Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:9]([O:10][CH2:11][CH2:12][CH3:13])=[CH:8][S:7][CH:6]=1)CC.C(O)C(O)CC[CH2:18][CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[O:10]1[CH:11]([CH2:12][CH2:13][CH2:18][CH2:19][OH:20])[CH2:1][O:4][C:5]2=[CH:6][S:7][CH:8]=[C:9]12
Reactant: CCCOc1cscc1OCCC
Reactant: OCCCCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: OCCCCC1COc2cscc2O1

Procedure:
9.06 g (45.2 mmol) of 3,4-di-n-propoxythiophene, 30.3 g (226 mmol) of 1,2,6-hexanetriol and 0.09 g (0.5 mmol) of p-toluenesulphonic acid are heated to 150 to 165° C. (bath temperature) under N2 for 3 h. During this time, 5.8 g of distillate (substantially n-propanol) were collected. The cooled liquid was diluted with 50 ml of methylene chloride, washed to neutrality and to free it of hexanetriol with water and the organic phase was dried over Na2SO4. After filtering and evaporating the methylene chloride, the residue (6.73 g=74.8% of theory) was identified by 1H NMR spectroscopy (in CDCl3 against TMS) using δ=6.30 ppm (2H, thiophene H) and 2.85 ppm (1H, OH) as being substantially 4-(2,3-dihydrothieno[3,4-b][1,4]dioxin-2-yl)-1-butanol.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[O:21][CH:9]3[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13][C:8]3([CH3:22])[C:6]=2[CH:7]=1.CC(C)([O-])C.[Na+].C(O)CO.CN(C)C=O.[C:38]1([SH:44])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>[Cu]I>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][C:8]2([CH3:22])[C:6]3[CH:7]=[C:2]([S:44][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:3]=[CH:4][C:5]=3[O:21][CH:9]2[CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: Sc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(C)c3cc(I)ccc3OC2C1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: OCCO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(C)c3cc(Sc4ccccc4)ccc3OC2C1
Temperature: 120 °C

Procedure:
Into a sealed tube was added tert-butyl 6-iodo-4a-methyl-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate P24 (0.491 g, 1.18 mmol), sodium tert-butoxide (341 mg, 3.55 mmol), copper (I) iodide (20 mg, 0.08 mmol), 1,2-ethanediol (132 μL, 2.38 mmol), N,N-dimethylformamide (17 mL, 210 mmol), and benzenethiol (123 μL, 1.19 mmol). The reaction was heated at 120° C. overnight. The reaction was concentrated and partitioned between DCM and water. The DCM layer was washed with brine, dried, filtered and concentrated under vacuum. The crude product was dissolved in DCM and purified on a 12 g silica gel column eluting with hexanes to 2:1 hexanes:ethyl acetate to give the product which was taken directly into the next step.
Reaction SMILES: C[O:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]3[C:12]([CH2:13][CH2:14][C:5]=2[CH:4]=1)=[N:11][NH:10][C:9](=[O:15])[CH:8]=3.B(Br)(Br)Br.[NH4+].[Cl-]>C(Cl)Cl>[OH:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]3[C:12]([CH2:13][CH2:14][C:5]=2[CH:4]=1)=[N:11][NH:10][C:9](=[O:15])[CH:8]=3
Reactant: COc1ccc2c(c1)CCc1n[nH]c(=O)cc1-2
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: O=c1cc2c(n[nH]1)CCc1cc(O)ccc1-2
Temperature: 25 °C

