Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C1C=CC2N(O)N=[N:18]C=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.N.CO>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: On1nnc2ccccc21
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 96 h
Yield: 66.1 %

Procedure:
To solution of 2-amino-4-chlorobenzoic acid (4.4 g, 25.8 mmol) in degassed DMF (75 mL) were added successively HOBt (4.19 g, 31 mmol), DIEA (5.4 mL, 31 mmol), EDCI (5.37 g, 28 mmol), and 2N NH3/MeOH (18 mL, 36 mmol), and the solution was stirred at rt for 4 d. The mixture was concentrated under reduced pressure and the residue was partitioned between H2O (200 mL) and DCM (200 mL). The separated aqueous phase was extracted with DCM (2×200 mL) and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 10-50% EtOAc/hexanes to afford 2-amino-4-chlorobenzamide as a solid (2.91 g, 66%). 1H NMR (300 MHz, DMSO-d6) δ 6.50 (dd, J=8.48, 2.26 Hz, 1H), 6.75 (d, J=2.26 Hz, 1H), 6.84 (br s, 2H), 7.18 (br s, 1H), 7.48-7.63 (m, 1H), 7.80 (br s, 1H).
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([CH:22]([CH3:24])[CH3:23])[C:4]([N:6]1[CH2:11][CH2:10][C@@:9]([C:13]2[CH:18]=[CH:17][C:16](Cl)=[CH:15][CH:14]=2)([OH:12])[C:8]([CH3:21])([CH3:20])[CH2:7]1)=[O:5].[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:2][C@H:3]([CH:22]([CH3:24])[CH3:23])[C:4]([N:6]2[CH2:11][CH2:10][C@:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:1])([OH:12])[C:8]([CH3:21])([CH3:20])[CH2:7]2)=[O:5])=[O:31])=[CH:28][N:27]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CC(C)[C@@H](N)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reactant: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)[C@@H](NC(=O)c1ccc(Cl)nc1)C(=O)N1CC[C@@](O)(c2ccccc2Cl)C(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-2-amino-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one hydrochloride (338 mg, 0.90 mmol), THF (5 mL), and 6-chloronicotinoyl chloride (132 mg, 0.75 mmol) was cooled to 0° C. and DIPEA (233 mg, 1.80 mmol) was added dropwise. The reaction was allowed to warm to rt and stir overnight. The solvent was then removed and residue was partitioned between methylene chloride and saturated sodium bicarbonate. The layers were separated and the organic extracts were dried, filtered, and concentrated to yield 6-chloro-N—((R)-1-((S)-4-(chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)nicotinamide as a white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][P:5]([C:18]([C:20]1[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=1[CH3:28])=[O:19])([C:7]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17])=[O:8])=[O:6].C[C:30]1[NH:31][CH:32]=[CH:33][N:34]=1.[C:35]1(C)C=CC=CC=1>>[Br-:1].[CH3:17][C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[C:14]([CH3:15])[C:9]=1[C:7]([P:5]([CH2:4][CH2:3][CH2:2][N+:34]1[CH:33]=[CH:32][N:31]([CH3:35])[CH:30]=1)([C:18](=[O:19])[C:20]1[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=1[CH3:28])=[O:6])=[O:8]
Reactant: Cc1ncc[nH]1
Reactant: Cc1ccccc1
Reactant: Cc1cc(C)c(C(=O)P(=O)(CCCBr)C(=O)c2c(C)cc(C)cc2C)c(C)c1
Product: Cc1cc(C)c(C(=O)P(=O)(CCC[n+]2ccn(C)c2)C(=O)c2c(C)cc(C)cc2C)c(C)c1
Product: [Br-]
Temperature: 50 °C
Reaction time: 24 h

Procedure:
((3-Bromopropyl)-phosphoryl)bis(mesitylmethanone) of example 5 (825 mg, 1.78 mmol, 1 eq.) and methylimidazol (0.15 mL, 155 mg, 1.89 mmol, 1.06 eq.) were dissolved in toluene (2 mL). The solution was stirred for 24 h at 50° C. A yellow precipitate was formed. The solution was decanted and the yellow solid was washed three times with 2 mL toluene. The microcrystalline product was dried for two hours in vacuo.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[C@H:10]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:9]1)C1C=CC=CC=1.[Cl:28]C(OC(Cl)C)=O>ClCCCl>[ClH:27].[ClH:28].[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C@@H:10]2[CH2:9][NH:8][CH2:13][CH2:12][NH:11]2)=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: Cl
Product: Clc1ccc([C@@H]2CNCCN2)cc1

