Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[C:23]([O:28]C)=[N:24][CH:25]=[CH:26][CH:27]=5)[CH:19]=[C:18]([CH3:30])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Si](I)(C)(C)C.CO>CC#N>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([CH3:30])[CH:19]=[C:20]([C:22]5[C:23](=[O:28])[NH:24][CH:25]=[CH:26][CH:27]=5)[N:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COc1ncccc1-c1cc(C)cc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)n1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: CC#N
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc(-c2ccc[nH]c2=O)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-4-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (69 mg, 0.17 mmol) in CH3CN (2.5 mL) was added TMSI (49 uL, 0.34 mmol) dropwise at 20° C. The reaction was stirred at 50° C. for 30 min. MeOH (1.0 mL) was added and the solution was evaporated to dryness. The residue was re-dissolved in DCM-EtOAc (1:3) before it was washed with NaHSO3 (2×) and brine. The organics were dried over MgSO4 and evaporated to dryness. The crude material was purified by column chromatography (0-10% MeOH-EtOAc) to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(4-methyl-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 387.2. found 388.1 (M+1)+. Retention time 1.38 minutes.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:25])[N:8]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:7]1=[O:36].[C:40]([O:44][CH2:45][CH3:46])(=[O:43])[CH:41]=[CH2:42].C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:11]2[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:25])[N:8]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)[C:7](=[O:36])[N:6]2[CH2:5][C:4]2[CH:37]=[CH:38][CH:39]=[C:2](/[CH:42]=[CH:41]/[C:40]([O:44][CH2:45][CH3:46])=[O:43])[CH:3]=2)=[CH:13][CH:14]=1)#[N:19]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(Cc2cccc(Br)c2)C1c1ccc(C#N)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cccc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)OCC)C2c2ccc(C#N)cc2)c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a stirred solution of ethyl 3-(3-bromobenzyl)-4-(4-cyanophenyl)-6-methyl-2-oxo-1-[3-(trifluoro-methyl-)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 35) (500 mg, 0.84 mmol) in dimethylformamide (7.0 ml) is added bis(triphenylphosphine)palladium(II) chloride (117.3 mg, 0.17 mmol), ethyl acrylate (457.2 μl, 4.18 mmol) and triethylamine (232.9 μl, 1.67 mmol). The reaction is stirred overnight (16 h) at 120° C., then cooled to room temperature, diluted with dimethylformamide (8 ml) and purified directly by preparative HPLC(RP18 column; eluent: acetonitrile/0.1% aq. formic acid 10:90→10:10). The title compound, which is still slightly impure, is isolated (356 mg) and then chromatographed again over silica gel 60 with cyclo-hexane/ethyl acetate (5:1) as eluent.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6]Br.Br[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.[P:19]([O-:26])(OCC)OCC.Cl>O1CCCC1.C1(C)C=CC=CC=1.O>[C:10]1([PH:19](=[O:26])[C:18]2[C:5]3[C:6](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:11]=[CH:10][CH:9]=2)[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][CH:9]=1
Reactant: CCOP([O-])OCC
Reactant: BrCCBr
Reactant: Brc1ccc2ccccc2c1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=[PH](c1cccc2ccccc12)c1cccc2ccccc12
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 53 %

