Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7](I)([CH3:9])[CH3:8].CS(C)=O.Br.[Br:16][C:17]1[CH:18]=[N:19][C:20]([OH:23])=[N:21][CH:22]=1>O>[Br:16][C:17]1[CH:18]=[N:19][C:20](=[O:23])[N:21]([CH:7]([CH3:9])[CH3:8])[CH:22]=1
Reactant: CC(C)I
Reactant: Oc1ncc(Br)cn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)n1cc(Br)cnc1=O
Temperature: 15 °C
Reaction time: 16 h
Yield: 30.6 %

Procedure:
With cooling with ice, potassium carbonate (17 g, 123 mmol) and isopropyl iodide (4.56 mL, 45.7 mmol) were added to a dimethyl sulfoxide (150 mL) solution of 5-bromo-2-hydroxypyrimidine hydrobromide (9.0 g, 35.2 mmol), and stirred at 15° C. for 16 hours. Water was added to the reaction mixture, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, hexane/ethyl acetate=3/2) to obtain the entitled compound (2.34 g, 31%) as a colorless solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]=1>CN(C)C=O>[O:23]([C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Reactant: Nc1ncccc1-c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncccc1-c1cnn(Cc2cccc(Oc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 44.9 %

Procedure:
To a solution of 3-(1H-pyrazol-4-yl)-pyridin-2-ylamine (20 mg, 0.13 mmol) described in Manufacturing Example 32-1-4 in N,N-dimethylformamide (10 mL) was added sodium hydride (7.5 mg, 0.19 mmol, 60% in oil) under nitrogen atmosphere on an ice bath (0° C.), which was stirred for 40 minutes at room temperature. 1-Chloromethyl-3-phenoxybenzene (32.8 mg, 0.15 mmol) described in Manufacturing Example 35-1-1 was then added and stirred for 30 minutes at room temperature. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1, then ethyl acetate only) to obtain the title compound (20 mg, 47%).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6](OC)=O)#[N:4].[Br:10][C:11]1[CH:18]=C[C:14]([C:15]#[N:16])=[C:13](F)[CH:12]=1.Cl>CS(C)=O.O>[Br:10][C:11]1[CH:18]=[CH:6][C:5]([C:3]#[N:4])=[C:13]([CH2:14][C:15]#[N:16])[CH:12]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: COC(=O)CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1cc(Br)ccc1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
Sodium hydride (47.2 g, 1.18 mol) was suspended in 320 mL DMSO and cooled to 0° C. in an ice-water bath. The mixture became viscous as the DMSO began to freeze. Methyl cyanoacetate (104 mL, 1.18 mol) was added slowly causing a slight temperature increase and thus a more easily stirrable solution. The mixture was stirred for 30 minutes at room temperature. 4-Bromo-2-fluorobenzonitrile (118 g, 590 mmol) (commercially available from Acros Organics (Order Number 29049)) was added via cannula as a solution in 500 mL DMSO. The mixture was heated to an internal temperature of 90° C. The mixture was cooled and allowed to stand overnight. 1.2 L of water was added to the reaction mixture. The mixture was heated to an internal temperature of 104° C. over 3 hours. 2.3 L of water was added and the mixture was heated at reflux 16 hours. The mixture was cooled to 5° C. and 700 mL of 0.2N HCl was added. The mixture was allowed to stir at 5° C. for 30 minutes. The resulting precipitate was filtered, washed with water, and dried to provide the product (102 g, 78%). LCMS (API-ES) m/z: 223, 221 (M+H+).
Reaction SMILES: [CH3:1]CCP(=O)=O.C[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:18]=[CH:17][N:16]=2)=[CH:10][C:9]=1[NH2:27].[O:28]=[C:29]1[NH:34][CH2:33][CH2:32][N:31]([CH2:35][C:36]2[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=2)[CH2:30]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[O:28]=[C:29]1[NH:34][CH2:33][CH2:32][N:31]([CH2:35][C:36]2[CH:44]=[CH:43][C:39]([C:40]([NH:27][C:9]3[CH:8]=[CH:13][C:12]([CH3:1])=[C:11]([NH:14][C:15]4[N:20]=[C:19]([C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)[CH:18]=[CH:17][N:16]=4)[CH:10]=3)=[O:41])=[CH:38][CH:37]=2)[CH2:30]1
Reactant: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1N
Reactant: CCCP(=O)=O
Reactant: O=C1CN(Cc2ccc(C(=O)O)cc2)CCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccc(CN3CCNC(=O)C3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of propylphosphonic anhydride in N,N-dimethylformamide (Fluka, Buchs, Switzerland; 1.3 mL of 50%, 2.25 mmol) is added dropwise to a stirred mixture of 4-methyl-N-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine (416 mg, 1.5 mmol), 4-[(3-oxo-1-piperazinyl)methyl]benzoic acid (351 mg, 1.5 mmol) and triethylamine (1.7 mL, 12 mmol) in dry N,N-dimethylformamide (4 mL). The mixture is stirred for 17 hours at room temperature and then treated with saturated aqueous sodium hydrogen carbonate solution (100 mL). The resulting precipitate is filtered, washed with water, dried and recrystallised from methanol to give the title compound as a cream crystalline solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH3:9].Br[C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)cnc1Br
Reactant: O=C(O)c1ccccc1Br
Product: Cc1cc(Nc2ccccc2C(=O)O)cnc1Br
Yield: 14 %

