Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH:8]2[O:13][CH2:12][CH2:11][O:9]2)=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1
Reactant: OCCO
Reactant: O=Cc1c(Cl)ncnc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Clc1ncnc(Cl)c1C1OCCO1
Yield: 82.5 %

Procedure:
Compound 4,6-Dichloro-pyrimidine-5-carbaldehyde (8.6 g, 0.049 mmol), anhydrous ethylene glycol (8.2 ml) and p-Toluene-sulfonic acid (150 mg) were mixture in benzene (200 mL) and heated under reflux for 3 hours. Concentrate under high vacuum, worked up with chloroform, water, sodium bicarbonate and sodium chloride, concentrate. The reaction mixture was purified on silica (CH2Cl2) to give 4,6-Dichloro-5-[1,3]dioxolan-2-yl-pyrimidine (8.86 g, 82.5%). 1H NMR 400 MHz CDCl3 δ(ppm): 8.8 (s, 1H), 6.3 (s, 1H), 4.3 (m, 2H), 4.1 (m, 2H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].Br[CH2:12][CH2:13][Cl:14]>>[Cl:14][CH2:13][CH2:12][C:3]([CH2:9][CH3:10])([CH2:1][CH3:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: ClCCBr
Reactant: CCOC(=O)C(CC)CC
Product: CCOC(=O)C(CC)(CC)CCCl

Procedure:
Using ethyl 2-ethylbutyrate and 1-bromo-2-chloroethane, the title compound was produced in the same manner as in Reference Example 6.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([CH:14]=[O:15])[N:10]=[CH:11]2)=[CH:6][CH:5]=1.CC[OH:18].Cl>O.[N+]([O-])([O-])=O.[Ag+]>[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([C:14]([OH:18])=[O:15])[N:10]=[CH:11]2)=[CH:6][CH:5]=1
Reactant: CCO
Reactant: O=Cc1cc2ccc(Cl)cc2cn1
Agent: [Ag+]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: O=C(O)c1cc2ccc(Cl)cc2cn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To 4.5 mL of a 1N NaOH solution at 0° C. is added a solution of AgNO3 (0.31 g, 1.8 mmol) in 3 mL of H2O, followed by a solution of of 7-chloro-isoquinoline-3-carbaldehyde (0.25 g, 1.3 mmol) in 3 of EtOH. The solution is stirred at 0° C. for 10 minutes, then at room temp. For 3 hours. The solution is acidified to pH=3 with 1H HCl. The resulting solution is extracted with CHCl3. The organic layer is dried over MgSO4, filtered and concentrated to give the product as a white solid (0.2 g, 0.96 mmol). 1H NMR (CD3OD, 300 MHz) δ9.18 (s, 1H), 8.63 (s, 1H), 8.18 (m, 1H), 7.80 (m, 2H), 6.94 (m, 1H), 4.15 (q, 2H), 3.48 (s, 2H), 1.20 (t, 3H). MS (EI): m/z 208, 210 (M+), Cl pattern.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:18])[N:3]=1.[CH2:19]([N:21]([CH2:26][CH3:27])[CH2:22][CH2:23][CH2:24][NH2:25])[CH3:20]>O1CCOCC1>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:6]2[CH:5]=[C:4]([Br:18])[N:3]=[C:2]([NH:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:26][CH3:27])[CH2:19][CH3:20])[CH:7]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: CCN(CC)CCCN
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Solvent: C1COCCO1
Product: CCN(CC)CCCNc1cc(S(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
0.20 g (0.00051 mol) of 4-(2,6-dibromopyridine-4-sulphonyl)-phenylamine was dissolved in 10 ml of dioxane and treated with 8.0 ml of 3-diethylamino-1propylamine. The mixture was stirred at room temperature for 18 hrs., the solvent was removed and the residue was chromatographed twice on silica gel, firstly with 20% methanol in dichloromethane and then with 10% methanol in dichloromethane. There was obtained 0.09 g (41%) of N-[4-(4-aminobenzenesulphonyl)-6-bromopyridin-2-yl]-N',N'-diethylpropane-1,3-diamine as a pale yellow, amorphous solid. MS (ISP): me/e=443, 441 (C18H26BrN4O2S+).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[C:48]2[C:43](=[C:44]([CH3:49])[CH:45]=[CH:46][CH:47]=2)[NH:42][CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[I:52][C:53]1[CH:60]=[CH:59][C:56]([CH2:57]Br)=[CH:55][CH:54]=1.Cl>CN(C)C=O>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:11][C@H:10]1[C:40]1[C:48]2[C:43](=[C:44]([CH3:49])[CH:45]=[CH:46][CH:47]=2)[N:42]([CH2:57][C:56]2[CH:59]=[CH:60][C:53]([I:52])=[CH:54][CH:55]=2)[CH:41]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccc(I)cc1