Procedure:
To a solution of (R)-1-benzyl-4-(tert-butoxycarbonyl)-3-(4-chlorophenyl)piperazine (11.6 g, 30.1 mmol) in 1,2-dichloroethane (80 ml) was added 1-chloroethyl chloroformate (4.91 ml, 45.1 mmol) at room temperature. Upon disappearance of the starting material, the reaction mixture was concentrated under reduced pressure. The residue was then dissolved in methanol (100 ml) and refluxed for 30 min. The resulting white precipitate was filtered and washed with methanol to afford (R)-2-(4-chlorophenyl)piperazine dihydrochloride, which was liberated with aqueous sodium hydroxide solution, and extracted with dichloromethane to afford (R)-2-(4-chlorophenyl)piperazine (3.04 g, 51.4%) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:21][CH3:22])=[C:11]([C:13]3[C:14](=[O:20])[CH2:15][CH2:16][C:17]=3[O:18][CH3:19])[N:12]=2)=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[O:31]1[CH2:36][CH2:35][CH:34]([CH:37]=[O:38])[CH2:33][CH2:32]1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:21][CH3:22])=[C:11]([C:13]3[C:14](=[O:20])[CH:15]([CH:37]([OH:38])[CH:34]4[CH2:35][CH2:36][O:31][CH2:32][CH2:33]4)[CH2:16][C:17]=3[O:18][CH3:19])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCc1sc(-c2ccc(Cl)cc2)nc1C1=C(OC)CCC1=O
Reactant: O=CC1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1sc(-c2ccc(Cl)cc2)nc1C1=C(OC)CC(C(O)C2CCOCC2)C1=O
Temperature: 78 °C
Reaction time: 0.67 h
Yield: 36.9 %

Procedure:
To a solution of 2-[2-(4-Chloro-phenyl)-5-ethyl-thiazol-4-yl]-3-methoxy-cyclopent-2-enone (175 mg, 0.52 mmol) in anhydrous tetrahydrofuran (5 ml) at −78° C. under an atmosphere of nitrogen was added lithium diisopropylamide (1.8M in THF/heptanes/ethylbenzene; 1.1 ml, 2 mmol) dropwise over a period of 1 minute and the reaction allowed to stir at 78° C. for 40 minutes. A solution of tetrahydro-pyran-4-carbaldehyde (228 mg, 2 mmol) in anhydrous tetrahydrofuran (1 ml) was then added dropwise over a period of 30 seconds before the reaction was allowed to warm to room temperature and stirred for a further 30 minutes. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (50 ml) and extracted with ethyl acetate (50 ml) and the organic layer separated, dry loaded onto silica and purified by flash chromatography to give 2-[2-(4-Chloro-phenyl)-5-ethyl-thiazol-4-yl]-5-[hydroxy-(tetrahydro-pyran-4-yl)-methyl]-3-methoxy-cyclopent-2-enone (86 mg).
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[N:28]5[C:24]([S:25][CH:26]=[CH:27]5)=[N:23][C:22]=4[C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=4)[CH:18]=[CH:17][N:16]=3)[CH2:9]2)[CH2:4][O:3]1.O.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:36][O:35][C:31]1[CH:30]=[C:29]([C:22]2[N:23]=[C:24]3[N:28]([C:21]=2[C:19]2[CH:18]=[CH:17][N:16]=[C:15]([NH:14][C@@H:10]4[CH2:11][CH2:12][CH2:13][N:8]([CH2:7][C@@H:5]([OH:6])[CH2:4][OH:3])[CH2:9]4)[N:20]=2)[CH:27]=[CH:26][S:25]3)[CH:34]=[CH:33][CH:32]=1
Reactant: COc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(C[C@@H]4COC(C)(C)O4)C3)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(C[C@@H](O)CO)C3)n2)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 86.7 %