Procedure:
In a 100 mL round bottom flask, 8-methoxy-5,6-dihydro-3H-benzo[f]cinnolin-2-one (1.05 g, 4.61 mmol) in methylene chloride (3 mL) was cooled to 0° C. Boron tribromide (23 ml of a 1M sol. in methylene chloride) was added and the reaction warmed to ambient temperature for 4 h. Re-cooled to 0° C. and sat. NH4Cl sol. (23 mL) was added. The solvents were removed under vacuum and water was added. Solids were filtered off and washed with cold methanol to produce 587 mg (59%). Mp>300° C. MS m/z 215 (M+H).
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:19]1[CH2:23][CH:20]1[CH2:21][OH:22]>>[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([NH:16][CH2:23][CH:20]([OH:19])[CH2:21][OH:22])=[CH:17][CH:18]=3)[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(C2=NOC(c3ccccc3)N2)cc1
Reactant: OCC1CO1
Product: OCC(O)CNc1ccc(C2=NOC(c3ccccc3)N2)cc1

Procedure:
0.9 g of 3-[4-(5-phenyl-1,2,4-oxadiazolin-3-yl)phenyl]-5-[4-(2-ethoxycarbonyl-2-N-butylsulfonyl-aminoethyl)phenoxymethyl]-2-oxazolidinone [obtainable as in Example 1 by reacting 4-(5-phenyl-1,2,4-oxadiazolin-3-yl)aniline with 2,3-epoxy-1-propanol to give N-[4-(5-phenyl-1,2,4-oxadiazolin-3-yl)phenyl]-2,3-dihydroxypropylamine, reacting with diethyl carbonate in the presence of tert-butoxide to give 3-[4-(5-phenyl-1,2,4-oxadiazolin-3-yl)phenyl]-5-hydroxymethyl-2-oxazolidinone, esterifying with methanesulfonyl chloride and reacting with Na p-(2-ethoxycarbonyl-2-N-butylsulfonylaminoethyl)phenolate] is dissolved in 50 ml of methanol and hydrogenated on Raney nickel. The reaction mixture is subsequently filtered and the filtrate is concentrated in vacuo. The resulting product is treated with 20 ml of hot ethyl acetate and, after cooling, filtered off with suction. 3-[4-(N-benzoylamidino)phenyl]-5-[4-(2-ethoxycarbonyl-2-N-butylsulfonylaminoethyl)phenoxymethyl]-2-oxazolidinone is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8](Cl)[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][S:14](=[O:17])[CH2:13][CH2:12]2)[C:5]=1[N+:18]([O-:20])=[O:19])[CH3:2].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.O>C(O)C>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][S:14](=[O:17])[CH2:13][CH2:12]2)[C:5]=1[N+:18]([O-:20])=[O:19])[CH3:2]
Reactant: C1CNCCN1
Reactant: CCOc1nc(Cl)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]
Solvent: O
Solvent: CCO
Product: CCOc1nc(N2CCNCC2)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]