Reactant: Cc1cccc2c([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c[nH]c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc2c([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cn(Cc3ccc(I)cc3)c12
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-7-methyl-1H-indole (1.18 g) in N,N-dimethylformamide (10 mL) was added 55% sodium hydride (87 mg) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. To this mixture was added 4-iodobenzyl bromide (0.62 g) at the same temperature, and the mixture was stirred at the same temperature for 15 minutes, and stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1-3/1) to give 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1-(4-iodo-benzyl)-7-methyl-1H-indole (1.48 g). A mixture of 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1-(4-iodobenzyl)-7-methyl-1H-indole (1.06 g), acrylic acid (0.18 g), palladium(II) acetate (14 mg), tris(2-methylphenyl)phosphine (37 mg), triethylamine (2 mL) and acetonitrile (2 mL) was stirred at 80° C. under an argon atmosphere overnight. The reaction mixture was diluted with diethyl ether, and the mixture was stirred at room temperature for 10 minutes. The insoluble material was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1-1/3) to give the title compound (0.85 g).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]1[NH:18][C:19]([C:21]1[NH:25][C:24]2[C:26]([Cl:30])=[C:27]([Cl:29])[S:28][C:23]=2[CH:22]=1)=[O:20].CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:29][C:27]1[S:28][C:23]2[CH:22]=[C:21]([C:19]([NH:18][C@@H:10]3[CH2:11][C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C@H:9]3[NH:8][S:39]([CH3:38])(=[O:41])=[O:40])=[O:20])[NH:25][C:24]=2[C:26]=1[Cl:30]
Reactant: N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 13.5 %

Procedure:
N-[(1R,2R)-1-Amino-2,3-dihydro-1H-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide trifluoroacetate salt (Method 8, 223 mg, 0.5 mmol) was dissolved in THF (4 mL) and the solution cooled to 0° C. Et3N (223 μL, 1.6 mmol) then methanesulfonyl chloride (43 μL, 0.55 mmol) were added and the reaction was stirred 0° C. for 5 mins. Saturated aqueous NaHCO3 (5 mL) was added, the phases separated and the aqueous phase extracted with EtOAc (3×10 mL). The combined organic fractions were washed with H2O (20 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was subjected to purification by reverse phase preparative HPLC to afford the title compound (30 mg, 15%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:12][CH2:11][CH2:10][Br:9])=[CH:4][CH:3]=1
Reactant: BrCCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: BrCCCCOc1ccc(Br)cc1

Procedure:
A solution of 4-bromophenol (3 g) and 1,4-dibromobutane (6.2 ml) in N,N-dimethylformamide (30 ml) was treated with potassium carbonate (2.89 g) at room temperature for 27 hours. The mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography (25:1 hexane-ethyl acetate elution) to give 1-bromo-4-(4-bromobutoxy)benzene (3.09 g).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:5]1.Cl[C:20]1[N:25]=[C:24]([C:26]2[C:27]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)=[N:28][N:29]([CH3:31])[CH:30]=2)[CH:23]=[CH:22][N:21]=1>C(O)CCC.O1CCOCC1>[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([NH:18][C:20]3[N:25]=[C:24]([C:26]4[C:27]([C:32]5[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=5)=[N:28][N:29]([CH3:31])[CH:30]=4)[CH:23]=[CH:22][N:21]=3)[CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:5]1
