Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=C)=[C:6]([NH:10][CH3:11])[N:5]=[CH:4][C:3]=1[C:12]([NH:14][NH:15][C:16](=O)[C:17]([O:19][CH3:20])=[O:18])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:23].O.[OH-].[Na+]>O1CCCC1.O1CCOCC1>[CH3:20][O:19][C:17]([C:16]1[S:23][C:12]([C:3]2[C:2]([Cl:1])=[C:7]3[CH:8]=[CH:11][NH:10][C:6]3=[N:5][CH:4]=2)=[N:14][N:15]=1)=[O:18]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: C=Cc1c(NC)ncc(C(=O)NNC(=O)C(=O)OC)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COC(=O)c1nnc(-c2cnc3[nH]ccc3c2Cl)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 35.4 %

Procedure:
To a suspension of methyl (2-{[4-chloro-6-(methylamino)-5-vinylpyridine-3-yl]carbonyl}hydrazino)(oxo)acetate (450 mg) in tetrahydrofuran (7 ml) and dioxane (7 ml) was added diphosphorus pentasulfide (383 mg) under cooling in an ice bath. After the mixture was stirred at ambient temperature for 5 hours. To the reaction mixture was added tetrahydrofuran (10 ml) and diphosphorus pentasulfide (190 mg). After the mixture was stirred at ambient temperature for 2 hours, water was added to the reaction solution, and the pH was adjusted to approximately 10 with aqueous sodium hydroxide, and the solution was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol) to obtain methyl-5-(4-chloro-1H-pyrrolo[2,3,b]pyridine-5-yl)-1,3,4-thiadiazole-2-carboxylate (90 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:30]=[N:31][C:32]([O:35][CH2:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:33][CH:34]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:30]=[N:31][C:32]([O:35][CH2:36][C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:33][CH:34]=1
Reactant: CC(C)(C)C(=O)COc1ccc(CN)cn1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: CC(C)(C)C(=O)COc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cn1
Yield: 49 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (210 mg, 0.5 mmol) with 3-aminomethyl-6-(3,3-dimethyl-2-oxo-butoxy)-pyridine (220 mg, 1 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (4:1) to give 7-chloro-6-{[6-(3,3-dimethyl-2-oxo-butoxy)-pyridin-3-ylmethyl]-amino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (122 mg, 50%). MS (ES+) m/z: 498 (M+H)+.
Reaction SMILES: [N:1]1([C:10]2[C:11]3[CH:18]=[CH:17][NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[C@H:9]2[C@H:4]([NH:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH:28]([S:31](Cl)(=[O:33])=[O:32])([CH3:30])[CH3:29]>C(#N)C.CN(C1C=CN=CC=1)C.CS(C)=O>[CH3:29][CH:28]([S:31]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:9]2[N:1]([C:10]3[C:11]4[CH:18]=[CH:17][NH:16][C:12]=4[N:13]=[CH:14][N:15]=3)[CH2:2][CH2:3][C@@H:4]12)(=[O:33])=[O:32])[CH3:30]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: c1nc(N2CC[C@H]3NCCC[C@H]32)c2cc[nH]c2n1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CS(C)=O
Product: CC(C)S(=O)(=O)N1CCC[C@@H]2[C@H]1CCN2c1ncnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-[(3aR,7aR)-octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine (12 mg, 0.049 mmol) in acetonitrile (493 tip was added DMAP (9.0 mg, 0.074 mmol) and DIPEA (17 μL, 0.099 mmol) followed by isopropylsulfonyl chloride (12 mg, 0.049 mmol). The reaction mixture was stirred for 20 hours at room temperature before being diluted with 1.0 mL DMSO and purified by mass-triggered reverse-phase HPLC using a Waters X-bridge Prep C18 column (5 micron, 19×100 mm), eluting with an ACN/water gradient (0.1% formic acid as modifier) to afford 4-{(3aR,7aR)-4-[(1-methylethyl)sulfonyl]octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl}-7H-pyrrolo[2,3-d]pyrimidine. LRMS calc'd for C16H24N5O2S [M+H]+, 350.2; found 350.2. 1H NMR (500 MHz, DMSO-D6) δ 11.6 (s, 1H); 8.04 (s, 1H); 7.09 (s, 1H), 6.51 (s, 2H); 4.29 (br s, 2H); 3.97-3.64 (br m, 21-1); 3.53 (d, 2H, J=11Hz); 3.38-3.34 (m, 1H); 3.02 (t, 1H. J=10Hz); 2.01 (br s, 1H); 1.64 (s, 1H), 1.62 (br s, 1H), 1.24-1.54 (br m, 2H). 1.21 (t, 6H, J=5.5Hz). Jak1 activity: ++