Procedure:
12 gm (0.037 mol) of 6-ethoxy-2-chloro-5-nitro-4-(1-oxido-thiomorpholino)-pyrimidine were stirred together with 22 gm (0.28 mol) of piperazine in ethanol at 40°C for 2 hours. Then, the reaction mixture was poured into water, and the precipitate formed thereby was suction-filtered off and recrystallized from ethanol. Yield: 13 gm (93.8% of theory); m.p. 223°-224°C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:11]([O:13][C:14](=[O:30])[CH2:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21](Cl)=[N:22][CH:23]=[N:24]2)=[CH:19][C:18]=1[O:28][CH3:29])[CH3:12]>>[CH2:11]([O:13][C:14](=[O:30])[CH2:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21]([N:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3][CH2:2]3)=[N:22][CH:23]=[N:24]2)=[CH:19][C:18]=1[O:28][CH3:29])[CH3:12]
Reactant: CCOC(=O)COc1cc2ncnc(Cl)c2cc1OC
Reactant: c1ccc2c(c1)CCCN2
Product: CCOC(=O)COc1cc2ncnc(N3CCCc4ccccc43)c2cc1OC
Yield: 2 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 2% yield from 1,2,3,4-tetrahydroquinoline and (4-chloro-6-methoxy-quinazolin-7-yloxy)-acetic acid ethyl ester. (film; LC-MS: 393 (MH+)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH3:30][CH:31]1[CH2:36][NH:35][CH2:34][CH:33]([CH3:37])[N:32]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:29]=[CH:28][C:25]([CH2:26][N:35]3[CH2:36][C@@H:31]([CH3:30])[N:32]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[C@H:33]([CH3:37])[CH2:34]3)=[CH:24][CH:23]=2)=[CH:6][CH:7]=1
Reactant: CC1CNCC(C)N1C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)C[C@@H](C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
A mixture of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (200 mg, 520 mmol), tert-butyl 2,6-dimethylpiperazine-1-carboxylate (335 mg, 1.56 mmol) in methylene chloride (10 mL) was stirred at room temperature overnight, then NaBCNH3 (129 mg, 2.08 mmol) was added and the mixture was stirred for another 5 hours. After removal of solvents, the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3:1 to 1:1) to give the title compound (72 mg, 24%). LC-MS (ESI) m/z: 584 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:10])=[CH:4][C:5]([NH2:9])=[C:6]([NH2:8])[CH:7]=1.Cl.[CH:12](OCC)(OCC)OCC>C(O)C>[Cl:1][C:2]1[C:3]([I:10])=[CH:4][C:5]2[NH:9][CH:12]=[N:8][C:6]=2[CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1cc(Cl)c(I)cc1N
Agent: Cl
Solvent: CCO
Product: Clc1cc2nc[nH]c2cc1I
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-chloro-4-iodo-1,2-phenylenediamine 1-6 (8.00 g, 29.8 mmol), 2.48 mL of 12 M HCl (29.8 mmol), triethyl orthoformate (39.7 mL, 238.4 mmol) in 30 mL ethanol was split evenly between four 20 mL reaction vials; the vials were sealed and stirred at 130° C. for 10 min each. After cooling to rt, the resulting solids were collected by filtration and washed with ethanol. Then the isolated solid was dissolved in 250 mL of water by heating to 80° C. To this solution was added slowly 25 mL of saturated aqueous NaHCO3. The mixture was confirmed to have a pH >8, and then cooled in an ice-bath. The resulting white solid was collected by filtration and then dissolved in 3:1 CH2Cl2/methanol, dried (MgSO4) and evaporated. The resulting solid was sonicated with CH2Cl2 and evaporated (2×) to provide 6-chloro-5-iodobenzimidazole 1-7 as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 7.87 (br s, 1H), 8.17 (br s, 1H), 8.28 (s, 1H), 12.66 (br s, 1H); LC-MS: calculated for C7H4ClIN2 277.9, observed m/e 279.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([CH:14]=1)[O:7][CH2:8][C:9](OCC)=[O:10]>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:15][C:9](=[O:10])[CH2:8][O:7][C:6]=2[CH:14]=1
Reactant: CCOC(=O)COc1cc(F)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1COc2cc(F)ccc2N1
Temperature: 80 °C
Yield: 62.6 %

Procedure:
Iron powder (36.42 g) was suspended in 5% aqueous acetic acid (69 ml) and heated to 80° C. To the suspension, a solution of ethyl 5-fluoro-2-nitrophenoxyacetate (15.86 g) in acetic acid (65 ml) and ethyl acetate (65 ml) was dropwise added, and the resultant mixture was heated at 60° to 80° C. under reflux for 3 hours. After removal of residue by filtration, the filtrate was extracted with ethyl acetate. The extract was washed with water and sodium bicarbonate solution, dried and concentrated to give 7-fluoro-2H-1,4-benzoxazin-3(4H)-one (6.82 g). m.p., 186.7° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>N1C=CC=CC=1>[C:2]1([CH3:1])[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([NH:12][C:13]2[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])(=[O:10])=[O:9])[CH:3]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1cccc(C)c1
Yield: 90.5 %