Reactant: Cc1ccc(-c2nn(C)cc2-c2ccnc(Cl)n2)cc1
Reactant: CN1CCC(COc2cccc(N)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCO
Product: Cc1ccc(-c2nn(C)cc2-c2ccnc(Nc3cccc(OCC4CCN(C)CC4)c3)n2)cc1

Procedure:
3-(1-Methyl-piperidin-4-ylmethoxy)-phenylamine dihydrochloride (206 mg, 0.7 mmol) is suspended in 1.5 mL n-butanol and 1.5 mL dioxane. 2-Chloro-4-(1-methyl-3-p-tolyl-1H-pyrazol-4-yl)-pyrimidine (100 mg, 0.35 mmol) is added and the mixture heated under reflux for 15 h. The yellow suspension is evaporated to dryness and the residue portioned between 8 mL 20% potassium carbonate solution and 10 mL dichloromethane. The organic phase is dried with sodium sulfate and evaporated. The crude product is purified by flash-chromatography on Silica Gel using dichloromethane/methanol 100:1.25→100:5 and then dichloromethane/methanol/conc. ammonia 100:5:0.25→100:10:0.25. The title compound is obtained as a foam.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[C:8]([CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C)([O-])C.[Na+]>CS(C)=O>[CH2:17]([O:16][CH2:15][CH2:14][CH2:13][O:10][C:9]1[C:2]([OH:1])=[C:3]([CH:6]=[CH:7][C:8]=1[CH3:11])[CH:4]=[O:5])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCCCOCc1ccccc1
Reactant: Cc1ccc(C=O)c(O)c1O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(C=O)c(O)c1OCCCOCc1ccccc1

Procedure:
Synthesized according to the methods of general procedure 4 in U.S. Pat. Pub. No. 20090227541 (U.S. patent application Ser. No. 12/142,692) using the following reactants and amounts: 2,3-dihydroxy-4-methyl-benzaldehyde (9 g, 59.21 mmol), (3-bromo-propoxymethyl)-benzene (11.5 mL, 65.13 mmol), sodium tert-butoxide (12.52 g, 130.26 mmol) and DMSO (100 mL). Purification: flash column chromatography (5-10% EtOAc/hexane): yield 15.1 g (85%). 1H NMR (400 MHz, CDCl3) δ (ppm): 11.05 (s, 1H), 9.84 (s, 1H), 7.38-7.26 (m, 5H), 7.20 (d, J=7.8 Hz, 1H), 6.80 (d, J=8.2 Hz, 1H), 4.55 (s, 2H), 4.15 (t, J=6.2 Hz, 2H), 3.73 (t, J=6.2 Hz, 2H), 2.31 (s, 3H), 2.19-2.00 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:45]=[CH:44][C:7]([CH2:8][O:9][C:10]([O:12][CH:13]([CH:15]2[C:21](=[O:22])[N:20]3[CH:16]2[CH2:17][C:18]([S:36]([C:38]2N=CC=CN=2)=O)=[C:19]3[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH2:46]>ClCCl.[Cl-].C([N+](C)(C)CCCCCCCCCCCCCCCC)C1C=CC=CC=1>[C:19]([NH:20]/[CH:16]=[CH:38]\[S:36][C:18]1[CH2:17][CH:16]2[N:20]([C:21](=[O:22])[CH:15]2[CH:13]([O:12][C:10]([O:9][CH2:8][C:7]2[CH:44]=[CH:45][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:11])[CH3:14])[C:19]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(=[O:46])[CH3:18]
Reactant: CC(OC(=O)OCc1ccc([N+](=O)[O-])cc1)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S(=O)c3ncccn3)CC12
Reactant: O
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)N/C=C\SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(C(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C2C1
Reaction time: 0.42 h
Yield: 52 %

Procedure:
p-Nitrobenzyl(5RS,6SR)-6-[(1RS)-1-p-nitrobenzyloxycarbonyloxyethyl]-3-(2-pyrimidylsulphinyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (230 mg) in dichloromethane (25 ml) was treated with benzyldimethyl-n-hexadecylammonium chloride (12 mg), cooled in an ice-bath, and treated with sodium Z-2-acetamidoethenylthiolate (contanimated by 1 molar equivalent NaCl) (77 mg) in water (25 ml). After stirring vigorously for 25 min. the layers were separated, and the dichloromethane layer was washed with dilute aqueous NaHCO3, followed by brine. After drying (MgSO4) the solution was evaporated in vacuo and the residue was chromatographed on silica gel (230-400 mesh ASTM), eluting with ethyl acetate to give the title compound (118 mg, 52% yield).