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].C(N(CC)CC)C.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26]>ClCCl>[N+:25]([C:16]1[CH2:17][N:18]([NH:1][CH2:2][C:3]([CH3:5])([NH2:6])[CH3:4])[C:19]2[C:24]([CH:15]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(N)CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(N)CNN1CC([N+](=O)[O-])=Cc2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Under a nitrogen atmosphere, a solution of 1,2-diamino-2-methylpropane (52.20 mL, 503.3 mmol), triethylamine (131.8 mL, 958.8 mmol), and dichloromethane (1.0 L) was chilled in an ice water bath. 4-Chloro-3-nitroquinoline (100.0 g, 479.4 mmol) was added in portions over a period of 5 minutes. The reaction mixture was stirred at 0° C. for 2 hours and then allowed to slowly warm to ambient temperature. After 16 hours the reaction mixture was concentrated under reduced pressure. The residue was triturated with water (500 mL) for 1 hour. The resulting solid was isolated by filtration and dried overnight in a vacuum desiccator to provide 124.6 g of N1-(3-nitroquinolin-1-yl)-2-methylpropane-1,2-diamine as a yellow crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:11][C:3]=1[C:4]([N:6]([CH2:9]C)[CH2:7]C)=[O:5].NC1C=C([F:37])C(Br)=C2C=1C(=O)N(C)C2.NC1C=CC(Br)=CC=1C(N(CC)CC)=O>>[NH2:1][C:2]1[CH:14]=[C:13]([F:37])[C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[C:11]2[C:3]=1[C:4](=[O:5])[N:6]([CH3:7])[CH2:9]2
Reactant: CN1Cc2c(Br)c(F)cc(N)c2C1=O
Reactant: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Agent: CCN(CC)C(=O)c1cc(Br)ccc1N
Product: CN1Cc2c(c(N)cc(F)c2-c2cnn(CCCO)c2)C1=O

Procedure:
Prepared analogously to Compound 3C substituting 7-amino-4-bromo-5-fluoro-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 31D) for 2-amino-5-bromo-N,N-diethylbenzamide (Compound 3D). 1H NMR (CDCl3, 400 MHz): δ 7.75 (d, J=4.5 Hz, 2H), 6.41 (d, J=13.1 Hz, 1H), 4.46 (t, J=6.1 Hz, 2H), 4.39 (s, 2H), 3.70 (t, J=5.6 Hz, 2H), 3.17 (s, 3H), 2.20-2.09 (m, 3H). MS (ESI): m/z=305.14 [M+H]+. UPLC: tR=0.95 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [BH4-].[Na+].CSC.[CH3:6][O:7][C:8](=[O:22])[CH2:9][C@@H:10]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11](O)=[O:12].[OH-].[Na+].OO.[Cl-].[Na+]>O1CCCC1>[CH3:6][O:7][C:8](=[O:22])[CH2:9][C@@H:10]([S:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:11][OH:12]
Reactant: COC(=O)C[C@@H](SCc1ccccc1)C(=O)O
Agent: OO
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CSC
Product: COC(=O)C[C@H](CO)SCc1ccccc1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a suspension of sodium borohydride (1.78 g) in tetrahydrofuran (70 ml)is added dimethylsulfide (2.8 ml) at room temperature, and thereto is added dropwise a solution of boron trifluoride·ether complex (6.3 ml) in tetrahydrofuran (10 ml) at room temperature, and the mixture is stirred for 30 minutes. To the mixture is added (3R)-3-benzylthio-3-carboxypropionic acid methyl ester (10 g) at room temperature, and the mixture is stirred for 1.5 hour. After the reaction is completed, to the reaction solution are added successively 2N aqueous sodium hydroxide solution (16 ml), 30% aqueous hydrogen peroxide solution (11 ml), and then further added a saturated aqueous sodium chloride solution. The mixture is extracted with chloroform, and the extract is dried, concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=2:1) to give (3R)-3-benzylthio-4-hydroxybutyric acid methyl ester (7.75 g) as an oily product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:10](OC)(OC)OC.Cl.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][CH:10]=[N:9][C:4]=2[CH:3]=1
Reactant: COC(OC)OC
Reactant: Nc1ccc(Br)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 4-bromobenzene-1,2-diamine (3 g, 16 mmol) in DMF (22 mL) were added trimethyl orthoformate (44 mL) and conc. HCl (1.5 mL) and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water (200 mL) and adjusted to pH7 with saturated aqueous NaHCO3, extract with ethyl acetate (200 mL). The organic layer was dried over Na2SO4, concentrated to give 5-bromo-1H-benzo[d]imidazole (3.25 g, 100%) as an off-white solid. LCMS: 197 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 7.33 (t, J=8.8 Hz, 1H), 7.55 (dd, J1=7.6 Hz, J=40 Hz, 1H), 7.79 (d, J=47.2 Hz, 1H), 8.26 (s, 1H), 12.61 (d, J=25.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[C:10]([O:13][CH2:14][CH2:15]Br)(=[O:12])[CH3:11]>>[CH2:14]([O:13][C:10](=[O:12])[CH2:11][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[F:9])[CH3:15]
