Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:7](=[O:16])[NH:8][CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+].[NH2:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:41])[CH2:39]Br)=[C:33]([Cl:42])[CH:32]=1)(=[O:30])=[O:29]>CN(C)C=O.C(OCC)(=O)C>[NH2:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:41])[CH2:39][N:8]2[CH:9]=[CH:10][C:11]([C:12]([F:15])([F:13])[F:14])=[C:6]([O:5][C:4]3[CH:17]=[C:18]([Cl:20])[CH:19]=[C:2]([Br:1])[CH:3]=3)[C:7]2=[O:16])=[C:33]([Cl:42])[CH:32]=1)(=[O:30])=[O:29]
Reactant: O=c1[nH]ccc(C(F)(F)F)c1Oc1cc(Cl)cc(Br)c1
Reactant: NS(=O)(=O)c1ccc(NC(=O)CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(NC(=O)Cn2ccc(C(F)(F)F)c(Oc3cc(Cl)cc(Br)c3)c2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-(3-bromo-5-chlorophenoxy)-4-(trifluoromethyl)pyridin-2(1H)-one (3B, 0.050 g, 0.136 mmol) and potassium carbonate (0.019 g, 0.136 mmol) suspended in dimethylformamide (1 mL) was added N-[4-(aminosulfonyl)-2-chlorophenyl]-2-bromoacetamide (0.046 g, 0.136 mmol) as a solution in dimethylformamide (1 mL). The reaction mixture was allowed to stir at room temperature. After 16 hours, the reaction mixture was diluted with ethyl acetate (20 mL), washed with water (3×10 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on a pre-packed silica gel Redi Sep 12 gram column, eluting with 0-5% methanol in CH2Cl2 to yield the title compound. 1H NMR (DMSO-d6) δ 10.23 (s, 1H), 8.0 (d, J=8.6 Hz, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.90 (d, J=2.1 Hz, 1H), 7.75 (dd, J=8.6 Hz, J=2.1 Hz, 1H), 7.48-7.44 (m, 2H), 7.44-7.42 (m, 1H), 7.19-7.17 (m, 1H), 7.12-7.10 (m, 1H), 6.66 (d, J=7.2 Hz, 1H), 5.02 (s, 2H). HRMS (M+1)=613.913.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[NH:18][C:17]=2[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Na].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](Cl)=[O:37]>CN(C=O)C>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:16]([CH2:15][CH2:14][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]2[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:17]1[CH3:27])=[O:37]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: COc1ccc2[nH]c(C)c(CCN3CCCCC3CC3CCCCC3)c2c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)n2c(C)c(CCN3CCCCC3CC3CCCCC3)c3cc(OC)ccc32)c1

Procedure:
1-(3-Methoxybenzoyl)-3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole is prepared by reaction of 3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole with sodium hydride in DMF and reaction of the resulting sodium salt with 3-methoxybenzoyl chloride following the procedure described above in Example 1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:21][C:22]1[CH:23]=[C:24]([CH:29]2[CH2:34][C:33](=[O:35])[NH:32][C:31]([CH3:36])=[C:30]2[C:37](O)=[O:38])[CH:25]=[CH:26][C:27]=1[F:28]>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:37]([C:30]3[CH:29]([C:24]4[CH:25]=[CH:26][C:27]([F:28])=[C:22]([F:21])[CH:23]=4)[CH2:34][C:33](=[O:35])[NH:32][C:31]=3[CH3:36])=[O:38])[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:20])[CH3:19]
Reactant: CC1=C(C(=O)O)C(c2ccc(F)c(F)c2)CC(=O)N1
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3=C(C)NC(=O)CC3c3ccc(F)c(F)c3)CC2)c1

Procedure:
Prepared by Procedure AC and Scheme AM using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide and 4-(3,4-difluorophenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridinecarboxylic acid: ESMS m/e: 525.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[OH:38][CH2:39][C:40]([CH3:45])([CH3:44])[C:41](=[S:43])[NH2:42]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:43][C:41]([C:40]([CH3:45])([CH3:44])[CH2:39][OH:38])=[N:42][C:9]=2[C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Reactant: CC(C)(CO)C(N)=S
Agent: O=C1CCC(=O)N1Br
Product: CC(C)(CO)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1