Reaction SMILES: [CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[C:25]([CH:40]=[CH:41][CH:42]=4)[CH2:26][CH:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)[CH:21]=3)[NH:16][CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>Cl.CO>[CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:42]=[CH:41][CH:40]=[C:25]([CH2:26][CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(-c3cnc4[nH]cc(-c5cnn(CCc6ccccc6)c5)c4c3)c2)CC1
Agent: Cl
Solvent: CO
Product: c1ccc(CCn2cc(-c3c[nH]c4ncc(-c5cccc(CC6CCNCC6)c5)cc34)cn2)cc1
Yield: 40.9 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(3-(3-(1-phenethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzyl)piperidine-1-carboxylate (60 mg, 0.106 mmol) was deprotected in HCl in methanol (5 ml). This afforded 20 mg (32.4% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.65-8.60 (bs, 1H), 8.52 (s, 1H), 7.92 (s, 1H), 7.87 (s, 1H), 7.74 (s, 1H), 7.61-7.58 (d, 2H), 7.53-7.41 (t, 1H), 7.33-7.26 (d, 1H), 7.26-7.22 (t, 2H), 7.15-7.09 (m, 3H), 4.49-4.45 (t, 2H), 3.41-3.38 (d, 2H), 3.22-3.18 (t, 2H), 2.99-2.93 (t, 2H), 2.77-2.76 (d, 2H), 2.01-1.90 (m, 3H), 1.56-1.46 (m, 2H). MS: m/z=462.7 (M+1), HPLC: 88.14% in method A.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH3:16][O:17][CH2:18][CH2:19]Br.C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][O:13][CH2:19][CH2:18][O:17][CH3:16])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CO)CCCCC1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(COCCOC)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
1-Hydroxymethyl-cyclohexanecarboxylic acid ethyl ester (2.0 g, 10.9 mmol) is added to a solution of 60% sodium hydride (0.86 g, 21.7 mmol) in 5.0 mL of DMF at 0° C. and the reaction mixture is stirred for 30 minutes; 2-bromoethyl methyl ether (3.0 g, 21.7 mmol) is added over a period of 10 minutes and then the reaction mixture is stirred at room temperature for 14 h. Ice water and 20% ethyl acetate in petroleum ether are added. The two phases are separated and the organic layer is washed with water and brine and dried over Na2SO4. After filtration the solvent is removed under reduced pressure to provide 2.0 g of the title compound as a yellow liquid that is used in the next step without further purification. m/z 245 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.[F-].[K+].C1([S:24][CH:25]([N:30]=[C:31]=S)[Si](C)(C)C)C=CC=CC=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([C:7]2[O:8][C:25]([SH:24])=[N:30][CH:31]=2)=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1
Reactant: C[Si](C)(C)C(N=C=S)Sc1ccccc1
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CC#N
Product: COc1cc(-c2cnc(S)o2)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
4,5-Dimethoxy-2-nitrobenzaldehyde (1.52 g, 7.19 mmol), 353.0 mg (6.07 mmol) of potassium fluoride, and 134.8 mg (0.59 mmol) of benzyltriethylammonium chloride were added to a solution of 1.51 g (5.97 mmol) of phenylthio(trimethylsilyl)methyl isothiocyanate, synthesized according to a document (J. Chem. Soc., Perkin Trans 1 1984, 435.), in acetonitrile (36 ml), and the mixture was stirred at room temperature overnight. The solvent was removed from the reaction solution by distillation, and the water and chloroform were then added to the residue. The aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1→1:1) to give 302.4 mg (yield 18%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:11][N:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.[NH2:62][C@@H:63]([CH2:77][C:78]1[CH:83]=[C:82]([F:84])[CH:81]=[C:80]([F:85])[CH:79]=1)[C@H:64]([OH:76])[CH2:65][NH:66][CH2:67][C:68]1[CH:73]=[CH:72][CH:71]=[C:70]([CH2:74][CH3:75])[CH:69]=1.[ClH:86]>C(Cl)Cl.CO.C(OCC)C>[ClH:86].[ClH:86].