Reactant: Nc1ccc(Cl)cc1F
Reactant: CC(=O)OCCBr
Product: CCOC(=O)CNc1ccc(Cl)cc1F

Procedure:
In a manner similar to that employed in Referential Example 267, the title compound was prepared from 4-chloro-2-fluoroaniline and bromoethyl acetate.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[C:13]1(C)C=CC(S(OC)(=O)=O)=CC=1>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]=[CH:7]2
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cc(Br)ccc21
Yield: 98.5 %

Procedure:
Sodium hydride (440 mg of a 60% dispersion in paraffin wax) was added to a stirred solution of 5-bromoindole (1.96 g, 10 mmol) in dimethylformamide (20 ml) at ambient temperature under a nitrogen atmosphere. After 30 minutes methyl p-toluenesulphonate (2.05 g 11 mmol) was added. After 20 hours the mixture was partitioned between diethyl ether and water. The organic layer was separated and washed twice with water. The organic layer was dried (magnesium sulphate) and the solvent was removed in vacuo. The residue was purified by flash column chromatography (using 50% hexane, 50% dichloromethane as eluant) to give 2.07 g of product as a waxy solid.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][N:5]([CH2:32][C:33]([O:35]C)=[O:34])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:31])[CH2:14][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])[CH:7]=1.[OH-].[Na+]>O1CCOCC1.CO>[C:3]([CH2:4][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:31])[CH2:14][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])[CH:7]=1)[CH2:32][C:33]([OH:35])=[O:34])([OH:37])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Nc1cccc(N(CC(=O)OC)CC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCCCCCCCCCCCCCCC(=O)Nc1cccc(N(CC(=O)O)CC(=O)O)c1
Reaction time: 18 h
Yield: 79.3 %

Procedure:
A mixture of 1.8 g N-(2-methoxy-2-oxoethyl)-N-[3-[(1-oxooctadecyl)amino]phenyl]glycine methylester and 2.4 ml of 6N NaOH in 30 ml of dioxane and 30 ml of methanol was heated to dissolve the solid and left at room temperature for 18 hours. The solid which precipitated was filtered, treated with 1N HCl and filtered again. Recrystallization from methanol-THF-water gave 1.35 g (79%yield, mp 133°-140°) of N-(carboxymethyl)-N-[3-[(1-oxooctadecyl)amino]phenyl]glycine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:24][C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]([CH2:24][C:25]([NH:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[O:26])[S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CNC(=O)CBr)cc1
Reactant: COC(=O)c1ccc(S(=O)(=O)Nc2cccc(Cl)c2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(S(=O)(=O)N(CC(=O)NCc2ccc(OC)cc2)c2cccc(Cl)c2C)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 80.7 %

Procedure:
220 mg of methyl 4-{[(3-chloro-2-methylphenyl)amino]sulfonyl}benzoate was dissolved in 1.10 mL of DMF, and 168 mg of 2-bromo-N-(4-methoxybenzyl)acetamide and 100 mg of potassium carbonate were added thereto, followed by stirring at room temperature for 7 hours. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3 to 4:6) to obtain 270 mg of methyl 4-[((3-chloro-2-methylphenyl)-{2-[(4-methoxybenzyl)amino]-2-oxoethyl}amino)sulfonyl]benzoate. The obtained methyl 4-[((3-chloro-2-methylphenyl)-{2-[(4-methoxybenzyl)amino]-2-oxoethyl}amino)sulfonyl]benzoate was dissolved in 2.00 mL of methanol and 1.50 mL of THF, and 1.05 mL of a 1 M aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for 2 days. The reaction liquid was acidified by addition of 1 M hydrochloric acid, and then extracted with a mixed solvent of chloroform/methanol (5/1), and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (chloroform:methanol=100:0 to 90:10) to obtain 204 mg of 4-[((3-chloro-2-methylphenyl) {2-[(4-methoxybenzyl)amino]-2-oxoethyl}amino)sulfonyl]benzoic acid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@@H:17]4[CH2:22][N:21]([C:23]5[N:28]=[CH:27][C:26]([C:29]6[CH2:34][CH2:33][N:32]([C:35](OC(C)(C)C)=O)[CH2:31][CH:30]=6)=[CH:25][N:24]=5)[CH2:20][CH2:19][O:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.[OH-].[Na+]>C=O.C(O)(=O)C>[CH3:35][N:32]1[CH2:31][CH:30]=[C:29]([C:26]2[CH:27]=[N:28][C:23]([N:21]3[CH2:20][CH2:19][O:18][C@H:17]([CH2:16][N:13]4[C:11]5=[N:12][C:7]([C:5]6[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=6)=[CH:8][N:9]=[C:10]5[N:15]=[N:14]4)[CH2:22]3)=[N:24][CH:25]=2)[CH2:34][CH2:33]1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(C6=CCN(C(=O)OC(C)(C)C)CC6)cn5)CCO4)c3n2)cn1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN1CC=C(c2cnc(N3CCO[C@H](Cn4nnc5ncc(-c6cnn(C)c6)nc54)C3)nc2)CC1