Procedure:
The N-((3R)-1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}piperidin-3-yl)-4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine (150 mg, 0.288 mmol) was dissolved in MeOH (10 ml) and water (1.2 ml) and treated with trifluoroacetic acid (90 uL). The mixture was stirred at 50° C. overnight (18 hours). The mixture was neutralized with potassium carbonate (160 mg) and the volatiles were removed in vacuo. The product was purified by flash chromatography (6:1 EtOAc/MeOH), affording the title compound as an off-white solid (120 mg, 87%). M.p.=106-108° C. 400 MHz 1H NMR (DMSO-d6) δ: 8.72 (br. s, 1H), 8.08 (d, J=5.5 Hz, 1H), 7.44 (d, J=4.4 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.16-7.10 (m, 2H), 7.06-6.97 (m, 2H), 6.36 (d, J=5.5 Hz, 1H), 4.40-4.15 (m, 1H), 4.02-3.90 (m, 1H), 3.77 (s, 3H), 3.68-3.56 (m, 2H), 3.40-3.28 (m, 2H), 3.05-2.95 (m, 1H), 2.80-2.64 (m, 1H), 2.42 (br. s, 1H), 2.32 (br. s, 1H), 2.14 (br. s, 1H), 1.90-1.80 (m, 1H), 1.75-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.45-1.30 (m, 1H). LCMS: 481 [M+H].
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:12](O)(=O)C.C=O.[H][H]>[Ni].C(O)C>[CH3:12][NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccccc1N
Reactant: CC(=O)O
Reactant: [H][H]
Agent: [Ni]
Agent: C=O
Solvent: CCO
Product: CNc1ccccc1C(=O)OC

Procedure:
In a 250 mL Parr shaking glass pressure reactor was placed methyl anthranilate (15.1 g, 0.10 mol), ethanol (70 mL), glacial acetic acid (6 g, 0.1 mol) and Raney nickel catalyst (2.1 g). To this cooled mixture at 5° C. was added 37% formaldehyde solution (8 mL, 0.10 mol). The mixture was then hydrogenated at 25° C. at an initial hydrogen pressure of 50 psig with continuous stirring. After hydrogen uptake had ceased (6 h), the mixture was filtered through filter-aid. The filtrate was washed to neutrality with saturated NaHCO3 (2×100 mL), and the layers were separated. The organic layer was washed with saturated NaCl (100 mL) and dried. The solvent was evaporated at reduced pressure. The residue was distilled to provide methyl N-methylanthranilate, b12.0 130°-133° C. as a colorless liquid. Yield: 14 g (85% of theor.). GLC purity: 98.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[C:4]([NH:13][C:14]([O:16]CC)=O)[CH:3]=1.[NH2:19][CH2:20][CH2:21][OH:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:8])[N:19]([CH2:20][CH2:21][OH:22])[C:14](=[O:16])[NH:13]2)=[CH:11][CH:12]=1
Reactant: NCCO
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C(=O)OCC
Solvent: CCO
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)n1CCO
Yield: 64 %

Procedure:
A mixture of 40 parts of ethyl 4-chloro-2-[(ethoxycarbonyl)amino]benzoate and 10 parts of 2-aminoethanol is stirred and heated to 160°-170° C. while the formed ethanol is distilled off. After stirring for about 30 minutes, the mixture is cooled and 2-propanol is added. The solid product is filtered off and dried, yielding 23 parts (64%) of 7-chloro-3-(2-hydroxyethyl)-2,4(1H,3H)-quinazolinedione.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][S:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)[C:4]([F:7])([F:6])[F:5].SC1SC2C=CC=CC=2N=1.[C:29]([O:32][C@@H:33]1[C@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@@H:36]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[O:35][C@H:34]1[N:47]1[CH:55]=[N:54][C:53]2[C:48]1=[N:49][C:50]([Cl:57])=[N:51][C:52]=2Cl)(=[O:31])[CH3:30]>N>[C:29]([O:32][C@@H:33]1[C@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@@H:36]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[O:35][C@H:34]1[N:47]1[C:48]2[N:49]=[C:50]([Cl:57])[N:51]=[C:52]([NH:2][CH:3]([CH2:8][S:9][C:10]3[S:11][C:12]4[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=4[N:14]=3)[C:4]([F:7])([F:6])[F:5])[C:53]=2[N:54]=[CH:55]1)(=[O:31])[CH3:30].[S:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[S:9][CH2:8][CH:3]([NH:2][C:52]1[C:53]2[N:54]=[CH:55][N:47]([C:48]=2[N:49]=[C:50]([Cl:57])[N:51]=1)[C@@H:34]1[O:35][C@H:36]([CH2:42][OH:43])[C@@H:37]([OH:38])[C@H:33]1[OH:32])[C:4]([F:7])([F:6])[F:5]
Reactant: N[C@@H](CSc1nc2ccccc2s1)C(F)(F)F
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: N
Agent: Sc1nc2ccccc2s1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC(CSc4nc5ccccc5s4)C(F)(F)F)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: OC[C@H]1O[C@@H](n2cnc3c(NC(CSc4nc5ccccc5s4)C(F)(F)F)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 45 %