Procedure:
Following a procedure analogous to the procedure described for Intermediate 9 using N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (750 mg, 1.7 mmol), NBS (317 mg, 1.782 mmol), and 3-hydroxy-2,2-dimethylpropanethioamide (248 mg, 1.86 mmol), the title compound was obtained as an yellow foam (460 mg, 45%). A portion of the sample was crystallized from ethyl acetate-hexanes. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (s, 1H) 8.54 (d, J=5.31 Hz, 1H) 7.64-7.74 (m, 1H) 7.41-7.50 (m, 2H) 7.31-7.36 (m, 1H) 7.24 (t, J=8.97 Hz, 2H) 6.87 (d, J=5.31 Hz, 1H) 5.2-5.4 (br s, 1H) 3.54 (s, 2H) 1.36 (s, 6H). MS (ESI): 555.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([OH:11])[C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[C@@:21]12(O)[N:28](C)[C@@H:25]([CH2:26][CH2:27]1)[CH2:24][CH:23]=[CH:22]2.[Na]>>[F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([OH:11])[C:7]([O:9][C@@:10]23[N:28]([CH3:21])[C@@H:25]([CH2:26][CH2:27]2)[CH2:24][CH:23]=[CH:22]3)=[O:8])=[CH:4][CH:3]=1
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Reactant: COC(=O)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Na]
Product: CN1[C@@H]2CC=C[C@@]1(OC(=O)C(O)(c1ccc(F)cc1)c1ccc(F)cc1)CC2

Procedure:
11.13 g (0.04 mol) of methyl 4,4′-difluorobenzilate 3d and 5.57 g (0.04 mol) of tropenol are reacted with 0.09 g sodium analogously to Example 3, step 3.2. The product is recrystallized from acetonitrile. Yield: 10.43 g (62% of theory); melting point: 233-235° C.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH:21]4[CH:27]([F:28])[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl>C(Cl)(Cl)Cl>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH:21]4[CH:27]([F:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CCC(F)C(Oc2cccc3ccc(-c4nnc5ccccn45)nc23)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: FC1CCNCCC1Oc1cccc2ccc(-c3nnc4ccccn34)nc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl 4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-5-fluoroazepane-1-carboxylate (0.157 g, 0.329 mmol) in CHCl3 (3.2 mL) was added HCl (3.29 mL, 13.2 mmol, 4.0 M in dioxane). The mixture was stirred at ambient temperature for 5 hours and was then filtered directly. The solid was washed with CH2Cl2 (5 mL) and Et2O (5 mL) and carefully dried in vacuo to afford the desired product as an off-white solid. The salt was purified directly by column chromatography (10% MeOH/CH2Cl2 with 1% NH3) to provide the free amine product as an off-white solid. MS ESI (+) m/z 378.1 (M+1) detected.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(C)=O.[I-].[K+]>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: c1nc[nH]n1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Brc1cccc(Cn2cncn2)c1
Temperature: 55 °C
Reaction time: 16 h
Yield: 65.1 %

Procedure:
To a solution of 3-bromobenzylbromide (20.0 g, 80.0 mmol) in acetone (300 mL) was added 1,2,4-triazole (10.8 g, 120 mmol), potassium carbonate (11.0 g, 80.0 mmol) and potassium iodide (0.790 g, 4.72 mmol). The resulting white suspension was heated to 55° C. with vigorous stirring for 16 h. The yellow reaction mixture was cooled and ethyl acetate (100 mL) added. This was then washed with distilled water (100 mL×2), 1M NaOH(aq) (100 mL×2) and brine (100 mL). The organic layer was dried over Na2SO4, filtered and solvent removed in vacuo to leave clear yellow oil. The crude product was purified by column chromatography (ethyl acetate) to give the title compound as a yellow crystalline solid (12.4 g, 65%),
Reaction SMILES: C([BH3-])#N.[Na+].[CH2:5]([O:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([O:19][CH3:20])[CH:13]=2)=[O:9])[CH3:6]>C(O)(C(F)(F)F)=O>[CH2:5]([O:7][C:8]([CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:19][CH3:20])=[CH:15][CH:16]=2)[NH:11]1)=[O:9])[CH3:6]
Reactant: CCOC(=O)c1cc2ccc(OC)cc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1Cc2ccc(OC)cc2N1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 75.3 %