Temperature: 95 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
(S)-tert-butyl 4-(2-(2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (36 mg, 0.06 mmol) was dissolved in 35% HCHO (0.1 ml) and acetic acid (0.5 ml), followed by stirring at 95° C. overnight. After the completion of the reaction, the reaction mixture was adjusted to pH 11-12 with NaOH (aq.), and extracted with H2O and EA, followed by drying (Na2SO4), filtration and concentration under reduced pressure, and the residue was purified by column chromatography (MeOH:MC=1:10), to give (S)-4-(5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-yl)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine (16.9 mg, 56%).
Reaction SMILES: [OH-:1].[K+].[N+:3]([C:6]1[CH:16]=[CH:15][CH:14]=[C:8]2[C:9]([NH:11][C:12](=[O:13])[C:7]=12)=[O:10])([O-:5])=[O:4].Cl>O>[N+:3]([C:6]1[CH:16]=[CH:15][CH:14]=[C:8]([C:9]([OH:1])=[O:10])[C:7]=1[C:12]([NH2:11])=[O:13])([O-:5])=[O:4]
Reactant: O=C1NC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)c1c(C(=O)O)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of potassium hydroxide (16.1 g, 286 mmol) in water (500 mL), was added 3-nitrophthalimide (25.0 g, 130 mmol) in portion at 0° C. The suspension was stirred at 0° C. for 3 hours, and then heated to 30° C. for 3 hours. To the solution, was added HCl (100 mL, 6N). The resulting suspension was cooled to 0° C. for 1 hour. The suspension was filtered and washed with cold water (2×10 mL) to give 3-nitro-phthalamic acid as a white solid (24.6 g, 90% yield): 1H NMR (DMSO-d6) δ 7.69 (brs, 1H, NHH), 7.74 (t, J=8 Hz, 1H, Ar), 7.92 (dd, J=1, 8 Hz, 1H, Ar), 8.13 (dd, J=1, 8 Hz, 1H, Ar), 8.15 (brs, 1H, NHH), 13.59 (s, 1H, OH); 13C NMR (DMSO-d6) δ 125.33, 129.15, 130.25, 132.54, 136.72, 147.03, 165.90, 167.31.
Reaction SMILES: O=[O+][O-].[O:4]=O.[C:6]1([CH:12]([O:19][C:20](=[O:59])[CH:21]([N:25]2[CH:28]([S:29][S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:27]([NH:40][C:41](=[O:57])[CH:42]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:26]2=[O:58])[C:22](=[CH2:24])C)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CSC>C(Cl)Cl>[C:6]1([CH:12]([O:19][C:20](=[O:59])/[C:21](/[N:25]2[CH:28]([S:29][S:30]([C:33]3[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=3)(=[O:31])=[O:32])[CH:27]([NH:40][C:41](=[O:57])[CH:42]([NH:49][C:50]([O:52][C:53]([CH3:55])([CH3:54])[CH3:56])=[O:51])[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:26]2=[O:58])=[C:22](\[OH:4])/[CH3:24])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=O
Reactant: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)c2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Agent: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Product: C/C(O)=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)c2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.12 h

Procedure:
An ozone/oxygen stream (0.5 mmol per minute) is passed for 7 minutes into a solution, cooled to -70° C., of 2.30 g (3.0 mmols) of 2-[4-(p-toluenesulphonylthio)-3-(α-tert.butoxycarbonylamino-α-phenylacetylamino)-2-oxoazetidin-1-yl]-3-methylene-butyric acid diphenylmethyl ester in 230 ml of methylene chloride. After adding 1 ml of dimethyl sulphide, the solution is stirred for a further hour without cooling and is then concentrated by evaporation in vacuo. The residue is recrystallised from methylene chloride/ether/hexane and gives 2-[4-(p-toluenesulphonylthio)-3-(α-tert.butoxycarbonylamino-α-phenylacetylamino)-2-oxoazetidin-1-yl]-3-hydroxy-crotonic acid diphenylmethyl ester of melting point 182°-184° C.; UV spectrum (ethanol): ~max = 259 mμ (ε =13,400); IR spectrum (methylene chloride): characteristic bands at 2.92, 5.59, 5.83, 5.92, 6.03 (shoulder), 6.18 and 6.68 μ; thin layer chromatogram: Rf value~ 0.55 (silica gel; toluene/ethyl acetate, 1:1).