Procedure:
N-[3-(2-Benzothiazolyl)thio-1,1,1-trifluoro-2-propyl]-2-chloroadenosine was prepared according to general method A as described in Example 1 by reacting 2-[(R)-2-amino-1,1,1 trifluoro-3-propylthio]benzothiazole hydrochloride [prepared by a Mitsunobu reaction as described in Example 1 using the above 2-(N-tert-butyloxycarbonyl)amino-1,1,1-trifluoro-3-propanol and 2-mercaptobenzothiazole followed by acidic hydrolysis] (0.13 g, 0.47 mmol) with 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (0.21 g, 0.45 mmol). Debenzoylation of the purified 2',3',5'-tri-O-acetyl-N-[3-(2-benzothiazolyl)thio-1,1,1-trifluoro-2-propyl]-2-chloroadenosine in methanolic ammonia (20 ml) (previously saturated at -10° C.) provided the title N-[3-(2-benzothiazolyl)thio-1,1,1-trifluoro-2-propyl]-2-chloroadenosine (0.12 g, 45%) (following column chromatography) [a mixture of (R)- & (S)- diastereoisomers]; 1H NMR (DMSO-d6) δ3.39-3.49 (1H, m, --CH), 3.58, 3.68 (2H, ABX, H-5'a and H-5'b), 3.98 (1H, q, H-4'), 4.11-4.18 (2H, m, H-3' and --CH--), 4.47-4.56 (1H, m, H-2'), 5.08 (1H, m, 5'-OH), 5.18-5.28 (1H, m, --CHCH2 --), 5.27, 5.57 (2H, 2d, 2'- and 3'-OH), 5.94 (1H, d, H-1'), 7.08, 7.22, 7.30 (3H, 3 t, Ar--H), 7.71 (1H, d, Ar--H), 8.75 (1H, s, H-8), 8.79 (1H, d, N--H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([CH2:16][N:17]([CH3:19])[CH3:18])[N:9]=[CH:10]2.[NH3:21]>CO>[Cl:15][C:14]1[C:5]([CH2:4][C:3]([NH2:21])=[O:2])=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][C:8]([CH2:16][N:17]([CH3:19])[CH3:18])=[CH:7]2
Reactant: COC(=O)Cc1c(Cl)ccc2cnc(CN(C)C)cc12
Reactant: N
Solvent: CO
Product: CN(C)Cc1cc2c(CC(N)=O)c(Cl)ccc2cn1
Temperature: 70 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
A solution of (6-chloro-3-dimethylaminomethyl-isoquinolin-5-yl)-acetic acid methyl ester (515 mg, 1.76 mmol) in a mixture of methanol (10 mL) and liquid ammonia (10 mL) was stirred for 16 h in an autoclave at 70° C. After careful evaporation of the ammonia, the remaining solvent was evaporated in vacuo to afford the title compound as a brown solid (410 mg, 1.48 mmol, 84%). MS (ES+): 278 (M(C14H1635ClN3O)+H)+.
Reaction SMILES: C[O:2][C:3]1[N:4]([CH2:18][CH:19]2[CH2:23][CH2:22][O:21][CH2:20]2)[C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:6]=2.[H][H].O1CCOCC1.O.[OH-].[Na+]>CO>[NH2:12][C:9]1[N:8]=[C:7]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:6]=[C:5]2[C:10]=1[NH:11][C:3](=[O:2])[N:4]2[CH2:18][CH:19]1[CH2:23][CH2:22][O:21][CH2:20]1
Reactant: [H][H]
Reactant: COCCOc1nc(N)c2nc(OC)n(CC3CCOC3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: COCCOc1nc(N)c2[nH]c(=O)n(CC3CCOC3)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
8-(Methoxy)-2-{[2-(methoxy)ethyl]oxy}-9-(tetrahydro-3-furanylmethyl)-9H-purin-6-amine (0.1233 g) was dissolved in methanol (5 mL). To this solution was added 4N hydrogen dioxane (2 mL), stirred at room temperature for 4 hours. The reaction mixture was evaporated under reduced pressure to give a gum. To this material was added water (3 mL) to give a solution, which was then neutralised (to pH 7) using 2N sodium hydroxide. This gave a white solid which was filtered under suction and then washed with a few drops of methanol. The solid was then air-dried under suction before being dried in under vacuo at 50° C. for 2 hours. This gave the title compound as a white solid (86 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])[CH:24]=[CH:23]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[C:25]([NH:30][C:31]([C:33]3[CH:37]=[CH:36][S:35][CH:34]=3)=[O:32])[CH:24]=[CH:23]4)[CH:3]=2)[NH:7]1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1Cc2cc(-c3ccc4cc(NC(=O)c5ccsc5)ccc4c3)ccc2N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 8.9 %

