Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C@@H:5]([NH2:15])[CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:2].C(N(CC)CC)C.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>ClCCl>[CH2:1]([O:3][C:4](=[O:16])[C@@H:5]([NH:15][S:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:32])=[O:31])[CH2:6][NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH3:2]
Reactant: CCOC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)[C@H](CNC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
The compound obtained in the above (3) is dissolved in dichloromethane (15 ml), and thereto are added triethylamine (2.0 ml) and benzenesulfonyl chloride (1.57 ml) at room temperature, and the mixture is stirred for 30 minutes. To the mixture are further added triethylamine (0.57 ml) and benzenesulfonyl chloride (0.52 ml), and the mixture is further stirred for 30 minutes. The reaction mixture is poured into water, and the mixture is extracted three times with ethyl acetate. The extract is washed successively with 1N hydrochloric acid (twice), a saturated brine (once), a saturated aqueous sodium hydrogen carbonate solution (twice) and a saturated brine (twice), and dried over anhydrous magnesium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (silica gel; 100 g, solvent; hexane/ethyl acetate=1:1). The fractions containing the title compound are concentrated under reduced pressure to give the title compound (2.69 g) as a colorless powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9][CH:10]=[CH2:11])[CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.O.P(=O)(O)(O)O.[K]>CS(C)=O.CCOC(C)=O.CCOCC>[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9][CH:10]=[CH2:11])[CH:3]=1
Reactant: Nc1ccccc1B(O)O
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(Cl)ccn1
Agent: O=P(O)(O)O
Agent: [K]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccccc2N)ccn1
Temperature: 90 °C
Yield: 83.3 %

Procedure:
45C (2 g, 7.07 mmol) and (2-aminophenyl)boronic acid (1.065 g, 7.78 mmol) in DMSO (35.4 ml) and H2O (0.637 ml, 35.4 mmol) was de-gassed for 30 min. Then, Phosphoric acid, potassium salt (3.00 g, 14.15 mmol) and 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(ii) dichloromethane complex (0.518 g, 0.707 mmol) were added. The dark red reaction mixture was sealed and heated at 90° C. overnight. The reaction mixture was diluted with EtOAc/Ether and washed with water and brine. The organic layer was dried over MgSO4. Filtered and concentrated to give the crude product as a black oil. The residue was purified by silica gel chromatography to give the desired product (2.0 g, 83%) as a light brownish foam. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.61 (d, J=4.8 Hz, 1H), 7.37-7.28 (m, 2H), 7.27-7.16 (m, 2H), 7.12 (d, J=7.7 Hz, 1H), 6.85 (t, J=7.5 Hz, 1H), 6.77 (d, J=7.9 Hz, 1H), 5.79-5.58 (m, 2H), 5.12-4.97 (m, 2H), 4.90-4.80 (m, 1H), 3.80 (br. s., 2H), 2.62 (t, J=6.6 Hz, 2H), 1.44 (s, 9H). MS (ESI) m/z: 340.1 (M+H)+.
Reaction SMILES: C(O)C.OS(O)(=O)=O.[Br:9][C:10]1[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:11]=1N.N([O-])=O.[Na+]>O.[Cu]>[Br:9][C:10]1[CH:11]=[CH:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:16]=1
Reactant: CC(C)c1ccc(N)c(Br)c1
Agent: [Cu]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CC(C)c1cccc(Br)c1
Temperature: -5 °C

