Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:5]=2[N:6]=1.[OH-].[K+].IC[C:17]#[N:18]>O.C(O)(=O)C.C(O)C>[NH2:6][C:5]1[C:7]([F:12])=[CH:8][C:9]([F:11])=[CH:10][C:4]=1[S:3][CH2:2][C:17]#[N:18]
Reactant: Nc1nc2c(F)cc(F)cc2s1
Reactant: N#CCI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: N#CCSc1cc(F)cc(F)c1N
Temperature: 2.5 °C

Procedure:
A suspension of 2-amino-4,6-difluoro-benzothiazole (7.00 g) was stirred for 6 h at 160° C. under nitrogen in a solution of potassium hydroxide (12.6 g) in water (20 ml). The resulting mixture was cooled to 0-5° C. and a solution of acetic acid (8.85 ml) in water (10 ml) and subsequently ethanol (40 ml) and iodoacetonitrile (2.75 ml) were added. After 30 min the mixture was neutralized with acetic acid (2.25 ml) and filtered. The filtrate was evaporated to approx. 30 ml and diluted with water (150 ml). A yellow precipitate was filtered off and dried. The crude product was purified by flash chromatography on silica gel eluted with ethyl acetate—heptane (3:7) yielding the title compound, Rf=0.26, as orange crystals, mp 66-67° C.; 1H-NMR (DMSO-d6), δ (ppm): 7.30-7.07 (m, 2H, Ar—H), 5.33 (br, 2H, NH2), 4.05 (s, 2H, CH2).
Reaction SMILES: N.[Si:2]([O:9][CH2:10][CH2:11][C:12]1[C:13]([F:36])=[C:14]([CH:33]=[CH:34][CH:35]=1)[CH2:15][N:16]1[CH2:32][CH2:31][C:19]2([O:24][CH2:23][CH2:22][N:21](C(=O)C(F)(F)F)[CH2:20]2)[CH2:18][CH2:17]1)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]>CO>[Si:2]([O:9][CH2:10][CH2:11][C:12]1[C:13]([F:36])=[C:14]([CH:33]=[CH:34][CH:35]=1)[CH2:15][N:16]1[CH2:17][CH2:18][C:19]2([O:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH2:31][CH2:32]1)([C:5]([CH3:8])([CH3:6])[CH3:7])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(CN2CCC3(CC2)CN(C(=O)C(F)(F)F)CCO3)c1F
Agent: N
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Reaction time: 1 h

Procedure:
‘880’ Aqueous ammonia (3.0 mL) was added to stirred solution of 1-(9-(3-(2-(tert-butyldimethylsilyloxy)ethyl)-2-fluorobenzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-2,2,2-trifluoroethanone (example 78, step c) (2.5 g) in MeOH (10 mL). After 1 h, the reaction mixture was evaporated to dryness. Acetonitrile was added, the solution was evaporated to dryness in vacuo, and the process repeated three times to give the subtitled compound as an oil. Yield 2.07 g. Used directly.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](=[O:8])[NH:4][CH:3]=1.[C:9](=O)([O-])[O-].[Cs+].[Cs+].CI>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5](=[O:8])[N:4]([CH3:9])[CH:3]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CI
Product: Cn1cc(Br)ccc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4.38 g of the product from Step A in DMP was added 81 g of cesium carbonate and 30 mL of methyl iodide. The mixture was stirred at ambient temperature overnight, diluted with ethyl acetate, extracted sequentially with two portions of saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, and concentrated. Purification by HPLC (silica gel, 60% ethyl acetate/hexane) gave the title compound. 1H NMR (500 MHz, CDCl3) δ 7.46 (d, 1H, J=2.7 Hz), 7.38 (dd, 1H, J=2.7, 9.8 Hz), 6.52 (d, 1H, J=9.8 Hz), 3.55 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].O[CH2:11][CH:12]([CH2:14]O)O.[N+](C1C=CC=CC=1)([O-])=O.S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[F:9])[N:6]=[CH:14][CH:12]=[CH:11]2
Reactant: OCC(O)CO
Reactant: Nc1ccc(Br)c(F)c1
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])c1ccccc1
Product: Fc1cc2ncccc2cc1Br
Reaction time: 7 h
Yield: 42.5 %