Procedure:
Prepared according to the procedure described for Example 121 using 3-methylbenzenesulfonyl chloride (1.91 g, 10 mmol), 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10 mmol), and pyridine (25 mL) to afford the product (3.587 g); m.p. 195-197° C. after trituration in hexanes/ethyl acetate (1:1).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])=[CH:23][CH:22]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: COc1ccc(-c2ocnc2C(=O)O)cc1
Product: COc1ccc(-c2ocnc2C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)c2)cc1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(4-methoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[N:14]([CH3:25])[C:15]1[CH:20]=[N:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:25][N:14]([C:15]1[CH:20]=[N:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][N:16]=1)[C@H:10]1[CH2:11][CH2:12][CH2:13][C@@H:9]1[NH2:8]
Reactant: [H][H]
Reactant: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1N

Procedure:
To a solution of (1S,2S)-1-N,1-N-dibenzyl-2-N-methyl-2-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (285 mg, 0.647 mmol) in ethyl acetate (2 ml) and ethanol (1 ml) was added palladium on carbon (10% wt, 50% wet, 100 mg, 0.094 mmol). The resulting mixture was stirred under a balloon of hydrogen gas for 18 hours. The reaction was filtered through diatomaceous earth (commercially sold under the trade mark “Celite”) and concentrated in vacuo to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([CH3:13])[CH2:11]O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([CH3:13])[CH2:11][N:18]2[C:14](=[O:24])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17]2=[O:19])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[C@@H](CO)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](CN1C(=O)c2ccccc2C1=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
A 250 mL three necked round bottom flask equipped with a mechanical stirrer, addition funnel, thermometer, and a reflux condenser is charged with (2R)-2-(4-nitrophenyl)propan-1-ol (2.0 g, 11.04 mmol), phthalimide (1.62 g, 11.04 mm), triphenylphosphine (4.3 g, 16.59 mmol) and THF (50.0 mL) at room temperature. To this solution was added DEAD (2.6 mL, 16.59 mmol) over a period of 5 minutes (reaction exothermed to reflux by the end of addition). The reaction was then stirred to room temperature overnight for convenience, quenched with water (50.0 mL) and extracted organic with methylene chloride (50.0 mL). The organic layer was then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure at 50° C. to an oil (11.62 g). Plug filtration of the oil over silica gel with 1:1 ethyl acetate/hexane (470.0 mL) and subsequent concentration of the fractions containing product afforded a light yellow precipitate. The precipitate was then dried in a house vacuum at 40° C. to provide 2-[(2R)-2-(4-nitrophenyl)propyl]isoindoline-1,3-dione (3.32 g, 96.9%); 1H nmr (CDCl3, 300 MHz) δ 1.50 (d, 3H, J=6.74 Hz), 3.45 (m, 1H), 3.89-3.95 (m, 2H), 7.5 (d, 2H), 7.67 (m, 2H), 7.68 (m, 2H), 8.10 (d, 2H); 13C nmr (CDCl3, 300 MHz δ 19.21, 38.90, 44.45, 123.59, 123.99, 128.50, 131.86, 134.35, 151.13, 168.34.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.O[CH2:35][CH2:36][CH2:37][C@@H:38]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[NH:39][C:40]([O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])=[O:41]>C(Cl)Cl>[Br:1][CH2:35][CH2:36][CH2:37][C@@H:38]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[NH:39][C:40]([O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])=[O:41]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)[C@H](CCCO)NC(=O)OCC[Si](C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](CCCBr)NC(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of N-bromosuccinimide (2.129 g, 11.96 mmol) in DCM (10 ml) was treated with triphenylphosphine (2.93 g, 11.17 mmol) in DCM (10 ml), followed by pyridine (0.387 ml, 4.79 mmol) and tert-butyl 5-hydroxy-N-{[2-(trimethylsilyl)ethoxy]carbonyl}-L-norvalinate (1.33 g, 3.99 mmol) in DCM (5 ml). The resulting black mixture was stirred at room temp for 24 h. The mixture was pre-absorbed onto SiO2 and purified by chromatography (silica gel, 0-5-10-20% Et2O/isohexane) to afford tert-Butyl 5-bromo-N-{[2-(trimethylsilyl)ethoxy]carbonyl}-L-norvalinate Intermediate 5 (1.1 g) as a colourless oil.
Reaction SMILES: O[CH:2]([C:4]1[O:5][C:6](=[O:29])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].P(Br)(Br)[Br:31].CN(C=O)C>C(Cl)Cl>[Br:31][CH:2]([C:4]1[O:5][C:6](=[O:29])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3]
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: BrP(Br)Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(Br)c1oc(=O)c2ccccc2c1-c1cccc(S(=O)(=O)N2CCOCC2)c1
Yield: 49.6 %