Procedure:
To a mixture of 1000 ml of 96% ethanol and 94 ml of 98% H2SO4, 117 g (0.55 mol) of 2-bromo-4-isopropylaniline was added over 15 min. with vigorous stirring at −5° C. Then, a solution of 63 g of NaNO2 in 125 ml of water was added at this temperature over 1 h, and the resulting mixture was stirred for about 30 min longer. Then, 12 g of copper powder was added. The reaction mixture was refluxed for 4 h and filtered through a glass frit (G3). The filtrate was poured into 2500 cm3 of cold water. The organic product was extracted with 4×400 ml of dichloromethane. The combined extract was dried over K2CO3 and evaporated to dryness. Fractional distillation gave the title product, b.p. 64-67° C./3 mm Hg. Yield 117.4 g (75%) of yellowish oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:15]3[CH:16]=[CH:17][C:18]4[O:22][CH2:21][CH2:20][C:19]=4[CH:23]=3)[C:11](OC)=[O:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[NH2:24][OH:25].[OH-].[K+].[OH-].[Na+].Cl>C(OCC)(=O)C.CO.C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:15]3[CH:16]=[CH:17][C:18]4[O:22][CH2:21][CH2:20][C:19]=4[CH:23]=3)[C:11]([NH:24][OH:25])=[O:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: NO
Reactant: COC(=O)C(c1ccc2c(c1)CCO2)c1ccc2c(c1)CCO2
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NO)C(c1ccc2c(c1)CCO2)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To a solution of 2 (380 mg, 1.22 mmol) and hydroxylamine (50% in water, 1.25 mL) in a 1:1 THF:methanol (10 mL) was added base (KOH (275 mg, 4.9 mmol) or NaOH). The mixture was stirred at room temperature for 2 h, acidified to pH 7 with 1M HCl solution, diluted with ethyl acetate and washed with water. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was triturated with 50% ethyl acetate:hexanes, filtered, and rinsed with hexanes to afford compound 3 as a white solid (170 mg, 45%). 1H NMR (DMSO-d6) δ (ppm): 10.81 (br s, 1H), 8.88 (br s, 1H), 7.16 (d, J=1.0 Hz, 2H), 6.99 (dd, J=8.4, 1.8 Hz, 2H), 6.67 (d, J=8.1 Hz, 2H), 4.53-4.45 (m, 5H), 3.12 (t, J=8.6 Hz, 4H). LRMS (ESI): (calc) 311.1 (found) 310.3 (M)−.
Reaction SMILES: [SH+]1CCCC1.[CH3:6][C:7]1([CH3:35])[C:9]2([C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:8]1[C:18]([O:20][CH2:21][C:22]1C=CC=C(OC2C=CC=CC=2)C=1)=[O:19].CC1(C)C2(C3C(=CC=CC=3)C=C2)C1C(O)=O>>[CH3:6][C:7]1([CH3:35])[C:9]2([C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:8]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CC1(C)C(C(=O)OCc2cccc(Oc3ccccc3)c2)C12C=Cc1ccccc12
Agent: C1CC[SH+]C1
Agent: CC1(C)C(C(=O)O)C12C=Cc1ccccc12
Product: CCOC(=O)C1C(C)(C)C12C=Cc1ccccc12

Procedure:
By the above procedure, but substituting tetrahydrothiophenium carboxymethylide-, m-phenoxybenzyl ester and tetrahydrothiophenium carboxymethylide-, 3,3-dimethylspiro[cyclopropane-1,1'-indene]-2-carboxylic acid, m-phenoxybenzyl ester and 3,3-dimethylspiro[cyclopropane-1,1'-indene]-2-carboxylic acid, are obtained, respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:24][CH:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([NH:1][S:27]([CH:25]([CH3:26])[CH3:24])(=[O:29])=[O:28])=[CH:3][CH:4]=2)=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Nc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)S(=O)(=O)Nc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
151 mg of 4-amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was reacted with 105 μL of propane-2-sulfonyl chloride and 205 μL DIPEA in 500 μL DCM. The reaction mixture was evaporated, subjected to basic workup conditions and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(1-methylethylsulfonamido)benzamide. MS (Q1) 430 (M)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19]N(C)[CH2:17][CH2:16]2)[CH:12]=[C:11]([Cl:22])[C:10]=1[F:23])(C)(C)C.Cl.[O:26]1[CH2:31]COC[CH2:27]1>>[Cl:22][C:11]1[C:10]([F:23])=[C:9]([CH:14]=[C:13]([N:15]2[CH2:16][CH2:17][CH:27]([O:26][CH3:31])[CH2:19][CH2:20]2)[CH:12]=1)[CH2:8][NH2:7]
Reactant: CN1CCN(c2cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c2)CC1
Reactant: C1COCCO1
Agent: Cl
Product: COC1CCN(c2cc(Cl)c(F)c(CN)c2)CC1