Procedure:
Under an argon atmosphere, a solution of magnesium (2.94 g, 2.00 equivalents), a slight amount of iodine and 1,2-dibromoethane in tetrahydrofuran (60 mL) was stirred at a room temperature for 1 hour. After addition of a solution of 2-bromonaphthalene (25.00 g, 2.00 equivalent) in tetrahydrofuran (20 mL) at 27° C., the mixture was stirred at 40° C. for 45 minutes. Then, after addition of a solution of diethyl phosphite (9.77 g, 0.06 mol) in tetrahydrofuran (10 mL) at −9° C., the mixture was stirred at 2° C. for 3 hours. Further, water (20 mL) was added thereto at −5° C., followed by further addition of toluene (60 mL) and 6M-HCl (20 mL). The resulting mixture was separated into layers, and the organic layer obtained was successively washed with an aqueous 5% NaHCO3 solution and an aqueous 5% NaCl solution. The organic layer was dried over dehydrated magnesium sulfate and then spontaneously filtered, and the filtrate obtained was concentrated under reduced pressure. The residue was recrystallized from isopropyl ether/n-hexane and dried (under reduced pressure at 40° C.) to obtain the titled compound (9.621 g, white powder). The yield was 53.0%.
Reaction SMILES: Br[CH2:2][CH:3]1[O:9][CH:8]2[N:5]([C:6](=[O:10])[CH2:7]2)[CH2:4]1.[C:11]1([S-:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:11]1([S:17][CH2:2][CH:3]2[O:9][CH:8]3[N:5]([C:6](=[O:10])[CH2:7]3)[CH2:4]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CC2OC(CBr)CN12
Reactant: [S-]c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CC2OC(CSc3ccccc3)CN12
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
(3RS, 5SR)-3-Bromomethyl-4-oxa-1-azabicyclo[3.2.0]heptan-7-one (210 mg, 1.0 mmole) in dry dimethylformamide (2 ml) was added dropwise to a stirred solution of sodium thiophenolate (1.2 mmole) in dry DMF (5 ml). The solution was stirred at room temperature with exclusion of moisture for 16 hours and was then diluted with ethyl acetate (30 ml). The solution was washed three times with water, dried, and the solvent removed to give a colourless oil. The oil was chromatographed on silica gel (15 g) using ethyl acetate/petroleum ether to give the title compound as a colourless gum (205 mg, 87%). (Found : M+, 235.06551. C12H13NO2S requires 235.06669. νmax (CHCl3) 1785 (β-lactam C=O)cm-1 δ p.p.m. (CDCl3) 2.6 - 3.5 [complex, 5H, C(6)H2, C(2)H, CH2SPh[; 4.10 [dd, J 11.5Hz, J' 6Hz, 1H, C(2)H]; 4.52 [quin., J 6Hz, 1H, C(3)H]; 5.43 [d, J 2.5Hz, 1H, C(5)H]; 7.48 (5H, aromatic H). m/e : 235 (M+, 100%), 192 (30), 123 (71).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=O)[CH2:7]2)([O-:3])=[O:2].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7]2)([O-:3])=[O:2]
Reactant: O=C1Cc2ccc([N+](=O)[O-])cc2C1
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1ccc2c(c1)CC(NCc1ccccc1)C2
Temperature: 0 °C
Reaction time: 14 h

Procedure:
5-Nitro-2-indanone (1.48 g, 8.36 mmol), benzylamine (4.40 ml, 41.8 mmol), acetic acid (15.0 ml), 4 Å molecular sieves (20 ml), THF (15 ml), and MeOH (15 ml) were introduced into a flask and cooled to 0° C. Sodium cyanoborohydride (1.05 g, 16.7 mmol) was then added portionwise over a 5-minute period. The mixture was stirred for 14 hr, filtered through celite, and concentrated to a syrup. The mixture was made basic with 2N NaOH and extracted with ether (3×50 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered, concentrated and chromatographed over silica gel (3% methanol/methylene chloride) to yield 5-nitro-2-(phenylmethyl)aminoindane: (1.18 g, 53%); M.S. (M+H)+ =269.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17](O)=[O:18])[N:6]=1)=[O:4].[CH:22]1[CH:23]=[CH:24][C:25]2N(O)N=N[C:26]=2[CH:27]=1.[CH2:32]([NH:34][CH:35]1CCCCC1)[CH3:33].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH:26]1([CH2:35][N:34]([CH2:32][CH3:33])[C:17](=[O:18])[CH2:16][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=3)[C:5]([C:3](=[O:4])[C:2]([CH3:20])([CH3:1])[CH3:21])=[N:6]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:27]1
Reactant: CCNC1CCCCC1
Reactant: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)O)c2c1
Reactant: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC1CCCCC1)C(=O)Cn1nc(C(=O)C(C)(C)C)c2ccc(OC)cc21
Temperature: 25 °C