Procedure:
5-bromoindolin-2-one (23.6 mg, 0.111 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (75.0 mg, 0.198 mmol), Fibercat palladium catalyst (Johnson-Matthey, 36.3 mg), and K2CO3 (2 M in water, 0.25 ml, 0.5 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.1 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C, first for 10 minutes, and then for 20 minutes. The reaction was cooled to room temperature, diluted with water (5 ml), and extracted with dichloromethane (3×10 ml) and EtOAc (6×10 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified two times on HPLC (10%->95% MeCN/water with 0.1% TFA) to afford title compound (3.8 mg, 9%). MS (ESI pos. ion) m/z: 385 (M+H). Calc'd Exact Mass for C23H16N2O2S: 384.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[NH:22]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:23][C:24](O)=[O:25].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:8]([O:7][C:5](=[O:6])[C@@H:4]([NH:12][S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14])[CH2:3][NH:2][C:24](=[O:25])[CH2:23][NH:22][C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])([CH3:11])([CH3:9])[CH3:10]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)CNC(=O)OCc1ccccc1)NS(=O)(=O)c1ccccc1
Reaction time: 8 h

Procedure:
Amine 1-5 (0.42 g, 1.25 mmol), Cbz-Gly-OH (288 mg, 1.38 mmol), NMM (0.55 mL, 5.0 mmol) and BOP (829 mg, 1.88 mmol) were combined in 6 mL DMF. After stirring overnight the solvent was evaporated, the residue was taken up in EtOAc, the organic solution was washed with water (2×), 5% KHSO4, sat. NaHCO3 and brine, dried (MgSO4), filtered and concentrated. Flash chromatography (silica, 60% EtOAc/hexane) provided 5-6 as a white glass.
Reaction SMILES: S(O[C@@H:6]1[CH2:10][C@H:9]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[O:8][C@@H:7]1[N:20]1[CH:27]=[C:26]([F:28])[C:24]([NH2:25])=[N:23][C:21]1=[O:22])(C)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Li+].CO>>[N:29]([C@H:6]1[CH2:10][C@H:9]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[O:8][C@@H:7]1[N:20]1[CH:27]=[C:26]([F:28])[C:24]([NH2:25])=[N:23][C:21]1=[O:22])=[N+:30]=[N-:31]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](OS(C)(=O)=O)[C@@H](n2cc(F)c(N)nc2=O)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@H](N=[N+]=[N-])[C@@H](n2cc(F)c(N)nc2=O)O1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 75 %