Procedure:
A mixture of 4-bromo-3-fluoroaniline (2.85 g, 15 mmol), ferric sulfate (0.95 g, 6.25 mmol), glycerol (5.66 g, 61 mmol), nitrobenzene (0.93 mL, 9.1 mmol), and concentrated sulfuric acid (2.61 ml) was heated gently. After the first vigorous reaction, the mixture was boiled for 7 h. Nitrobenzene was then evaporated in vacuo. The aqueous solution was acidified with glacial acetic acid, and a dark brown precipitate separated, which was collected and purified by flash chromatography (silica gel, petroleum/ethyl acetate=8/1) to give 1.44 g of 6-bromo-7-fluoro-quinoline as white crystals (42.5% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][C:13](O)=[O:14])[CH:6]=[C:5]2[CH2:16][C:17]1[NH:18][CH:19]=[CH:20][N:21]=1.[CH3:22][S:23]([NH2:26])(=[O:25])=[O:24].N1C=CN=C1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][C:13](=[O:14])[NH:26][S:23]([CH3:22])(=[O:25])=[O:24])[CH:6]=[C:5]2[CH2:16][C:17]1[NH:18][CH:19]=[CH:20][N:21]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)CCn1cc(Cc2ncc[nH]2)c2cc(Br)ccc21
Agent: c1c[nH]cn1
Solvent: CCO
Product: CS(=O)(=O)NC(=O)CCn1cc(Cc2ncc[nH]2)c2cc(Br)ccc21
Temperature: 120 °C
Yield: 29.2 %

Procedure:
A mixture of 5-bromo-1-(2-carboxyethyl)-3-(1-imidazolylmethyl) indole (0.87 g) and N,N'-carbonyldiimidazole (0.51 g) was heated on a steam bath for 1.5 hours to give a clear melt. Methanesulphonamide (0.47 g) was added and the mixture was heated at 120° C. for 2 hours and then cooled and dissolved in a small volume of ethanol. Some insoluble material was filtered off and the filtrate was evaporated and the residue was chromatographed on silica gel. Elution with chloroform gave initially some impurity. Further elution with a mixture of chloroform and methanol (9:1) gave a mixture of product and imidazole. The product containing fractions were evaporated and the residue was crystallised from a mixture of methanol and ether to give 5-bromo-1-[2-(N-methanesulphonylcarbamoyl)ethyl]-3-(1-imidazolylmethyl)indole (0.31 g,), m.p. 199°-201° C. Found: C, 45.21; H, 4.18; N, 12.95. C16H17BrN4O3S requires: C, 45.18; H, 4.03; N, 13.17%.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.[NH:22]1[CH2:26][CH2:25][CH:24]([C:27]#[N:28])[CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:17])[CH3:18])[C:13]([N:22]3[CH2:26][CH2:25][CH:24]([C:27]#[N:28])[CH2:23]3)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Reactant: N#CC1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)[C@H](C(=O)N1CCC(C#N)C1)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Yield: 10.5 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (10 mg, 0.032 mmol). THF (0.5 mL), pyrrolidine-3-carbonitrile (3.12 mg, 0.032 mmol) and HATU (14.83 mg, 0.039 mmol) were added and the solution was stirred at 25° C. for 1 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (1.3 mg, 10.4%). 1H NMR (400 MHz, CD3OD) δ 0.92 (s, 3 H) 1.00-1.12 (m, 3 H) 2.27-2.35 (m, 1 H) 2.56 (d, J=6.57 Hz, 1 H) 3.40 (d, J=6.82 Hz, 1 H) 3.51-3.68 (m, 1 H) 3.74 (d, J=6.57 Hz, 1 H) 3.79-3.94 (m, 1 H) 3.96-4.03 (m, 1 H) 4.88-5.00 (m, 2 H) 5.03-5.23 (m, 1 H) 5.39-5.48 (m, 1 H) 7.87 (d, J=12.63 Hz, 1 H) 8.21-8.30 (m, 1 H). [M+H] calc'd for C19H20ClN5O2, 386; found, 386.4.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][NH:15][C:16](=[O:22])[O:17][CH2:18][CH2:19][O:20][CH3:21])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][NH:15][C:16](=[O:22])[O:17][CH2:18][CH2:19][O:20][CH3:21])[CH2:9]1
Reactant: COCCOC(=O)NC[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOC(=O)NC[C@@H]1CCCNC1
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To 2-methoxyethyl ((S)-1-(tert-butoxycarbonyl)piperidin-3-yl)methylcarbamate (496 mg, 1.6 mmol) dissolved in 10 mL CH2Cl2 was added 5 mL TFA, and the reaction was stirred for 1 hour. After neutralizing the mixture with a 1 N NaOH solution it was extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give 2-methoxyethyl ((R)-piperidin-3-yl)methylcarbamate (300 mg, 87%) which was used without further purification. LC/MS: m/z 217.5 (M+H)+ at 0.49 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:10]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:9]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:8]([C:36]2[CH:41]=[C:40]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH3:51])=[CH:45][CH:44]=3)[C:39]([Cl:52])=[CH:38][C:37]=2[OH:53])[O:7]1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:73](O)/[CH:74]=[CH:75]\[CH2:76][OH:77].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:10]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@@H:9]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:8]([C:36]2[CH:41]=[C:40]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH3:51])=[CH:45][CH:44]=3)[C:39]([Cl:52])=[CH:38][C:37]=2[O:53][CH2:73]/[CH:74]=[CH:75]\[CH2:76][OH:77])[O:7]1)(=[O:3])[CH3:2]
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Reactant: OC/C=C\CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OC/C=C\CO)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a solution of ((2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-5-(4-ethoxybenzyl)-2-hydroxyphenyl)tetrahydro-2H-pyran-2-yl)methyl acetate (45, 2.19 g, 2.97 mmol) from Step 1 in tetrahydrofuran (30 mL) were added triphenylphosphine (1.57 g, 5.94 mmol) and cis-2-butene-1,4-diol (0.5 mL, 5.94 mmol) at 0° C., and diisopropyl azodicarboxylate (1.35 mL, 6.53 mmol) was added dropwise thereto. The reaction mixture was stirred at ambient temperature for 0.5 h and warmed up to room temperature for 4 h. After cooling to 0° C., the reaction mixture was quenched with H2O, extracted with ethyl acetate and dried over magnesium sulfate. The crude residue was purified on Biotage® purification apparatus (silica gel, 10 to 45% tetrahydrofuran in hexanes) to yield the title compound (46, 2.08 g, 2.57 mmol, 87%) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[C:4]([CH3:19])[C:3]=1[CH3:20]>N.CO.O>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:19])[C:3]=1[CH3:20]
Reactant: Cc1cc(N2C(=O)c3ccccc3C2=O)nc(Cl)c1C
Agent: N
Solvent: CO
Solvent: O
Product: Cc1cc(N)nc(Cl)c1C
Yield: 45 %