Procedure:
To a solution of 28.3 mg [3-(2,2-dimethylpropanoyl)-6-methoxy-1H-indazol-1-yl]acetic acid in 1 mL DMF was added 23.0 mg HOBt, 19.1 mg N-ethylcyclohexylamine, 38.3 mg EDC, and 45.2 mg DIEA in that order. The mixture was stirred at room temperature over night and purified by RP-HPLC using 65-100% MeCN gradient. The pure product fractions were pooled and lyophilized to give the title compound as white solid. LC-MS: 4.20 min. (m/Z=318.2, 400.3, 422.2).
Reaction SMILES: C(=O)([O-])O.[K+].C(OC(=O)C)(=O)C.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N+:22]([O-:24])=[O:23])=[C:18]([CH:21]=1)[CH:19]=O.[C:25]([O:33][CH2:34][CH3:35])(=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N+:22]([O-:24])=[O:23])=[C:18]([CH:19]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:25]([O:33][CH2:34][CH3:35])=[O:32])[CH:21]=1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=Cc1cc(Cl)ccc1[N+](=O)[O-])C(=O)OCC
Temperature: 110 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
Potassium hydrogen carbonate (8.12 g) was added to an acetic acid anhydride (18 ml) solution of 5-chloro-2-nitrobenzaldehyde (9.99 g) and diethyl malonate (8.64 g), which was stirred at 110° C. for 2 hours. The reaction mixture was added to iced-water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/10) to obtain the entitled compound (15.10 g). 1H-NMR δ: 1.10(3H, t), 1.36(3H, t), 4.15(2H, q), 4.44(2H, q), 7.42(1H, d), 7.52(1H, dd), 8.11(1H, s), 8.18(1H, d).
Reaction SMILES: BrC1C(C(N[C@H]2CCC[C@@H]2NC2C=NC(C(F)(F)F)=CN=2)=O)=NC=CC=1.Cl.[F:28][C:29]([F:44])([F:43])[C:30]1[N:31]=[CH:32][C:33]([NH:36][C@H:37]2[CH2:41][CH2:40][CH2:39][C@@H:38]2[NH2:42])=[N:34][CH:35]=1.[CH2:45]([O:47][C:48]1[C:49]([C:55](O)=[O:56])=[N:50][C:51]([CH3:54])=[CH:52][CH:53]=1)[CH3:46]>>[CH2:45]([O:47][C:48]1[C:49]([C:55]([NH:42][C@H:38]2[CH2:39][CH2:40][CH2:41][C@@H:37]2[NH:36][C:33]2[CH:32]=[N:31][C:30]([C:29]([F:28])([F:43])[F:44])=[CH:35][N:34]=2)=[O:56])=[N:50][C:51]([CH3:54])=[CH:52][CH:53]=1)[CH3:46]
Reactant: CCOc1ccc(C)nc1C(=O)O
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Agent: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ncccc1Br
Product: CCOc1ccc(C)nc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1

Procedure:
Prepared according to the procedure for 3-bromo-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]pyridine-2-carboxamide (Example 28) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14, 75 mg, 0.27 mmol) and 3-ethoxy-6-methylpyridine-2-carboxylic acid (CAS number 1228188-14-4; 58 mg, 0.32 mmol) and was then purified by column chromatography (silica, 40-100% ethyl acetate/petrol) followed by partitioning between ethyl acetate and a saturated solution of sodium bicarbonate. The organics were filtered through a hydrophobic frit and concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][NH2:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][C:26](Cl)=[O:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][C:26]([NH:14][CH2:13][CH2:12][CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(CCCN)cc1OC
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CCCNC(=O)Cc2ccc(OC)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 13 h
Yield: 53.5 %