Procedure:
The title compound was made in a similar way as that of the intermediate C6, using 3-(1-hydroxyethyl)-4-(3-(morpholinosulfonyl)phenyl)-1H-isochromen-1-one (intermediate B9, 163 mg, 0.392 mmol), 1M PBr3 (0.68 ml, 0.667 mmol) in DCM (3.2 ml) at RT. The crude was tritured with DMF to give the title compound (93 mg, 49%). The solution was purified via reverse phase chromatography with a Biotage C18 SNAP 30 g column (Phase A, water 95%, ACN 4.9%, formic acid 0.1%); Phase B ACN 99.9%, formic acid 0.1%) to give further compound (68 mg, 36.2%).
Reaction SMILES: [C:1]1([N:7]=[N:8][CH:9]([C:13](=O)[CH3:14])[C:10](=O)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:17](=[NH:20])([NH2:19])[CH3:18].[Na]>C(O)C>[CH3:14][C:13]1[C:9]([N:8]=[N:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:10]([CH3:11])[N:20]=[C:17]([NH2:19])[CH:18]=1
Reactant: CC(=O)C(N=Nc1ccccc1)C(C)=O
Reactant: CC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1cc(N)nc(C)c1N=Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.8 %

Procedure:
To a stirred solution of 50 parts of 3-(phenylazo)-2,4-pentanedione and 35 parts of ethanimidamide monohydrochloride in 711 parts of ethanol was added a solution of 8.5 parts of sodium in 126 parts of ethanol. After stirring overnight at room temperature, the precipitate was filtered off and the filtrate was stirred for 2 days at room temperature. The mixture was evaporated and the residue was diluted with a sodium hydroxide solution 10%. The separated aqueous layer was extracted with methylbenzene. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated with methylbenzene, yielding 7.5 parts (13.8%) of 4,6-dimethyl-5-(phenylazo)-2-pyridinamine as a residue (int. 95).
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[C:9]([CH2:12]O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:34]>O1CCCC1.CC#N>[Br:34][CH2:12][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:11][CH:10]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1csc(-c2ccccc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCOC1
Product: BrCc1csc(-c2ccccc2)c1
Temperature: 0 °C
Yield: 98.3 %

Procedure:
Prepare a solution of (5-phenylthiophene-3-yl)methanol (394 mg, 2.07 mmol) in tetrahydrofuran (30 mL). Cool to 0° C. under nitrogen. Add PPh3 (723 mg, 2.75 mmol). Add dropwise a solution of carbon tetrabromide (912 mg, 2.75 mmol) in CH3CN (15 mL). Stir the reaction at 0° C. for 2 hours, then warm to room temperature overnight. Concentrate the mixture and flash-chromatograph on silica gel eluting with 7:3 ethyl acetate/hexane to afford 515 mg of 4-bromomethyl-2-phenylthiophene as a white solid. MS: m/e=254 [MH+].
Reaction SMILES: [C:1](/[N:3]=[C:4](\SC)/[NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]#[N:14])=[C:8]([Cl:15])[CH:7]=1)#[N:2].[NH2:18][NH2:19]>C(O)C>[NH2:2][C:1]1[NH:19][N:18]=[C:4]([NH:5][C:6]2[CH:11]=[C:10]([Cl:12])[C:9]([C:13]#[N:14])=[C:8]([Cl:15])[CH:7]=2)[N:3]=1
Reactant: NN
Reactant: CS/C(=N\C#N)Nc1cc(Cl)c(C#N)c(Cl)c1
Solvent: CCO
Product: N#Cc1c(Cl)cc(Nc2n[nH]c(N)n2)cc1Cl
Yield: 70.6 %