Procedure:
Obtained (0.17 g, yield 14%) following the procedure described in Intermediate 13 starting with 6-bromo-5-methylpyridin-3-amine (2.70 mmol, 0.5 g) and 2-bromobenzoic acid (4.03 mmol, 0.81 g).
Reaction SMILES: Cl[CH:2]([C:6](=[O:8])[CH3:7])[C:3](=[O:5])[CH3:4].[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)#[N:10].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[C:3]([CH:2]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=1)[C:6](=[O:8])[CH3:7])(=[O:5])[CH3:4]
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(=O)C(Cl)C(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(=O)C(Oc1ccc(C#N)cc1)C(C)=O
Temperature: 60 °C
Yield: 94 %

Procedure:
A mixture of commercially available 3-chloro-2,4-pentanedione (1.2 ml, 10 mmol), 4-cyanophenol (1.19 g, 10 mmol), caesium carbonate (3.25 g, 10 mmol) and acetone (50 ml) was heated at 60° C. for 4 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The resulting oil was diluted with dichloromethane (25 ml) and washed with 1M hydrochloric acid (30 ml). The aqueous layer, at pH 1, was extracted with dichloromethane (20 ml). The combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure to provide 4-(1-acetyl-2-oxopropoxy)benzonitrile (2.06 g, 9.4 mmol) which was used crude in the next step. 2-Hydroxyethyl hydrazine (169 μL, 2.5 mmol) was added to a stirred solution of a portion of the crude 4-(1-acetyl-2-oxopropoxy)benzonitrile (500 mg, 2.3 mmol) in acetic acid (5 ml) at room temperature under nitrogen, and the mixture was stirred at room temperature for 5 hours. Water (20 ml) was then added, and a solid triturated out and filtered off. This was recrystallised from ethyl acetate to provide the title compound (154 mg, 6%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>CO>[ClH:1].[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(-c2ccc(F)cn2)c(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cl
Product: O=C(O)c1cc(-c2ccc(F)cn2)c(Cl)cc1Cl
Temperature: 50 °C
Yield: 167.6 %