Procedure:
was prepared according to Scheme C1 (step B) from [3-chloro-2-fluoro-5-(4-methyl-piperazin-1-yl)-benzyl]-carbamic acid tert-butyl ester and 4N HCl in dioxane. MS (LC-MS): 273.0 [M]+; tR (HPLC conditions c): 2.97 min.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH+:7]=1.[C:16](=[C:19]1[C:23](=O)[C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[S:20]1(=[O:30])=[O:29])([CH3:18])[CH3:17]>>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:18][C:16]1[C:19]2[S:20](=[O:30])(=[O:29])[C:21]3[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=3[C:23]=2[N+:7]2[CH2:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[CH:17]=1
Reactant: C1=[NH+]CCc2ccccc21
Reactant: CC(C)=C1C(=O)c2ccccc2S1(=O)=O
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: Cc1cc2[n+](c3c1S(=O)(=O)c1ccccc1-3)CCc1ccccc1-2

Procedure:
3,4-Dihydroisoquinolinium perchlorate (1.2 g) and 2-isopropylidenebenzothien-3-one-1,1-dioxide (2 g) were heated together at 150° for 16 hours. The reaction mixture was triturated with hot methanol and filtered. The product was purified by recrystallization from acetonitrile. Yield 0.6 g, m.p. > 330°.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(N(CC)CC)C>CO>[CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1
Reactant: CNc1ccc(O)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CNC1CCC(O)CC1
Reaction time: 16 h

Procedure:
17 Grams of p-methylaminophenol, 20 ml of triethylamine and 9 g of 5% rhodium alumina are added to 200 ml of methanol and the mixture is shaken at the temperature of 60° to 70° C. and under hydrogen pressure of 3 to 4 atm. for 16 hours to effect hydrogenation. After the reaction, the catalyst is filtered off and the mother liquor is concentrated and evaporated to dryness, and the residue is added with 500 ml of chloroform and 200 ml of 5% aqueous NaOH solution. After separating the liquid, the chloroform layer is washed with water and concentrated, and the residue is further distilled under reduced pressure. This treatment gives 11 g of 4-methylaminocyclohexanol with boiling point of 123°-129° C. (at 22 mmHg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:14][C:13](=[O:15])[C@@H:12]2[C@H:10]1[C@H:11]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[CH:35](N(C)C)[N:36]([CH3:38])[CH3:37])(C)(C)C.C(OCC)C.CCCCCC>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14](=[CH:35][N:36]([CH3:38])[CH3:37])[C:13](=[O:15])[C@@H:12]2[C@H:10]1[C@H:11]2[C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)CC(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CN(C)C=C1C(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]2[C@]1(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 97.2 %