Procedure:
A solution of 2-(6-chloro-4,5-dimethylpyridin-2-yl)isoindoline-1,3-dione (650 mg, 2.27 mmol) in ammonia in methanol (2 M, 50 mL) was stirred at the room temperature overnight. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give a crude residue that was purified by silica gel column chromatography (10-15% ethyl acetate in petroleum ether) to give 6-chloro-4,5-dimethylpyridin-2-amine (160 mg, 46%). 1H NMR (300 MHz, d-DMSO) δ 6.21 (s, 1H), 5.93 (brs, 2H), 2.11 (s, 3H), 2.05 (s, 3H). MS (ESI) m/z (M+H+): 157.2.
Reaction SMILES: [N:1]([CH2:4][C:5]1([CH2:8][O:9][C:10]2[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:11]=2[C:20]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:21]=2[CH2:22][CH2:23][C:24]3=[O:29])[CH2:7][CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][C:5]1([CH2:8][O:9][C:10]2[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:11]=2[C:20]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:21]=2[CH2:22][CH2:23][C:24]3=[O:29])[CH2:6][CH2:7]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN=[N+]=[N-])CC2)c1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)CC2)c1OC
Temperature: 80 °C

Procedure:
To a stirring solution of 4-(2-((1-(azidomethyl)cyclopropyl)methoxy)-3,4-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-one (1.5 g, 3.947 mmol) in tetrahydrofuran (50 mL), were added triphenylphosphine (4.14 g, 15.78 mmol) and the reaction mixture was stirred at RT for 2 h. water (5 mL) was added to the above reaction mixture and the resultant reaction was heated to 80° C. for 1 h. The reaction mixture was concentrated under reduced pressure and the obtained residue was acidified with 1N hydrochloric acid solution. Then extracted with ethyl acetate (3×) and the aq layer was basified with sodium bicarbonate solution and extracted with ethyl acetate and the combined ethyl acetate layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afforded the title compound as a liquid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]([CH2:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34])[CH3:29].[OH-].[Na+]>CN(C=O)C.CO>[CH3:29][N:28]([CH2:30][C:31]1[CH:32]=[C:33]([NH:34]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:35]=[CH:36][CH:37]=1)[CH3:27]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CN(C)Cc1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)Cc1cccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 3-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH2:12][C:13]3[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([CH3:26])[CH:14]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>>[C:20]([O:19][C:17]([C:16]1[CH:24]=[CH:25][C:13]([CH2:12][N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[C:7]=3[CH2:8]2)=[CH:14][C:15]=1[CH3:26])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)ccc1C(=O)OC(C)(C)C
Reactant: O=COc1ccccc1
Product: Cc1cc(CN2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)ccc1C(=O)OC(C)(C)C
Yield: 90 %