Procedure:
Sodium cyanoborohydride (750 mg, 12 mmol) (Aldrich) was added in small portions to a mixture of 6-Methoxy-1H-indole-2-carboxylic acid ethyl ester (500 mg, 2.4 mmol) (Aldrich) in TFA (10 mL), which was cooled in ice-water bath, at such a rate that gas evolution was not too vigorous. When the addition was complete, the mixture was allowed to warm to room temperature and stirred for 2.5 hr. The resulting mixture was concentrated in vacuo and the residue was dissolved in DCM. The organic layer was washed with Na2CO3 solution, dried with Na2SO4, and concentrated to give 400 mg rac-6-Methoxy-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester. MS: [M+H]+=222
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([CH:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([N:25]=[CH:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[OH:33])=[CH:21][CH:20]=3)[C:11]=12>CS(C)=O>[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([CH:34]3[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH2:39]3)[N:17]=[C:18]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][CH:26]4[CH2:2][O:33][C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]4=5)=[CH:23][CH:24]=3)[C:11]=12
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(N=Cc4ccccc4O)cc3)c3c(N)ncnc32)CC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(NC4COc5ccccc54)cc3)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Salicylaldehyde (0.063 g, 0.000513 mol) and tert-butyl 4-[4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (0.200 g, 0.000489 mol) were combined in absolute ethanol (5 mL) and stirred at ambient temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and the residue dried overnight to yield tert-butyl 4-[4-amino-3-(4-{[-1-(2-hydroxyphenyl)methylidene]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate which was used without further purification. Trimethylsulfoxonium iodide (0.269 g, 0.00122 mol) was dissolved in anhydrous dimethylsulfoxide (2 mL) and a 60% dispersion of sodium hydride in parafine (0.049 g, 0.00122 mol) was added at once. After 10 min., the solution of tert-butyl 4-[4-amino-3-(4-{[-1-(2-hydroxyphenyl)methylidene]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate in anhydrous dimethylsulfoxide (2 mL) was added and the resulting mixture was stirred at ambient temperature under an atmosphere of nitrogen for 2.5 hours. The solution was poured into ice-cold water (70 mL) and extracted with dichloromethane (2×50 mL). The combined organic extracts were dried with magnesium sulfate and concentrated under reduced pressure to yield crude tert-butyl 4-{4-amino-3-[4-(2,3-dihydrobenzo[b]furan-3-ylamino)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-1-piperidinecarboxylate which was used without further purification. The crude compound was dissolved in ethyl acetate (5 mL )and treated with a 4N aqueous solution of hydrochloric acid (1.5 mL). The resulting emulsion was vigorously stirred for 1 hour; the water layer was neutralized with saturated solution of sodium bicarbonate in water and the layers were separated. The organic phase was concentrated under reduced pressure and residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield 3-[4-(2,3-dihydrobenzo[b]furan-3-ylamino)phenyl]-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate (0.038 g, 0.000078 mol) as a white solid
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: NCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCc2ccccn2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 2-(aminomethyl)pyridine in DME. ES-MS m/e (%): 293 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].C([O-])([O-])=O.[K+].[K+].[N+](C1C=C(S(O[CH2:31][CH:32]2[CH2:34][O:33]2)(=O)=O)C=CC=1)([O-])=O>CC#N>[O:33]1[CH2:34][CH:32]1[CH2:31][O:1][C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OCC2CO2)c1
Reactant: N#Cc1ccc(O)cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(OCC2CO2)cc1C#N

