Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([NH2:11])[CH:9]=[CH:10][C:2]1=2.F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:11][C:8]1[CH:9]=[CH:10][C:2]2[O:1][CH2:6][CH2:5][O:4][C:3]=2[CH:7]=1)([O-:21])=[O:20]
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccccc1Nc1ccc2c(c1)OCCO2
Temperature: 120 °C
Reaction time: 10 h
Yield: 67.2 %

Procedure:
5.9 g (39 mmol) of 2,3-dihydrobenzo[b]1,4-dioxin-6-amine and 5.0 g (35 mmol) of 2-fluoronitrobenzene were dissolved in N-methylpyrrolidone (70 mL) and 20.8 g (150 mmol) of potassium carbonate was added thereto. The solvent was heated with stirring for 10 hours at 120° C. The reaction mixture was poured into water, and extracted with ethyl acetate. The extracted organic layer was washed with water, 10% hydrochloric acid, water, and a saturated aqueous solution of sodium chloride in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (developing solvent: ethyl acetate:hexane=1:4), to obtain 6.4 g (yield: 66%) of N-(2-nitrophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-amine as a red liquid.
Reaction SMILES: [OH:1][CH:2]([PH:5](=[O:7])[OH:6])[CH2:3][Cl:4].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>CO>[OH:1][CH:2]([PH:5](=[O:6])[O-:7])[CH2:3][Cl:4].[NH2+:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=[PH](O)C(O)CCl
Reactant: C1COCCN1
Solvent: CO
Product: C1COCC[NH2+]1
Product: O=[PH]([O-])C(O)CCl
Yield: 99.4 %

Procedure:
To a solution of α-hydroxy-β-chloroethylphosphinic acid (1.45 g) in methanol (10 ml), a solution of morpholine (0.87 g) in methanol (10 ml) was added, and the resultant mixture was stirred for 2 hours. After removal of methanol by distillation, there was obtained 2.30 g (98%) of morpholinium α-hydroxy-β-chloroethylphosphinate (Compound No. 12) as a creamy solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:19])([F:18])[C:9]([F:17])([F:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N:20]1C2C(=CC=CC=2)C=C[CH:21]=1>CN(C)C=O>[F:18][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:21]#[N:20])([F:19])[C:9]([F:17])([F:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc2ncccc2c1
Reactant: FC(F)(c1ccccc1)C(F)(F)c1ccccc1Br
Solvent: CN(C)C=O
Product: N#Cc1ccccc1C(F)(F)C(F)(F)c1ccccc1

Procedure:
A mixture of 3.33 g. (0.01 mole) of 2-bromo-α,α,α',α'-tetrafluorobibenzyl, 2.70 g. of cuprous cyanide, 30 ml. of dry quinoline, and 3 ml. of dry dimethylformamide are stirred and heated to refluxing for about 30 hours. After cooling and dilution with ether, the precipitate is removed by filtration and washed with ether. Solvents are evaporated from the filtrate under reduced pressure leaving the product as an oily brown solid. Purification is effected by column chromatography on 150 g. of silica, the product being eluted with benzene-hexane (3:1). The fractions which show one spot of rf 0.7 on a silica thin layer plate developed with benzene are combined. Evaporation of the solvents under reduced pressure leaves white crystals, m.p. 84°-86°C. A sample for analysis is sublimed at 55°C. and 0.05 mm; m.p. 85°-86°C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]=[C:4]([C:8]2[C:9]([O:13][CH2:14][CH2:15][CH2:16]N3CCCC3=O)=[N:10][S:11][N:12]=2)[CH2:3]1.CN1CCC=[C:26]([C:30]2C(OCCN3CCCC3=O)=NSN=2)[CH2:25]1.CN1CCC=C(C2C(OCCN3C(=O)CO[CH-]3)=N[S:54]N=2)C1.CN1CCC=C(C2C(OCCCN3CCCC3)=NSN=2)C1>>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]=[C:4]([C:8]2[C:9]([O:13][CH2:14][CH2:15][C:16]3[S:54][CH:25]=[CH:26][CH:30]=3)=[N:10][S:11][N:12]=2)[CH2:3]1
Reactant: CN1CCC=C(c2nsnc2OCCCN2CCCC2=O)C1
Reactant: CN1CCC=C(c2nsnc2OCCN2[CH-]OCC2=O)C1
Reactant: CN1CCC=C(c2nsnc2OCCN2CCCC2=O)C1
Agent: CN1CCC=C(c2nsnc2OCCCN2CCCC2)C1
Product: CN1CCC=C(c2nsnc2OCCc2cccs2)C1