Procedure:
To a solution of di-tert-butyl (1S,2S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylate (15.15 g, 36.82 mmol, See WO03/104217/A2 for synthesis details) in toluene (90.90 mL) is added tert-butoxybis(dimethylamino)methane (12.83 g, 73.63 mmol). This mixture is then heated to 80° C. for 1 hour and then allowed to cool to ambient temperature. The solvent volume is reduced to about 35 ml. The mixture is stirred while diethyl ether and hexane are added to cause a precipitate to form. The solids are collected by filtration, washed with hexanes, and air dried to obtain the title compound (16.7 g, 35.79 mmol, 97.2% yield). MS (m/z): 467.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:66]=[CH:65][C:6]([CH2:7][O:8][C:9]([C:11]2[N:12]3[C@H:15]([S:16][CH2:17][C:18]=2[CH2:19]Cl)[C@H:14]([NH:21][C:22](=[O:63])/[C:23](/[C:57]2[N:58]=[C:59]([NH2:62])[S:60][CH:61]=2)=[N:24]\[O:25][C@H:26]([C:41]([O:43][CH:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])[C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34](=[O:36])[CH3:35])=[C:29]([O:37][C:38](=[O:40])[CH3:39])[CH:28]=2)[C:13]3=[O:64])=[O:10])=[CH:5][CH:4]=1.[I-:67].[Na+].O>CC(C)=O>[CH3:1][O:2][C:3]1[CH:66]=[CH:65][C:6]([CH2:7][O:8][C:9]([C:11]2[N:12]3[C@H:15]([S:16][CH2:17][C:18]=2[CH2:19][I:67])[C@H:14]([NH:21][C:22](=[O:63])/[C:23](/[C:57]2[N:58]=[C:59]([NH2:62])[S:60][CH:61]=2)=[N:24]\[O:25][C@H:26]([C:41]([O:43][CH:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])[C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34](=[O:36])[CH3:35])=[C:29]([O:37][C:38](=[O:40])[CH3:39])[CH:28]=2)[C:13]3=[O:64])=[O:10])=[CH:5][CH:4]=1
Reactant: [I-]
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)/C(=N\O[C@H](C(=O)OC(c4ccccc4)c4ccccc4)c4ccc(OC(C)=O)c(OC(C)=O)c4)c4csc(N)n4)C(=O)N23)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(CI)CS[C@@H]3[C@H](NC(=O)/C(=N\O[C@H](C(=O)OC(c4ccccc4)c4ccccc4)c4ccc(OC(C)=O)c(OC(C)=O)c4)c4csc(N)n4)C(=O)N23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of the product obtained in Step 6 (14 g) in acetone (210 ml) was added sodium iodide (4.85 g) in total darkness and the mixture was stirred at room temperature for one hour. The reaction mixture was then poured into water (300 ml) and extracted twice with ethyl acetate (500 ml). The combined organic layer was washed with 5% sodium thiosulfate solution (200 ml) and brine (200 ml), and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure, giving 15.1 g of the objective compound as yellow crystals.
Reaction SMILES: [C:1]([CH2:9][C:10]([NH:12][CH2:13][C:14]([NH:16][CH2:17][C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])=[O:15])=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.O[N:41]1[C:45](=[O:46])[CH2:44][CH2:43][C:42]1=[O:47]>CN(C)C=O>[C:1]([CH2:9][C:10]([NH:12][CH2:13][C:14]([NH:16][CH2:17][C:18]([NH:20][CH2:21][C:22]([O:24][N:41]1[C:45](=[O:46])[CH2:44][CH2:43][C:42]1=[O:47])=[O:23])=[O:19])=[O:15])=[S:11])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CNC(=O)CNC(=O)CNC(=S)CC(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(CNC(=O)CNC(=S)CC(=O)c1ccccc1)NCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1.0 g of (2-benzoylthioacetyl)glycylglycylglycine (2.72 mmol) in 10 mL of dimethylforamide was added 0.56 g of dicyclohexylcarbodiimide (2.72 mmol) and 0.31 g of N-hydroxysuccinimide (2.72 mmol). The solution was stirred at room temperature for 24 hours. The resultant white solid was filtered off. The solvent was removed from the filtrate by rotary evaporator (vacuum pump, 35.) to give the product as a yellow semisolid. This solid was dried under vacuum overnight. The product was then recrystallized from 100 mL of hot 2-propanol to give 0.27 g of a white powder after filtration and drying under vacuum (21%). NMR (DMSO-d6)δ 2.81 (s, 4H), 3.79 (m, integral obscured by water), 3.89 (s, integral obscured by water), 4.28 (d, 2H), 7.58 (d, 2H), 7.71 (t, 1H), 7.93 (d,2H), 8.29 (br t, 1H), 8.54 (m, 2H).
Reaction SMILES: C(NCC)C.[CH2:6]([O:8][C:9](=[O:29])[CH:10]([CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:16]=1)[C:11](O)=O)[CH3:7].C=O>C(Cl)Cl>[CH2:6]([O:8][C:9](=[O:29])[C:10]([CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:16]=1)=[CH2:11])[CH3:7]
Reactant: CCOC(=O)C(Cc1ccnc(NC(=O)OC(C)(C)C)c1)C(=O)O
Agent: C=O
Solvent: CCNCC
Solvent: ClCCl
Product: C=C(Cc1ccnc(NC(=O)OC(C)(C)C)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.2 %