Reaction SMILES: C[O:2][C:3](=[O:37])[C@@H:4]([NH:14][C:15](=[O:36])[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[NH:23][S:24]([C:27]1[C:32]2=[N:33][S:34][N:35]=[C:31]2[CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1.C1COCC1.[Li+].[OH-].Cl>O>[N:35]1[S:34][N:33]=[C:32]2[C:27]([S:24]([NH:23][C:17]3[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=3[C:15]([NH:14][C@@H:4]([CH2:5][C:6]3[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=3)[C:3]([OH:37])=[O:2])=[O:36])(=[O:25])=[O:26])=[CH:28][CH:29]=[CH:30][C:31]=12
Reactant: COC(=O)[C@H](Cc1ccc(Cl)c(Cl)c1)NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid methyl ester (0.81 mmol), THF (10 mL), and LiOH (2 M in water, 5 mL) was stirred vigorously overnight at rt. The mixture was poured into water, acidified to pH 1 with conc. HCl, and extracted with EtOAc (4×). The combined organic layers were dried (Na2SO4) and concentrated to provide the desired acid as a tan solid. The acid was purified by preparative reverse phase HPLC to provide 0.44 g (94%, 2 steps) of the acid as a white solid. HPLC: RT=10.08 min. MS (ESI−): mass calcd. for C22H15Cl3N4S5O2, 583.95; m/z found, 583 [M−H]−. 1H NMR (400 MHz, CD3OD): 8.34 (dd, J=7.0, 1.0, 1H), 8.25 (dd, J=8.8, 1.0, 1H), 7.77 (dd, J=8.8, 7.0, 1H), 7.66 (d, J=2.0, 1H), 7.45-7.37 (m, 3H), 7.18 (dd, J=8.2, 2.0, 1H), 6.99 (dd, J=8.5, 2.1, 1H), 4.75 (dd, J=9.3, 5.2, 1H), 3.28 (dd, J=14.0, 5.1, 1H), 3.03 (dd, J=14.0, 9.4, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[CH:10]=[C:6]2[N:5]=[CH:4][CH:3]=1.[I:18]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:10]([I:18])=[C:6]2[N:5]=[CH:4][CH:3]=1
Reactant: Clc1ccccc1-c1cc2nccc(Cl)n2n1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Clc1ccccc1-c1nn2c(Cl)ccnc2c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a solution of 7-chloro-2-(2-chlorophenyl)-pyrazolo[1,5-a]pyrimidine (I-1A-1c; 6.00 g, 22.7 mmol) in chloroform (23 ml) and methylene chloride (207 ml) cooled in an ice bath was added N-iodosuccinimide (7.67 g, 34.1 mmol), portionwise. The ice bath was removed and the reaction was stirred overnight at room temperature. After concentrating the red-brown reaction, in vacuo, an ethyl acetate solution of the residue was washed with saturated aqueous Na2S2O4 and brine. The solution was dried (MgSO4), concentrated, in vacuo, and the resulting solids repulped at room temperature from ethyl acetate (30 ml) to give product I-1A-1d as a solid (6.8 g, 77%): +APcI MS (M+1) 390.1; 1H NMR (400 MHz, CD2Cl2) δ 8.52 (d, J=4.6 Hz, 1H), 7.59–7.56 (m, 1H), 7.53–7.42 (m, 3H), 7.14 (d, J=4.6 Hz, 1H).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>CN(C)C=O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCCCCCCCBr
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c(CCCCCCCBr)cccc21

Procedure:
Potassium phthalimide (5.4 mmoles) was added to a solution of 1,7-dibromoheptane (4.18 g; 16.2 mmoles) in dimethylformamide (8 ml) and heated to 80° C. approx. under stirring. Reaction times and process as per Example 4.