Procedure:
A stirred suspension of 4-hydroxyphthalonitrile (3.5 g; 24.3 mmol), K2CO3 (4.03 g; 29.2 mmol) and 2-{[(3-nitrophenyl)sulfonyloxy]methyl}-oxirane (6.50 g; 25.0 mmol; see Example B above) in MeCN (170 mL) was refluxed for 1.5 h. The cooled reaction mixture was filtered, the filtrate concentrated and the solid residue recrystallized from IPA to give the sub-title compound.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:22][C:23]#[C:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([SnH:37]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH3:36]>C1COCC1.[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>[CH2:1]([O:8][N:9]([CH2:22]/[CH:23]=[C:24](\[P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])/[Sn:37]([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:33][CH2:34][CH2:35][CH3:36])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(C#CCN(OCc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-])OCC
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)/C(=C/CN(OCc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-])P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a solution of Diethyl 3-[N-benzyloxy,N-(2-nitrobenzenesulfonyl)amino]-propynylphosphonate (109) (10.4 g, 21.6 mmol) and Tetrakis(triphenylphosphine)-palladium(0) (Pd(PPh3)4) (474 mg, 0.430 mmol) in dry THF (100 mL) was added tributyltin hydride (BU3SnH) (6.28 g, 21.6 mmol) over a period of 40 min at 0° C. The reaction mixture was stirred at 0° C. for one hour and was allowed to warm to room temperature over a period of time of 2 hours. The solvent was removed under reduced pressure and the crude oil was purified by column chromatography using a mixture of pentane/acetone (volume ratio 3/1), yielding 15 g of an amber oil (90%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)([CH3:4])([CH3:3])[CH3:2].C(N1CCC(OC2C=C(C(F)(F)F)C=C(N[C:46]([C:48]3[C:49]([Cl:54])=[N:50][CH:51]=[CH:52][CH:53]=3)=[O:47])C=2)CC1)(OC(C)(C)C)=O>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:46](=[O:47])[C:48]2[CH:53]=[CH:52][CH:51]=[N:50][C:49]=2[Cl:54])=[CH:7][C:6]=1[O:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(NC(=O)c3cccnc3Cl)cc(C(F)(F)F)c2)CC1
Reactant: CN1CCC(COc2cc(N)ccc2C(C)(C)C)CC1
Product: CN1CCC(COc2cc(NC(=O)c3cccnc3Cl)ccc2C(C)(C)C)CC1

Procedure:
N-[4-tert-Butyl-3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-2-chloro-nicotinamide was prepared from 4-tert-butyl-3-(1-methyl-piperidin-4-ylmethoxy)-phenylamine by a procedure similar to that described in the preparation of 1-Boc-4-{3-[(2-chloro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C[Al](C)C.N#N.[NH:20](/[C:24](/[CH3:30])=[CH:25]\[C:26](OC)=[O:27])[C:21]([CH3:23])=O>C(Cl)Cl>[CH3:23][C:21]1[N:13]([C:10]2[CH:11]=[N:12][C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:8][CH:9]=2)[C:26](=[O:27])[CH:25]=[C:24]([CH3:30])[N:20]=1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Agent: N#N
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)nc2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
To a solution of 6-morpholinopyridin-3-amine (1.79 g, 10 mmol) in CH2Cl2 (100 mL) was added trimethylaluminium (40 mL, 40 mmol, 1 M in heptane) carefully under N2. The mixture was stirred at rt for 30 min, followed by the addition of a solution of methyl 3-acetaminocrotonate (1.89 g, 12 mmol) in CH2Cl2 (5 mL). The reaction was stirred at rt for 6 h, then quenched with saturated NH4Cl aqueous solution (100 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by recrystallized from EtOAc to give the title compound as a pale yellow solid (1.11 g, 39%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: N1CCCC1.[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:15])[CH3:14].[C:16]([OH:23])(=[O:22])[CH2:17][CH2:18][C:19]([CH3:21])=O>C1(C)C=CC=CC=1>[CH3:21][C:19]1([CH2:18][CH2:17][C:16]([OH:23])=[O:22])[CH2:14][C:13](=[O:15])[C:8]2[C:7](=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6]1
Reactant: CC(=O)CCC(=O)O
Reactant: CC(=O)c1ccccc1O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CC1(CCC(=O)O)CC(=O)c2ccccc2O1
Reaction time: 72 h

Procedure:
24 g of pyrrolidine are added carefully, at under 30°, to a solution of 41 g of o-hydroxyacetophenone, 25 g of levulinic acid and 100 ml of toluene. The mixture is left to stand for 3 days at 25° and the solution is extracted by shaking with 150 ml of concentrated sodium carbonate solution. The aqueous phase is acidified with 2 N HCl and then extracted by shaking with ether. The ethereal solution is concentrated and distilled, 14 g (20% of the theoretical yield) of 2-methyl-2-β-carboxyethyl-chroman-4-one being obtained: boiling point: 230°/0.1 mm Hg.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[S:33](=[O:35])(=[O:34])[NH:32][C:31](=[O:36])[CH2:30]2)=[CH:25][CH:24]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[O:4].C(N(CC)C(C)C)(C)C.[CH3:46][O:47][C:48](=[O:60])[C@@H:49]([N:57]=[C:58]=[O:59])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C)C=O>[CH2:50]([C@@H:49]([C:48](=[O:60])[O:47][CH3:46])[NH:57][C:58](=[O:59])[NH:1][C@@H:2]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]2[S:33](=[O:35])(=[O:34])[NH:32][C:31](=[O:36])[CH2:30]2)=[CH:27][CH:28]=1)[C:3](=[O:4])[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:12]=1[C:13]([O:15][CH3:16])=[O:14])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@@H](N)Cc1ccc(C2CC(=O)NS2(=O)=O)cc1
Reactant: COC(=O)[C@H](Cc1ccccc1)N=C=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)cc1)NC(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.5 %