Procedure:
A solution of diethylamine (0.26 g, 2.67 mmol) in methylene chloride (4 mL) was added to a mixture of 2-(2-tert-butoxycarbonylamino-pyridin4-ylmethyl)-malonic acid monoethyl ester (0.90 g, 2.66 mmol) and 37% aq. solution of formaldehyde (0.24 g, 3.00 mmol) at 0° C. The mixture was stirred for 5 h at room temperature and the mixture was poured onto ice-water and extracted with methylene chloride. The organic layer was washed with 5% NaHCO3 and dried. The crude product was purified by flash chromatography (1% methanol in CH2Cl2) to yield 2-(2-tert-butoxycarbonylamino-pyridin4-ylmethyl)-acrylic acid ethyl ester (0.58 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=[O:6].C1(O)C=CC=CC=1.[CH3:21][O:22][C:23](=[O:27])[CH:24](Br)[CH3:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[O:10][CH:24]([CH3:25])[C:23]([O:22][CH3:21])=[O:27]
Reactant: O=Cc1cc(Cl)c(O)c([N+](=O)[O-])c1
Reactant: COC(=O)C(C)Br
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1c(Cl)cc(C=O)cc1[N+](=O)[O-]

Procedure:
Using 3-chloro-4-hydroxy-5-nitrobenzaldehyde as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives a light yellow oil: 1H NMR (DMSO-d6, 400 MHz): δ ppm 9.98 (s, 1H), 8.43 (d, J=1.8 Hz, 1H), 8.35 (d, J=2.0 Hz, 1H), 5.08-5.15 (m, 1H), 3.62 (s, 3H), 1.57 (d, J=6.8 Hz, 3H). ESI-MS: m/z 328.1 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[CH:14][C@H:13](O)[CH2:12][N:11]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:43]([O:46][NH:47][S:48]([C:51]1[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][C:52]=1[N+:60]([O-:62])=[O:61])(=[O:50])=[O:49])[CH:44]=[CH2:45].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[CH2:43]([O:46][N:47]([C@H:13]1[CH2:12][N:11]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2])[CH:15]=[CH:14]1)[S:48]([C:51]1[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][C:52]=1[N+:60]([O-:62])=[O:61])(=[O:50])=[O:49])[CH:44]=[CH2:45]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C=C[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: C=CCONS(=O)(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCON([C@@H]1C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a stirred solution of (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxy-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 125, 17.50 g, 50.94 mmol), phosphorus triphenyl (14.70 g, 56.04 mmol), N-(allyloxy)-2,4-dinitrobenzenesulfonamide (16.22 g, 53.49 mmol) in toluene (380 mL) was added diisopropyl azodicarboxylate (11.03 ml, 56.04 mmol) at room temperature. The reaction mixture was stirred at rt overnight. The mixture was concentrated and the residue was purified by silica gel column (220 g, 0-40% Hex/EA) to give the desired product (30.8 g) as a yellow gum.
Reaction SMILES: C(OC(O[CH2:8][CH3:9])CBr)C.Cl.[C:11]1([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(O)=O.[Na+]>O.O1CCOCC1.CO>[C:11]1([C:17]2[CH:22]=[CH:21][N:20]3[CH:8]=[CH:9][N:23]=[C:19]3[CH:18]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cc(-c2ccccc2)ccn1