Procedure:
A solution of 3-(3,4-dimethoxy-phenyl)-propylamine (12.51 g, 64.06 mmol) and TEA (10 ml, 71.84 mmol) in anhydrous THF (70 ml) was cooled to 0° C. and (3,4-dimethoxy-phenyl)-acetyl chloride (13.75 g, 64.07 mmol) in THF (28 ml) was added dropwise. After stirring at RT for 13 h under nitrogen, a saturated aqueous NaHCO3 solution was added and the reaction mixture was extracted three times with AcOEt. The organic phase was dried over anhydrous MgSO4, filtered and the solvent was removed in vacuo. A subsequent washing of the crude solid with toluene gave the title compound (12.81 g, 34.30 mmol, 53%) as a beige solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].S(Cl)([Cl:18])=[O:17].[CH2:20]([N:22](CC)CC)[CH3:21]>>[N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([Cl:18])=[O:7])([O-:3])=[O:2].[NH2:22][CH2:20][C:21]([O:8][CH2:6][C:5]1[CH:4]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:17]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCN(CC)CC
Reactant: O=S(Cl)Cl
Product: NCC(=O)OCc1ccccc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
As shown in scheme B, treatment of 2,4-dinitrobenzoic acid with chlorinating agent such as thionyl chloride gave 2,4-dinitrobenzoyl chloride which on further treatment with benzyl glycinate in the presence of triethylamine gave benzyl 2-(2,4-dinitrobenzamido)acetate (intermediate 1). The intermediate 1 is treated either with K18F or K19F in the presence of a catalyst such as kryptofix[2.2.2] or 18-crown-6 to yield benzyl 2-(2-fluoro-4-nitrobenzamido)acetate, which on reduction with hydrogen gas or hydrogen source in the presence of Pd/C gave 2-(4-amino-2-fluorobenzamido)acetic acid (compound 1) in good yield. Alternatively, treatment of 2,4-dinitrobenzoyl chloride with glycine in presence of a mild base such as sodium carbonate gave 2-(2,4-dinitrobenzamido)acetic acid (intermediate 2). Treatment of intermediate 2 either with K18F or K19F gave 2-(2-fluoro-4-nitrobenzamido)acetic acid, which on reduction with zinc dust and ammonium formate or hydrogen gas/hydrogen source in the presence of Pd/C gave compound 1. Treatment of intermediate 2 either with K18F or K19F and further reduction with iron powder in the presence of acetic anhydride-acetic acid gave 2-(4-acetamido-2-fluorobenzamido)acetic acid (compound 2).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([CH:11]([NH:20][C:21](=[O:24])[O:22]C)[C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5]1)([CH3:3])[CH3:2].[H-].[Na+].CC(O)=O.O>CN(C=O)C>[CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[NH:20][C:21](=[O:22])[O:24][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5]1)([CH3:2])[CH3:3]
Reactant: COC(=O)NC(C(=O)c1ccccc1)c1ccc(=O)n(C(C)C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1nc(-c2[nH]c(=O)oc2-c2ccccc2)ccc1=O
Temperature: 72.5 °C
Yield: 70.2 %

