ: 8.06-7.98 (m, 1H), 7.72-7.54 (m, 3H), 7.49-7.44 (m, 2H), 7.02-6.96 (m, 1H), 6.28 (br s, 1H), 4.72 (br t, J=5.6 Hz, 1H), 4.66 (br t, J=5.4 Hz, 1H), 3.37 (q, J=6.0 Hz, 2H), 3.18 (q, J=6.4 Hz, 2H), 2.12 (s, 3H).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[ClH:4].[CH3:5][O:6][C:7]1[CH:27]=[CH:26][CH:25]=[CH:24][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>C(OCC)C>[ClH:4].[CH3:5][O:6][C:7]1[CH:27]=[CH:26][CH:25]=[CH:24][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:20](=[NH:21])[O:3][CH2:1][CH3:2])=[CH:22][CH:23]=1
Reactant: COc1ccccc1OCCCCCOc1ccc(C#N)cc1
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)c1ccc(OCCCCCOc2ccccc2OC)cc1
Temperature: 5 °C
Reaction time: 84 h

Procedure:
Ethanol (2 B anhydrous, 16.5 L) is cooled with an ice-salt bath to 0° C. Anhydrous hydrogen chloride is introduced until the solution is saturated (~8 hours). At this time the internal temperature is 5° C. To this is added 4-[5-(2-methoxyphenoxy)pentoxy]benzonitrile (1.64 kg, 5.26 mol) as a solid within a period of 10 minutes. At this point additional hydrogen chloride is introduced to maintain saturation at 5° C. for another 8 hours. Almost complete solution is achieved and the color is yellow. The reaction mixture is stirred for a total of 84 hours and the temperature range maintained is 5°-10° C. The resulting slurry is diluted with diethyl ether (52 L) to complete precipitation. The slurry is stirred for 1 hours and filtered. The filter cake is washed with diethyl ether (3×4 L) and air-dried for 1/2 hour to yield ethyl 4-[5-(2-methoxyphenoxy)pentoxy]benzenecarboximidate hydrochloride which is used directly in the next step.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([CH3:21])([CH3:20])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[OH-].[Pd+2]>[C:15]([NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1([CH3:20])[CH3:21])([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)NC1CCN(Cc2ccccc2)CC1(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)NC1CCNCC1(C)C

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.3 g) and 1-benzyl-4-carbethoxyamino-3,3-dimethylpiperidine (1.3 g, 4.48 mmol) in methanol (15 ml) was stirred in hydrogen atmosphere (1 atm.) at 30° C. for 3 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-carbethoxyamino-3,3-dimethylpiperidine. Yield 0.8 g (90%), C10H20N2O2, m/z 201 (M+1).