Procedure:
To a suspension of methyl 2,4-dichloro-5-(5-fluoropyridin-2-yl)benzoate (Preparation 34, 1 g, 3.33 mmol) in methanol (20 mL) was added 2M aqueous sodium hydroxide solution (3.3 mL, 6.66 mmol) and the reaction was heated at 50° C. for 1 hour. The reaction was concentrated in vacuo and the residue stirred with 2M aqueous hydrochloric acid (30 mL). The resulting precipitate was filtered, washed with water and dried in vacuo to afford the title compound as a white solid (900 mg, 84%).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C:11](=[O:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH2:32]([NH:35][CH2:36][CH:37]=[CH2:38])[CH:33]=[CH2:34]>C(Cl)Cl>[CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C:11](=[O:12])[C@@:7]2([CH3:31])[CH2:6]1)/[C:17](=[CH:18]\[N:35]([CH2:36][CH:37]=[CH2:38])[CH2:32][CH:33]=[CH2:34])/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[O:3]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: C=CCNCC=C
Solvent: ClCCl
Product: C=CCN(/C=C1/C(=O)O[C@H](COC)[C@@]2(C)C1=C(O)C(=O)C1=C2[C@H](OC(C)=O)C[C@]2(C)C(=O)CC[C@@H]12)CC=C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of wortmannin (10.7 mg, 25.0 μmol) in CH2Cl2 (125 μL) was added a freshly prepared 0.2 M stock solution of diallylamine (138 μL, 27.5 μmol) in CH2Cl2. The reaction mixture was stirred at room temperature for 1 h. The solvent and excess amine were removed in vacuo, and the product was purified via chromatography on SiO2 (hexanes/ethyl acetate, 1:9) to give PX-866 (9.0 mg, 17 μmol, 68%) as an orange oil. The product was analyzed by several experimental methods and shown to be of the correct structure and of high purity as: [α]D−630 (c 0.0015, CH2Cl2, 23° C.); IR (KBr) 3391, 1743, 1695, 1685, 1622, 1569, 1222, 1111, 1100 cm−1; 1H NMR δ 8.20 (s, 1H), 6.81 (s, 1H), 6.06 (dd, 1H, J=7.4, 4.8 Hz), 5.85 (br s, 1H), 5.62 (br, 1H), 5.44-5.04 (m, 4H), 4.48 (dd, 1H, J=7.2, 1.9 Hz), 4.05-3.60 (m, 4H), 3.26 (s, 3H), 3.27-3.20 (m, 1H), 3.16 (dd, 1H, J=10.9, 7.2 Hz), 3.00-2.90 (m, 2H), 2.59 (dd, 1H, J=19.4, 8.6 Hz), 2.40 (dd, 1H, J=14.4, 7.7 Hz), 2.35-2.07 (m, 2H), 2.07 (s, 3H), 1.83 (dd, 1H, J=14.4, 4.7 Hz), 1.54 (s, 3H), 0.86 (s, 3H); 13C NMR δ 217.0, 178.5, 169.6, 164.8, 156.3, 151.5, 139.0, 136.9, 132.2, 131.3, 127.7 (2C), 119.2, 89.0, 81.9, 73.1, 67.6, 59.1, 50.9 (2C), 48.9, 42.3, 42.2, 37.5, 36.0, 24.6, 22.2, 20.8, 16.1; MS (EI) m/z (rel. intensity) 525 (M+, 11), 466 (17), 391 (15), 350 (14), 323 (13), 266 (17), 239 (17), 60 (100); HRMS (EI) calculated for C29H35NO8 525.2363. found 525.2386.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.Br[CH2:19][CH2:20][O:21][CH2:22][CH2:23]Br.C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O>[O:21]1[CH2:22][CH2:23][N:1]([C@@H:2]2[CH2:6][CH2:5][C@H:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:3]2)[CH2:19][CH2:20]1
Reactant: N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)C1
Reactant: BrCCOCCBr
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CC[C@@H](N2CCOCC2)C1)OCc1ccccc1

Procedure:
A solution of EXAMPLE 111B (400 mg), 1-bromo-2-(2-bromoethoxy)ethane (0.246 mL), and triethylamine (0.595 mL) in N,N-dimethylformamide (6 mL) was stirred at 70° C. for 24 hours. The solution was cooled and poured into ethyl acetate (200 mL). The solution was extracted with 3× water, washed with brine, concentrated, and chromatographed on silica gel using 10% methanol/ethyl acetate to give the pure product.
Reaction SMILES: [CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=O)[CH:12]=2)[N:7]([CH3:17])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:18][C@@H:19]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[C:36]([F:41])[CH:35]=1)[C@H:20]([OH:32])[CH2:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH3:31])[CH:25]=1>C(Cl)Cl.O1CCCC1>[CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([NH:18][C@@H:19]([CH2:33][C:34]3[CH:35]=[C:36]([F:41])[CH:37]=[C:38]([F:40])[CH:39]=3)[C@H:20]([OH:32])[CH2:21][NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH3:31])[CH:25]=3)=[O:16])[CH:12]=2)[N:7]([CH3:17])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C)c2ccc(C(=O)O)cc12
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCc1cn(C)c2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc12
Temperature: 40 °C
Reaction time: 18 h
Yield: 31.1 %