Procedure:
A solution of methyl [1-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-oxo-2-phenylethyl]carbamate (2.46 g) in DMF (10 ml) was added to a suspension of NaH (60% dispersion in mineral oil) (314 mg) in DMF (15 ml) and the mixture was heated at 70-75° C. for 3 hours. A mixture of AcOH (0.5 ml) and water (75 ml) was added to the mixture to give a precipitate. The precipitate was collected by filtration and dried under reduced pressure to give 2-isopropyl-6-(2-oxo-5-phenyl-2,3-dihydro-oxazol-4-yl)-3(2H)-pyridazinone as a solid (1.56 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:8]#[C:9][NH2:10].[N+:11]([O-:14])([OH:13])=[O:12].C(OCC)C>C(O)C>[N+:11]([O-:14])([OH:13])=[O:12].[C:2]1([NH:1][C:9]([NH2:10])=[NH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CN
Reactant: Nc1ccccc1
Solvent: CCOCC
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: N=C(N)Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
To a solution of aniline (1.28 ml, 14 mmol) in ethanol (14 ml) was added cyanamide (1.25 ml, 16.1 mmol) and nitric acid (1 ml, 14 mmol), and the reaction was heated to reflux. After 16 hours, the reaction was cooled to room temperature and poured into diethyl ether. The resulting precipitate was filtered and dried to afford the title compound as a gray solid (2.50 g, 13 mmol, 90%). NMR (300 MHz, CD3OD): δ 7.47 (m, 2H), 7.36 (m, 1H), 7.30 (m, 2H).
Reaction SMILES: CO[C:3]([C:5]#[C:6][C:7]([O:9]C)=[O:8])=[O:4].[OH:11][C:12]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][C:16]([CH3:25])([CH3:24])[O:17]2.[OH-].[Na+]>O1CCOCC1.O.OS(O)(=O)=O>[CH3:23][O:22][C:20]1[C:21]2[C:3](=[O:4])[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[O:11][C:12]=2[C:13]2[CH2:14][CH2:15][C:16]([CH3:25])([CH3:24])[O:17][C:18]=2[CH:19]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: COc1cc(O)c2c(c1)OC(C)(C)CC2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc2c(c3oc(C(=O)O)cc(=O)c13)CCC(C)(C)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.3 %

Procedure:
To a solution of dimethylacetylenedicarboxylate (7.5 g) in dioxan (100 ml) containing `Triton 8` (10 drops) was added 5-hydroxy-7-methoxy-2,2-dimethylchroman (10.0 g) and the resulting mixture was warmed on a steam bath for 2 hours. A solution of sodium hydroxide (4.0 g) in water (20 ml) was added and heating was continued for 2 hours more. The organic solvent was removed and water (50 ml) was added to the residue and the mixture was acidified to give an oil which was extracted into ethylacetate. This solution was dried over MgSO4, filtered and the filtrate was evaporated to dryness. The oil so obtained was dissolved in concentrated H2SO4 (50 ml) and the solution was stirred at room temperature for 30 minutes, poured into ice and extracted with ethyl acetate. This solution was washed with water, dried (MgSO4), filtered and evaporated to dryness. The oil so produced was triturated with ethyl acetate, cooled to 0°, and the solid produced was filtered and dried. The solid was crystallised from ethanol to give 8,9-dihydro-5-methoxy-8,8-dimethyl-4-oxo-4H,10H-benzo[1,2-b:3,4-b']dipyran-2-carboxylic acid as a white solid (3.4 g, 23%) mp 225°-6°.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14]>CCN(CC)CC.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:17][O:16][C:12](=[O:15])/[CH:13]=[CH:14]/[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Brc1cnc2ccccc2c1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1cnc2ccccc2c1
Temperature: 100 °C
Yield: 100 %

Procedure:
A Fisher-Porter pressure bottle was charged with 3-bromoquinoline (2.77 mL, 20 mmol), methyl acrylate (2.25 mL, 25 mmol), palladium diacetate (44 mg, 0.2 mmol), and tri-o-tolylphosphine (244 mg, 0.802 mmol) in Et3N (10 mL). The atmosphere was replaced with argon, the bottle sealed and the mixture was stirred and heated at 100° C. for 6 h. The cooled mixture was partitioned between CH2Cl2 (200 mL) and H2O (100 mL) and the aqueous layer was extracted with CH2Cl2 (2×100 mL). The combined organic layers were washed with H2O (100 mL) dried (Na2SO4) and concentrated to give 5.56 g of crude product which was purified by silica gel chromatography, eluting with a mixture of EtOAc and hexane in (1:1) to give (E)-3-(3-quinolinyl)-2-propenoic acid methyl ester (4.26 g, 20 mmol) in quantitative yield, mp 118° -120° C.
Reaction SMILES: C(OC[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14]COCC)[C:7]=1[CH3:19])C.Cl.O>CO>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[C:7]([CH3:19])[C:8]=1[OH:14]
Reactant: CCOCOc1ccc(OC)c(OCOCC)c1C
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccc(O)c(C)c1O
Yield: 98 %