Procedure:
To a solution of 20 (442 mg, 1.01 mmol) in anhydrous dilmethylformamide (12 mL) was added lithium azide moistened with 10% methanol (265 mg, 4.87 mmol). The reaction mixture was stirred at 100° C. during 2.5 h, and then cooled to room temperature, poured onto ice/water (200 mL) and extracted with chloroform (3×100 mL). Combined extracts were washed with a saturated aqueous sodium hydrogen carbonate solution (2×100 mL), with water (5×100 mL) and then dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent : methanol (4%) in chloroform] to give pure 21 (291 mg, 75% yield) as a white solid: mp 147-148° C.; UV (ethanol): λmax 242 nm (ε 7700), 283 nm (ε 7400), λmin 226 nm (ε 6600), 264 nm (ε 5800); 1H NMR (DMSO-d6): δ 8.05 (d, 1H, H-6, J6-F5=7.0 Hz), 7.9-7.4 (br d, 2H, NH2), 5.7 (br s, 1H, H-1′), 4.37 (d, 1H, H-2′, J2′-3′=5.5 Hz), 4.3 (m, 1H, H-4′), 4. (m, 1H, H-5′), 3.7 (m, 1H,H-5″), 2.0 (m, 1H, H-3′), 1.8 (m, 1H, H-3″), 0.88 (s, 9H, (CH3)3C—Si), 0.05 (s, 6H, (CH3)2Si); MS (matrix GT): FAB>0 m/z 769 (2M+H)+, 385 (M+H)+, 130 (BH2)+; FAB<0 m/z 1151 (3M−H)−, 767 (2M−H)−, 383 (M−H)−, 128 (B)−; [α]D20=+25 (c, 0.95 DMSO).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][N:19]2[CH2:24][CH2:23][N:22]([S:25]([C:28]3[CH2:29][O:30][C:31]4[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:32]=4[CH:33]=3)(=[O:27])=[O:26])[CH2:21][C:20]2=[O:39])([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C.CO>[ClH:38].[Cl:38][C:36]1[CH:35]=[CH:34][C:32]2[CH:33]=[C:28]([S:25]([N:22]3[CH2:23][CH2:24][N:19]([CH2:18][C:11]4([C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[C:20](=[O:39])[CH2:21]3)(=[O:27])=[O:26])[CH2:29][O:30][C:31]=2[CH:37]=1
Reactant: COC(=O)C1(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C1(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 196.8 %

Procedure:
To 1-[1-(tert-butoxycarbonyl)-4-methoxycarbonylpiperidin-4-ylmethyl]-4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-piperazinone (260 mg) was added 4N hydrochloric acid in ethyl acetate (10 ml) and methanol (4 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated to give colorless solid of 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-(4-methoxycarbonylpiperidin-4-ylmethyl)-2-piperazinone hydrochloride (228 mg). A solution of 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-(4-methoxycarbonylpiperidin-4-ylmethyl)-2-piperazinone hydrochloride (228 mg), chloropyridine hydrochloride (80 mg) and triethylamine (225 mg) in ethanol (14 ml) was allowed to react in a sealed tube at 150% for 15 hours. The reaction solution was concentrated, and the residue was dissolved in dichloromethane. The solution was washed with 1N sodium hydroxide solution, dried and concentrated, and the residue was purified with silica gel column chromatography (dichloromethane:methanol containing 10% ammonia solution=20:1) to give colorless solid of the title compound (126 mg).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[CH2:15]([NH2:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CC)CC)C.[Cl:39]CCl>>[Cl:39][C:6]1[CH:5]=[CH:4][C:3]([S:11]([NH:31][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:13])=[O:12])=[CH:2][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CCCCCCCCCCCCCCCCN
Reactant: ClCCl
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCNS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
1 liter of dichloromethane was added to 800 g of 4 chloro-3-nitrobenzenesulfonyl chloride and cooled to 0° C. To the solution was added dropwise a mixture comprising 600 g of hexadecylamine, 251 ml of triethylamine and 780 ml of dichloromethane at 20 to 30° C. After being reacted for 2 hours at room temperature, the dichloromethane was removed by distillation under reduced pressure, and 3 liters of methanol was added to the residue and dissolved under heat. The resulting solution was gradually cooled and crystallized out at room temperature. Further, 3 liters of methanol was added and the resulting solution was again crystallized out under ice-cooling, and the crystal precipitated was taken out by filtration and dried. Yield: 1020 g, 88%.