Reactant: CCOC(CBr)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: c1ccc(-c2ccn3ccnc3c2)cc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A mixture of bromoacetaldehyde diethyl acetal (0.88 mL, 5.9 mmol, 2.0 equiv) and concentrated HCl (0.1 mL, 0.4 equiv) in water (15 mL) was stirred at 23° C. for 2 h, then heated at 80° C. for 30 min. The mixture was allowed to cool to 23° C., and 4-phenylpyridin-2-amine (1-3, 0.50 g, 2.9 mmol, 1 equiv) and NaHCO3 (0.59 g, 7.1 mmol, 2.4 equiv) were added. The resulting mixture was then heated to 50° C. where MeOH (2 mL) and dioxane (3 mL) were added to increase solubility. The reaction mixture was stirred at 50° C. for 18 h, then concentrated. The residue was partitioned between EtOAc (200 mL) and brine (200 mL). The organic layer was concentrated to provide 7-phenylimidazo[1,2-a]pyridine (1-4) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 8.18 (d, 1H, J=7.3 Hz), 7.84 (s, 1H), 7.67 (s, 1H), 7.66 (s, 2H, J=7.3 Hz), 7.60 (s, 1H), 7.49 (t, 2H, J=7.5 Hz), 7.40 (t, 1H, J=7.3 Hz), 7.09 (dd, 1H, J=7.0, 1.2 Hz).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:15]2[CH:20]=[CH:19][N:18]=[C:17](F)[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:7]=1)[CH3:2].[CH:22]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])O.[Na+]>>[CH:22]1([NH:27][C:17]2[CH:16]=[C:15]([C:5]3[S:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=3[C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=3)[CH:20]=[CH:19][N:18]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NC1CCCC1
Reactant: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(F)c2)s1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(NC3CCCC3)c2)s1
Temperature: 25 °C
Yield: 32.7 %

Procedure:
A mixture of 2-ethyl-5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazole (0.48 g, 1.6 mmol) and cyclopentylamine (1.6 mL, 16 mmol) was heated under reflux for 14 hrs. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained crude crystals were recrystallized from ethyl acetate to give the title compound (0.19 g, yield 33%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[O:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:28]=[C:27]3[C:22]([CH2:23][CH2:24][NH:25][CH:26]3[CH3:29])=[CH:21][CH:20]=2)=[CH:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][C:19]([C:16]5[CH:17]=[CH:18][O:14][CH:15]=5)=[CH:20][CH:21]=4)[CH:26]3[CH3:29])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2ccc(-c3ccoc3)cc21
Product: CC1c2cc(-c3ccoc3)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Furan-3-yl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C1(C(=[N:14][CH:15]([CH2:21][CH:22]=[C:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])C2C=CC=CC=2)C=CC=CC=1.O.C(O)(=O)C>C1COCC1>[NH2:14][CH:15]([CH2:21][CH:22]=[C:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(CC=C1CCOCC1)N=C(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C(N)CC=C1CCOCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.4 %

Procedure:
To a solution of ethyl 2-[(diphenylmethylidene)amino]-4-(tetrahydro-4H-pyran-4-ylidene)butanoate (162) (6.8 g, 18.0 mmol) in THF (30 mL) was added water (30 mL) and glacial acetic acid (20 mL) and the reaction stirred at room temperature for 2.5 h. The reaction was concentrated in vacuo and the residue dissolved in 0.1 N HCl. It was extracted twice with ethyl acetate and the organic layer was discarded. To the aqueous layer was added solid potassium carbonate until the solution gave blue pH paper. The aqueous layer was extracted with 15% isopropanol/dichloromethane (3×) and the organic layer dried over sodium sulfate and concentrated in vacuo to afford the title compound as a clear oil (3.05 g, 79% yield).