Procedure:
The title compound is prepared in 90% yield (280 mg, brown oil) from tert-butyl 4-((4-chloro-1-oxo-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)methyl)-2-methylbenzoate (250 mg, 0.67 mmol, Step-1) and phenyl formate (160 mg, 1.3 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:15]1[C:16]([Cl:21])=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[Cl:21][C:16]1[C:15]([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[OH:14])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=C(c1ccccc1)c1cccnc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: c1ccncc1
Product: OC(c1ccccc1)c1cccnc1Cl
Reaction time: 2 h
Yield: 42.1 %

Procedure:
2.4 g lithium aluminium hydride is added very slowly to 10.6 g 3-benzoyl-2-chloropyridine in 100 ml anhydrous pyridine. After stirring for 2 hrs. at room temperature, the solvent is distilled in vacuo, the residue is added to 5% aqueous HCl and extracted with ether. Working as usual there is obtained 4.5 g of a product, identical with that obtained as in (a).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.C(C1C=CC(C)=NC=1)C.Cl[C:22](OCC)=[O:23].Cl>C(OCCCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:22](=[O:23])[NH:9][C:7](=[O:8])[C:6]=2[CH:10]=1
Reactant: CCOC(=O)Cl
Reactant: NC(=O)c1cc(Cl)ccc1O
Agent: CCc1ccc(C)nc1
Agent: Cl
Solvent: O
Solvent: CCCCOC(C)=O
Product: O=c1[nH]c(=O)c2cc(Cl)ccc2o1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
5-chlorosalicylamide (300 g, 1.75 mol) and water (900 ml) were placed in a 3 liter, 4-neck round-bottomed flask under a nitrogen atmosphere and stirred. 5-ethyl-2-methyl-pyridine (284 g, 2.27 mol) and n-butyl acetate (900 ml) were added to the mixture. The mixture was cooled to 0-5° C. (jacket-10° C.) and dropwise addition of ethyl chloroformate (233 g, 2.10 mol) was started. This addition continued over a period of approximately one hour. When the addition was completed, the reaction mixture was slowly heated (in about two hours) to reflux and kept under reflux for an additional period of about 5 hours (jacket 110° C., internal temperature (IT) 90° C.). The resulting slurry was allowed to cool to room temperature, and hydrochloric acid (28 ml, 37% m/m, 0.34 mol) was added and the mixture stirred for about 30 minutes. The resulting slurry was vacuum filtered, the filter cake was washed with n-butyl acetate followed by water (600 ml) and was allowed to dry overnight in vacuo at 60° C. 321 g (93%) of 6-chloro-2H-1,3-benzoxazine-2,4(3H)-dione (6-chloro carsalam) was isolated after drying.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][CH2:11][CH2:12][OH:13])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>C(Cl)Cl>[CH3:21][S:22]([O:13][CH2:12][CH2:11][O:10][CH2:9][P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])(=[O:24])=[O:23]
Reactant: CCOP(=O)(COCCO)OCC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOP(=O)(COCCOS(C)(=O)=O)OCC
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
A solution of 2-diethylphosphonomethoxy-1-ethanol (40.7 g, 192 mmol) in 500 mL of CH2Cl2 was cooled to 0° C. and then triethylamine (29.1 g, 288 mmol) was added in one portion, followed by addition of methanesulfonyl chloride (26.4 g, 230 mmol) dropwise over 20 min. The reaction mixture was kept at 0° C. for 0.5 hours and then poured into water. The aqueous phase was extracted with two portions of CH2Cl2 and the combined organic phases dried over MgSO4, filtered and concentrated to afford 54.4 g (98%) of 1-methanesulfonyloxy-2-(diethylphosphonomethoxy)ethane as a clear, pale orange oil. The mesylate could be employed without purification or purified by column chromatography on silica gel (5% methanol in CH2Cl2). 1H NMR (200 MHz, CDCl3): 4.46-4.50 (m,2H), 4.26 (quintet, J=6.8 Hz,4H), 3.92-3.99(m,4H), 3.20 (s,3H), and 1.40 (t, J=7 Hz, 6H).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:11][CH:10]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])=[CH:11][CH:10]=1
Reactant: COc1ccc(CCCCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 70.1 %