Procedure:
To a solution of methyl 2-[4-({(2S)-2-amino-3-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoyl}amino)butoxy]-6-hydroxybenzoate (8.0 mg, 0.015 mmol) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (0.008 mL, 0.045 mmol) and (S)-2-isocyanato-3-phenyl-propionic acid methyl ester (3.5 mg, 0.017 mmol) and stirred overnight at room temperature. The product was purified by preparative LCMS to afford the desired product (1.9 mg, 17%). LCMS found for C35H41N4O11S (M+H)+: m/z=725.1
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:32]([N:34]([CH2:36][C:37]([NH:39][C@H:40]([C:62]([NH:64][CH2:65][C:66]([OH:68])=[O:67])=[O:63])[CH2:41][CH2:42][CH2:43][NH:44][C:45](=[NH:61])[NH:46][S:47]([C:50]1[C:59]([CH3:60])=[C:57]([CH3:58])[C:54]([O:55][CH3:56])=[CH:53][C:51]=1[CH3:52])(=[O:49])=[O:48])=[O:38])[CH3:35])=[O:33])[CH2:11][S:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[NH:69]1[C:73](=[O:74])[CH2:72][CH2:71][C@H:70]1[C:75](O)=[O:76]>>[NH:69]1[C:73](=[O:74])[CH2:72][CH2:71][C@H:70]1[C:75]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:32]([N:34]([CH2:36][C:37]([NH:39][C@H:40]([C:62]([NH:64][CH2:65][C:66]([OH:68])=[O:67])=[O:63])[CH2:41][CH2:42][CH2:43][NH:44][C:45](=[NH:61])[NH:46][S:47]([C:50]1[C:59]([CH3:60])=[C:57]([CH3:58])[C:54]([O:55][CH3:56])=[CH:53][C:51]=1[CH3:52])(=[O:49])=[O:48])=[O:38])[CH3:35])=[O:33])[CH2:11][S:12][C:13]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:76]
Reactant: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)CN(C)C(=O)[C@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)[C@@H](N)CC(N)=O)C(=O)NCC(=O)O)c(C)c1C
Reactant: O=C1CC[C@@H](C(=O)O)N1
Product: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)CN(C)C(=O)[C@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H]2CCC(=O)N2)C(=O)NCC(=O)O)c(C)c1C

Procedure:
The coupling and Nα -deprotection processes were repeated in the same manner to prepare H-Asn-Cys(Trt)-Sar-Arg(Mtr)-Gly-resin, followed by another coupling process using pGlu-OH to obtain pGlu-Asn-Cys(Trt)-Sar-Arg(Mtr)-Gly-resin. After drying, the resin was stirred in TFA-anisolethiophenol (10-1-1 ml) for 4 hours, filtered and washed with TFA.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:15]([CH2:16][C:17]([OH:19])=O)[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=1.[CH3:20][NH2:21]>O1CCCC1>[CH3:20][NH:21][C:17](=[O:19])[CH2:16][N:15]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=C(O)Cn1c(-c2ccccn2)nc2cccnc21
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2ccccn2)nc2cccnc21
Reaction time: 8 h
Yield: 76 %

Procedure:
A solution of 2-(2-pyridinyl)-3-H-imidazo[4,5-b]pyridine-3-acetic acid (2.44 g, 0.0096 mole), 1-1'-carbonyldiimidazole (1.56 g, 0.0096 mole), and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 5 hours. A solution of 1M monomethylamine in tetrahydrofuran (15 ml) was added and the reaction stoppered and stirred overnight. The tetrahydrofuran was evaporated in vacuo and the residue triturated in water (30 ml) and filtered. The filter cake was again triturated in water (30 ml) and filtered, giving 1.94 g (76%) of solid, mp 228°-230° C. Recrystallization from tetrahydrofuran-methanol gave 1.49 g of a white solid, mp 228.5°-230° C.