[F:84][C:82]1[CH:83]=[C:78]([CH:79]=[C:80]([F:85])[CH:81]=1)[CH2:77][C@H:63]([NH:62][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([CH2:11][N:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:10]=[C:2]([CH3:1])[CH:3]=1)[C@H:64]([OH:76])[CH2:65][NH:66][CH2:67][C:68]1[CH:73]=[CH:72][CH:71]=[C:70]([CH2:74][CH3:75])[CH:69]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCCN(C)Cc1cc(C)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCN(C)Cc1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 3-methyl-5-{[methyl(pentyl)amino]methyl}benzoic acid (110 mg, 0.44 mmol) in methylene chloride (3 mL) is added HBTU (250 mg, 0.66 mmol), HOBt (90 mg, 0.66 mmol), and N,N-diisopropylethylamine (0.222 mL, 1.32 mmol), followed by (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol prepared by the method of Example SP-272 (180 mg, 0.44 mmol), and the reaction mixture is stirred for 12 h at room temperature. The reaction mixture is diluted with methylene chloride, washed with water, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 10% methanol/chloroform) affords a clear oil, which is dissolved in methanol (2 mL). To this solution is added hydrochloric acid (5 mL, 4 N dioxane, 20 mmol), and the reaction mixture is stirred for 1 h at room temperature. The reaction mixture is then diluted with ethyl ether (10 mL). The precipitate that is formed is collected by filtration to provide the title compound. ESI MS m/z 566.5 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][B:5]([OH:7])[C:4]2[CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=[CH:11][C:3]1=2.Cl.C(Cl)Cl.CO>CO.[Zn]>[NH2:12][C:9]1[CH:10]=[CH:11][C:3]2[C:2]([CH3:1])([CH3:15])[O:6][B:5]([OH:7])[C:4]=2[CH:8]=1
Reactant: CC1(C)OB(O)c2cc([N+](=O)[O-])ccc21
Agent: Cl
Agent: [Zn]
Solvent: CO
Solvent: ClCCl
Product: CC1(C)OB(O)c2cc(N)ccc21
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 60.3 %

Procedure:
To a solution of 1.20 g of 3,3-dimethyl-6-nitrobenzo[c][1,2]oxaborol-1(3H)-ol (XCVII) (1.20 g, 5.8 mmol) in MeOH (30 mL) was added 3M aqueous HCl (30 mL), and the mixture was cooled to 0° C. To this mixture was added portion-wise zinc dust (3.77 g, 0.058 mol), maintaining the temperature below 5° C. The mixture was stirred for 40 min at room temperature. A gray solid was removed by filtration through a Celite pad. The filtrate was concentrated in vacuo and the residue was dissolved in EtOAc and stirred. 1M aqueous K2CO3 was added to pH=7 and stirring was continued for 10 min. The two phases were separated and the aqueous layer was extracted with EtOAc. The combined organic phases were dried over MgSO4 filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography using DCM then DCM/MeOH 500/1→300/1→200/1→100/1 to give 6-amino-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (XCVIII) as an orange solid (0.62 g, 3.5 mmol, yield 60%). 1H NMR (DMSO-d6) δ ppm 1.46 (s, 6H), 7.43 (dd, J=8 Hz, J=2 Hz, 1H), 7.55 (d. J=8 Hz, 1H), 7.67 (d, J=2 Hz, 1H), 9.95-10.72 (brs, 3H) ESIMS found for C9H12BNO2 m/z 178.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:14]=1[NH2:15])([O-:12])=[O:11].C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N+:10]([C:13]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)([O-:12])=[O:11]
Reactant: Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: N#Cc1ccc(Br)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: N#Cc1ccc(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
4-bromobenzonitrile (218 mg, 1.2 mmol), 2-nitro-4-(trifluoromethyl)aniline (206 mg, 1.0 mmol), Pd2dba3 (23 mg, 0.025 mmol), PCy2dmab (30 mg, 0.075 mmol), and Cs2CO3 (489 mg) are added to a round bottom flask. The flask is evacuated and filled with nitrogen two times and then left under vacuum for 5 min. After filling with nitrogen, toluene (4 mL Sureseal, degassed with nitrogen for 20 min) is added via syringe and the resultant dark red/black solution is heated to 100° C. with an oil bath. After 18 hr, the solution is cooled to room temperature and excess ethyl acetate is added. After washing with 1M HCl two times, the organic layer is washed with brine, dried over MgSO4, filtered through Celite, and concentrated to give crude material. This solid was purified by flash chromatography to afford 4-{[2-nitro-4-(trifluoromethyl)phenyl]amino}benzonitrile. The yield is 288 mg (94%).