Procedure:
Pyridine (15 mL) was added drop wise to a cooled (0° C.) solution of 4-(4-methoxyphenyl)butanol (10.0 g, 0.055 mol) and p-toluenesulfonyl chloride (13.6 g, 0.072 mol) in dry chloroform (100 mL) under stirring. The reaction mixture was stirred overnight at room temperature. After this time, the reaction was quenched with 10% HCl (300 mL) and extracted with chloroform. The organic fraction was washed with saturated NaHCO3, water and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography (eluent: hexane/ethyl acetate 15:1) to provide 12.9 g (66%) of 1 as clear oil. 1H NMR (360 MHz, CDCl3) δ 1.61 (m, 4H), 2.44 (s, 3H), 2.52 (m, 2H), 3.78 (s, 3H), 4.05 (m, 2), 6.77 (d, 2H), 7.05 (d, 2H), 7.34 (d, 2H), 7.78 (d, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([O-:6])=[O:5].[Na+].COCC(O)=O.[OH-].[Na+].COCC(Cl)=O.[CH2:22]([O:29][C:30]1[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][C:33]([CH:34]=O)=[C:32](O)[CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CCO.CN(C=O)C.CCOC(C)=O>[CH2:22]([O:29][C:30]1[CH:31]=[C:32]2[C:33]([CH:34]=[C:3]([O:2][CH3:1])[C:4](=[O:6])[O:5]2)=[CH:36][C:37]=1[N+:38]([O-:40])=[O:39])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COCC(=O)[O-]
Reactant: O=Cc1cc([N+](=O)[O-])c(OCc2ccccc2)cc1O
Agent: COCC(=O)Cl
Agent: COCC(=O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1cc2cc([N+](=O)[O-])c(OCc3ccccc3)cc2oc1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Sodium methoxyacetate (0.739 g, 6.6 mmol), prepared from methoxyacetic acid and NaOH in EtOH, is dissolved in 3.3 mL of DMF and cooled to 0° C. Methoxyacetyl chloride (0.39 mL, 4.0 mmol) is added dropwise. The mixture is stirred for 15 min at ambient temperature. 4-Benzyloxy-2-hydroxy-5-nitrobenzaldehyde (0.360 g, 1.32 mmol) is added and the solution refluxed for 3 h. After cooling to ambient temperature, EtOAc is added and the mixture is washed with 10% aqueous HCl, water, and sat. NaCl, then dried over sodium sulfate. The solvent is removed under reduced pressure and the residue purified by recrystallization from EtOAc to afford 7-benzyloxy-3-methoxy-6-nitrochromen-2-one as a yellow solid: mp=226-228° C.; 1H NMR (DMSO-d6) δ 8.27 (s, 1H), 7.48-7.35 (m, 7H), 5.36 (s, 2H), 3.82 (s, 3H); (M−H)−=326.
Reaction SMILES: [CH2:1]([CH:4]([CH2:16][CH2:17][CH3:18])[C:5]([NH:7][C@@H:8]([CH2:13][CH:14]=[CH2:15])[C:9]([O:11][CH3:12])=[O:10])=[O:6])[CH2:2][CH3:3].I[CH3:20].[H-].[Na+]>C1COCC1>[CH3:20][N:7]([C@@H:8]([CH2:13][CH:14]=[CH2:15])[C:9]([O:11][CH3:12])=[O:10])[C:5](=[O:6])[CH:4]([CH2:1][CH2:2][CH3:3])[CH2:16][CH2:17][CH3:18]
Reactant: C=CC[C@H](NC(=O)C(CCC)CCC)C(=O)OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@@H](C(=O)OC)N(C)C(=O)C(CCC)CCC
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 25.6 %

Procedure:
Step A (2): (S)-Methyl 2-(2-propylpentanamido)pent-4-enoate (852 mg, 3.34 mmol) from Step A (1) was dissolved in THF (20 mL). Iodomethane (620 μL, 10 mmol) was added and resulting mixture chilled to 0° C. Sodium hydride (120 mg, 5.00 mmol) was added and the ice-bath was removed. After 75 min, the reaction was chilled again to 0° C. and quenched with aqueous 1 N HCl. The slurry was poured into H2O, and extracted with EtOAc (3×200 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography to give (S)-methyl 2-(N-methyl-2-propylpentanamido)pent-4-enoate 230 mg (26% yield). LC-MS (M+H)+=270.22. 1H NMR (300 MHz, CDCl3) δ 0.78-0.90 (m, 5H) 1.10-1.41 (m, 6H) 1.49-1.69 (m, 3H) 2.36-2.50 (m, 1H) 2.60-2.79 (m, 2H) 2.92 (s, 3H) 3.67 (s, 3H) 4.96-5.12 (m, 2H) 5.29 (dd, J=10.98, 4.76 Hz, 1H) 5.58-5.77 (m, 1H).