Procedure:
To a mixture of 3-Butyl-1-methyl-1H-indole-5-carboxylic acid (0.15 g) in methylene chloride (5 mL) and tetrahydrofuran (10 mL) was added 1,1-carbonyldiimidazole (0.105 g). The mixture was stirred at 40° C. at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.2 g) in methylene chloride (5 mL) was added. The mixture was stirred at 40° C. for 18 h then poured into methylene chloride (50 mL). The mixture was washed with water then brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using 85:10:5 (methylene chloride: hexanes: methanol) as eluent to give 0.102 g of the title compound: MS (ESI+) for C33H39F2N3O2 m/z 547.9 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[C:11]([N:13]=[C:14]([NH2:16])[NH2:15])#[N:12].[OH-].[K+]>COCCO.O>[NH2:12][C:11]1[N:13]=[C:14]([NH2:16])[N:15]=[C:6]([C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([S:2][CH3:1])[CH:4]=2)[N:7]=1
Reactant: N#CN=C(N)N
Reactant: CSc1cccc(C#N)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCO
Product: CSc1cccc(-c2nc(N)nc(N)n2)c1

Procedure:
4.0 g of m-methylthiobenzonitrile, 2.7 g of dicyanodiamide and 2.0 g of caustic potash are dissolved in 20 ml of methyl cellosolve, and the mixture is refluxed for 4 hours. After cooling, the mixture is diluted with water and the separated crystals are recrystallized from dioxane. Melting point: 229°-230° C.; Yield: 3.4 g.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][N+:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6])[CH3:3].[F:14][C:15](F)=[CH:16]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>CN(C)C=O.O>[CH2:2]([O:4][C:5]([C:7]1[N:8]2[C:13]([CH:12]=[CH:11][CH:10]=[CH:9]2)=[CH:16][C:15]=1[F:14])=[O:6])[CH3:3]
Reactant: CCOC(=O)C[n+]1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC=C(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(F)cc2ccccn12
Temperature: 70 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a solution of 1-ethoxycarbonylmethylpyridinium bromide (4.8 g) in N, N-dimethylformamide (50 mL) were added toluene-4-sulfonic acid 2, 2-difluorovinyl ester (4.6 g), potassium carbonate (4.0 g) and triethylamine (3.0 g), and the mixture was stirred at 70° C. overnight. After cooling to room temperature, to the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give 2-fluoroindolizine-3-carboxylic acid ethyl ester (1.9 g). To a solution of the obtained. compound (1.9 g) in dichloromethane (30 mL) was added N-bromosuccinimide (1.8 g), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1 mol/L sodium thiosulfate aqueous solution, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give 1-bromo-2-fluoroindolizine-3-carboxylic acid ethyl ester (1.3 g). To a mixed solution of the obtained compound (1.3 g) in tetrahydrofuran (20 mL), ethanol (7 mL) and water (7 mL) was added lithium hydroxide monohydrate (0.29 g), and the mixture was stirred at room temperature overnight. To the reaction mixture were added 1 mol/L hydrochloric acid and water. The precipitated solid was collected by filtration, washed with water and n-hexane, and dried under reduced pressure at 50° C. to give 1-bromo-2-fluoroindolizine-3-carboxylic acid (0.76 g). To a suspension of the obtained compound (0.56 g) and quinoline (5 mL) was added copper (0.03 g), and the mixture was stirred at 220° C. for 30 minutes. After cooling to room temperature, to the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid, water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.47 g).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[O:21][C@H:20]3[C@H:16]([N:17]=[C:18]([N:22]4[CH2:25][CH2:24][CH2:23]4)[S:19]3)[C@@H:15]([OH:26])[C@@H:14]2[OH:27])(=O)=O)=CC=1.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:22]1([C:18]2[S:19][C@H:20]3[O:21][C@H:13]([CH2:12][NH:33][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[C@@H:14]([OH:27])[C@H:15]([OH:26])[C@H:16]3[N:17]=2)[CH2:23][CH2:24][CH2:25]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H]3SC(N4CCC4)=N[C@@H]3[C@@H](O)[C@@H]2O)cc1
Reactant: NC1CCCC1
Product: O[C@H]1[C@H](O)[C@@H](CNC2CCCC2)O[C@@H]2SC(N3CCC3)=N[C@H]12
Reaction time: 0.08 h
Yield: 11 %