Procedure:
A solution of (Z)-methyl N′-cyano-N-(3,5-dichloro-4-cyanophenyl)carbamimidothioate (234 mg, 821 μmol, Eq: 1.00) and hydrazine (263 mg, 258 μl, 8.21 mmol, Eq: 10) in ethanol (10 mL) was heated at 65° C. o/n. The reaction mixture was concentrated and chromatographed (23 Supelco, 100% DCM to 5% to 10% MeOH/DCM to give 156 mg (71%) of desired product as an off-white solid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([CH3:26])([CH3:25])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:21]([O:20][C:18]([NH:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][C:13]1([CH3:26])[CH3:25])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCNCC1(C)C
Reaction time: 3.5 h
Yield: 99.4 %

Procedure:
(+)-1-Benzyloxycarbonyl-4-t−butyloxycarbonylamino-3,3-dimethylpiperidine (75 g, 0.207 mol) was dissolved in 500 ml methanol and the solution was transferred to a Parr reactor. Wet 10% palladium on carbon (7.5 g) was added to the solution and was stirred at 200 psi hydrogen pressure. Reaction progress was monitored on TLC and reaction was completed in 3-4 hrs. The reaction mixture was filtered as soon as it was completed. The residue was washed with 100 ml methanol. Fitrate was evaporated to dryness to afford the required product (47 g) in quantitative yield.
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12])([O-:7])=[O:6]>>[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([Cl:3])=[O:12])([O-:7])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Product: O=C(Cl)c1cccc([N+](=O)[O-])c1

Procedure:
Thionyl chloride (25 mL) was added to 3-nitrobenzoic acid (3 g, 18 mmol) and the mixture was stirred at reflux for 6 hr. Thionyl chloride was evaporated under reduced pressure and the residues was dried to obtain 3-nitrobenzoyl chloride as a yellow solid. 3-Hydroxyanthranilic acid (0.92 g, 6.0 mmol) and pyridine (1.45 mL, 18.0 mmol) were added to toluene (30 mL) and the mixture was stirred at room temperature for 30 min. Then 3-nitrobenzoyl chloride prepared above (3.34 g, 18 mmol) was added. The mixture was stirred at room temperature for 30 min and then at 80° C. for 2 hr. The solvents was evaporated under reduced pressure and the residue was washed with 5% aqueous hydrochloric acid (100 mL×3), filtered, the solid was washed with water (100 mL×3), dried in vacuum at 50° C. to obtain 3-hydroxy-2-(3-nitrobenzeneamido)benzoic acid as a yellow solid (1.8 g, yield 100%). LC-MS (ESI) m/z 303 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][N:7]2[C:12]([OH:13])=[C:11]([CH2:14][CH2:15]O)[C:10]([CH3:17])=[N:9][C:8]=12)(=O)[NH2:2].P(Cl)(Cl)([Cl:20])=O>>[Cl:20][CH2:15][CH2:14][C:11]1[C:10]([CH3:17])=[N:9][C:8]2[N:7]([CH:6]=[N:5][C:4]=2[C:1]#[N:2])[C:12]=1[OH:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2c(C(N)=O)ncn2c(O)c1CCO
Product: Cc1nc2c(C#N)ncn2c(O)c1CCCl
Reaction time: 0.5 h

Procedure:
0.17 mol of the compound obtained in Stage A of Example 3, dissolved in 200 ml of phosphorus oxychloride, is brought to 85° C. for one hour 30 minutes. The phosphorus oxychloride is then removed by evaporation under vacuum. 100 ml of water are added and the pH is adjusted to 7 using sodium bicarbonate to crystallize the expected compound. The latter is filtered off.