Procedure:
A solution of 5a (910 mg, 3.37 mmol) in MeOH (28.0 mL) at room temperature was treated dropwise with 3 M HCl (9.00 mL, 26.9 mmol), then heated to reflux for 1 hour. Water (30 mL) was added and the solution was extracted with EtOAc (3×30 mL). Combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 6:1 Hexane:EtOAc) to afford 6a as a red amorphous solid (509 mg, 98%): 1H NMR (Acetone-d6, 500 MHz) 7.68 (s, 1H), 7.24 (s, 1H), 6.60 (d, J=11 Hz, 1H), 6.29 (d, J=11 Hz, 1H), 3.74 (s, 3H), 2.09 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 144.7, 142.1, 139.7, 115.6, 110.2, 108.6, 55.6, 7.6; IR (film) νmax 3583, 2920, 2359, 1616, 1259, 1090, 1020, 798 cm−1.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]([C:14]([C:20]#[N:21])=[C:15](SC)SC)#[N:13].[H-].NN.[NH2:25][CH2:26][CH2:27][CH2:28][S:29][C:30]1[O:31][CH:32]=[CH:33][N:34]=1.BrCCCC1C=CC=C2C(NC(=O)C=12)=O>>[C:12]([C:14]([C:20]#[N:21])=[C:15]([NH:25][CH2:26][CH2:27][CH2:28][S:29][C:30]1[O:31][CH:32]=[CH:33][N:34]=1)[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])#[N:13]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: NCCCSc1ncco1
Reactant: CSC(SC)=C(C#N)C#N
Agent: NN
Agent: O=C1NC(=O)c2c(CCCBr)cccc21
Agent: [H-]
Product: Cc1nc[nH]c1CSCCNC(NCCCSc1ncco1)=C(C#N)C#N

Procedure:
Reaction of 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole with 1,1-dicyano-2,2-bis methylthioethylene by the procedure of Example 8(i) yields1,1-dicyano-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene. (iii) Reaction of this methylthio compound with 2-(3-aminopropyl)thiooxazole by the procedure of Example 1(a) (ii) gives the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([C:13]3[N:17]4[CH:18]=[CH:19][C:20]([CH:22]=O)=[CH:21][C:16]4=[N:15][CH:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH:2]=1.Cl.[NH2:25][OH:26]>C(O)C.CO.ClCCl>[NH3:1].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([C:13]3[N:17]4[CH:18]=[CH:19][C:20]([CH:22]=[N:25][OH:26])=[CH:21][C:16]4=[N:15][CH:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH:2]=1
Reactant: O=Cc1ccn2c(-c3cccc(-c4cccnc4)c3)cnc2c1
Reactant: NO
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: N
Product: ON=Cc1ccn2c(-c3cccc(-c4cccnc4)c3)cnc2c1
Temperature: 60 °C
Yield: 189 %

Procedure:
3-[3-(Pyridin-3-yl)phenyl]imidazo[1,2-α]pyridine-7-carboxaldehyde (0.30 g, 1.0 mmol) and hydroxylamine hydrochloride (0.208 g, 3.0 mmol) were suspended in ethanol (15 ml) then heated at 60° C. for 45 min. The mixture was diluted with 50% methanol in dichloromethane (200 ml) and pre-adsorbed onto silica. Purification by flash column chromatography on silica gel eluting with dichloromethane/methanol/conc. ammonia (95:5:0.5) gave the title compound (297 mg, 94%) as a white foam. Further purification of this material by preparative thin-layer chromatography eluting with dichloromethane/methanol/conc. ammonia (95:5:0.5) gave (E)-3-[3-(pyridin-3-yl)phenyl]imidazo[1,2-α]pyridine-7-carboxaldehyde oxime as a white solid followed by (Z)-3-[3-(pyridin-3-yl)phenyl]imidazo[1,2-α]pyridine-7-carboxaldehyde oxime also as a white solid.