Procedure:
A solution of ((3aR,5R,6S,7R,7aR)-2-(azetidin-1-yl)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl 4-methylbenzenesulfonate (350 mg, 0.85 mmol) in cyclopentanamine (3 mL) was heated to 50° C. for overnight. The reaction mixture was condensed under vacuum to give a residue, which was purified by Prep-HPLC with the following conditions [(Agilent 1200 prep HPLC): Column, x-Bridge 19*50 mm; mobile phase, Water with 0.05% NH4OH and CH3CN (15% CH3CN up to 28.6% in 5 min Flow rate 20 mL/min; Detector, UV 220 nm)] to give compound 5 as a light yellow solid (30 mg, 11%). (ES, m/z) [M+H]+ 328.0; 1H NMR (300 MHz, DMSO+D2O) 6.25-6.27 (d, J=6.3 Hz, 1H), 3.97 (m, 1H), 3.86 (m, 4H), 3.71 (m, 1H), 3.45 (m, 1H), 3.25 (m, 1H), 2.95 (m, 1H), 2.75 (m, 1H), 2.55 (m, 1H), 2.23 (m, 2H), 1.56-1.72 (m, 6H), 1.25 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](NC)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH2:16]([N:18](CC)CC)C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C1COCC1>[C:28]1([CH2:27][O:26][C:24](=[O:25])[NH:18][CH2:16][S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=2)(=[O:9])=[O:10])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 31.8 %

Procedure:
A solution of 4-fluoro-N-methyl-3-nitrobenzenesulfonamide (2 g, 8.54 mmol) in THF (20 mL) was treated with triethylamine (2.380 mL, 17.08 mmol) followed by dropwise addition of benzyl chloroformate (3.75 mL, 11.10 mmol). The mixture was stirred at 25° C. for 5 hours before being concentrated. The residue was treated with water and extracted with CH2Cl2. The organic extracts were washed (brine), dried (sodium sulfate), concentrated, and subjected to flash chromatography (25-50% EtOAc-hexanes) to give a yellow solid, which was suspended in EtOAc-hexanes, collected by filtration, and washed with hexanes to give phenylmethyl[(4-fluoro-3-nitrophenyl)sulfonyl]methylcarbamate (1 g, 32%) as a white solid. MS (m/z) 391.0 (M+Na+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]#[N:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=[CH:30][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N-:35]=[N+:36]=[N-:37].[Na+].[Cl-].[NH4+]>CN(C=O)C.CCOC(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[N:35]=[N:36][NH:37][N:26]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:27]=[C:28]([C:31]([F:33])([F:34])[F:32])[CH:29]=[CH:30][C:16]=3[CH2:15]2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C#N)cc32)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(-c4nn[nH]n4)cc32)cc1
Temperature: 130 °C

Procedure:
A mixture of 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbonitrile (intermediate 54, 26 mg, 0.0534 mmol), sodium azide (17.4 mg, 0.267 mmol), and ammonium chloride (14.3 mg, 0.267 mmol) in DMF (1 mL) was heated in a microwave reactor at 130° C. for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, and organic layer was separated, washed with aqueous NaHCO3, water, brine, dried over MgSO4 and concentrated. The residue was purified via reverse phase HPLC to provide the title compound. LC/MS: m/e 530.0 (M+H)+. 1H NMR (500 MHz, CD3OD): δ 8.15 (1H, s), 7.88 (1H, d), 7.65 (1H, d), 7.10-7.20 (4H, m), 6.93 (2H, d), 4.60-5.00 (2H, br s), 1.25 (9H, s).
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][CH2:7][C:8]([CH3:16])([CH3:15])[CH2:9]OS(C)(=O)=O)([CH3:4])([CH3:3])[CH3:2].[C-:19]#[N:20].[K+].O>CS(C)=O>[C:1]([Si:5]([CH3:18])([CH3:17])[O:6][CH2:7][C:8]([CH3:16])([CH3:15])[CH2:9][C:19]#[N:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)COS(C)(=O)=O
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(CC#N)CO[Si](C)(C)C(C)(C)C
Temperature: 120 °C
Yield: 57.6 %

Procedure:
To the solution of methanesulfonic acid 3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propyl ester (5 g, 16.8 mmol) in anhydrous dimethyl sulfoxide (50 mL) was added KCN (2.85 g, 44 mmol). The reaction mixture was heated at 120° C. for 16 h. The mixture was cooled, and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1; 4) to give 4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butyronitrile as a yellow oil (2.2 g, 57%).