Procedure:
1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-(3-thienyl)-1-ethoxy)-1,2,5-thiadiazol-4yl)pyrid 1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-thienylmethoxy)-1,2,5-thiadiazol-4yl)pyrid 1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-thienylmethoxy)-1,2,5-thiadiazol-4yl)pyridine; 1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-(2-pyrrolidon-1-yl)-1-propoxy)-1,2,5-thiadiazol -4-yl)pyridine; 1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-(2-pyrrolidon- 1-yl)- 1-ethoxy)- 1,2,5thi adiaz o l-4- y l )p yri din e; 1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-(2-oxazolidon-3-yl)- 1-ethoxy)- 1,2,5thiadiazo l-4- yl )p yri dine; 1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-(1-pyrrolidyl)- 1-propoxy)- 1,2,5-thiadiazol- -yl)pyridine; or a pharmaceutically acceptable salt thereof.
Reaction SMILES: [F:1][C:2]1[N:3]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][OH:10])[N:6]=1.[C:30](Cl)(=[O:32])[CH3:31].O>N1C=CC=CC=1>[C:30]([O:10][CH2:9][CH2:8][CH2:7][C:5]1[N:6]=[C:2]([F:1])[N:3]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:4]=1)(=[O:32])[CH3:31]
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reaction time: 1.67 h

Procedure:
A solution of 2-fluoro-4-(3-hydroxy)propyl-1-triphenylmethylimidazole (386 mg. in dry pyridine (2 ml.) and acetyl chloride (78.5 μl.) was heated with stirring at 85° for 100 minutes. The solution was poured into water (25 ml.) and the mixture extracted with CH2Cl2 (3×15 ml.). The extract was washed with water and brine, dried (MgSO4), filtered, evaporated, and the residue azeotroped with toluene. The resulting orange oil was purified by column chromatography on silica gel eluting with CH2Cl2 /MeOH 100:0 to 98:2 v/v to give 4-(3-acetoxy)propyl-2-fluoro-1-triphenylmethylimidazole (127 mg.) having the following n.m.r. in CDCl3 : 1.9 (m, 2H); 2.02 (s, 3H); 2.47 (t, 2H); 4.07 (t, 2H) 6.22 (s, 1H); 7.0-7.5 (m, 15H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][C:14]#[N:15])[CH2:10][C@H:9]1[C:16](O)=O)=[O:7])(C)(C)C.[O:19]([C:26]1[CH:34]=[CH:33][C:29](C(Cl)=O)=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:35]1([NH2:42])[C:36]([NH2:41])=[CH:37][CH:38]=[CH:39][CH:40]=1>>[NH:41]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:42]=[C:16]1[CH:9]1[N:8]([C:6](=[O:7])[C:29]2[CH:28]=[CH:27][C:26]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:34][CH:33]=2)[CH2:12][C:11](=[CH:13][C:14]#[N:15])[CH2:10]1
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: Nc1ccccc1N
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C[C@H]1C(=O)O
Product: N#CC=C1CC(c2nc3ccccc3[nH]2)N(C(=O)c2ccc(Oc3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tertbutoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylic acid, 4-phenoxybenzoyl chloride, and 1,2-benzenediamine the title compound was obtained in 90% purity by LC/MS. MS(ESI+): m/z=421.2.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH:7]([C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1)=[O:8].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>CO.C1(C)C=CC=CC=1.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH:7]=[O:8]
Reactant: Brc1ccccn1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: O=Cc1cccc(-c2ccccn2)c1
Yield: 88.8 %

Procedure:
2M aq. Na2CO3 (5 mL) and a solution of 3-formylphenylboronic acid (1.14 g, 7.60 mmol) in methanol (5 mL) were added to a solution of 2-bromopyridine (1.00 g, 6.33 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.22 g, 0.19 mmol) in toluene (10 mL) and the mixture was heated to reflux for 18 h. The cooled reaction mixture was diluted with dichloromethane, washed with sat. aq. NaHCO3 and brine, dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 4:1 hexane/ethyl acetate) yielded 1.03 g (89%) of the title compound. MS 184(M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5](F)=[O:6].[NH3:16]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([NH2:16])=[O:6]
Reactant: O=C(F)c1ccc(OC(F)(F)F)c(Cl)c1
Reactant: N
Product: NC(=O)c1ccc(OC(F)(F)F)c(Cl)c1
Reaction time: 0.5 h

Procedure:
242.5 g (1 mole) of 3-chloro-4-trifluoromethoxybenzoyl fluoride were allowed to drip into 500 ml of 25% strength by weight aqueous ammonia solution with ice cooling, the mixture was then stirred for a further 30 minutes and the precipitate which deposited was filtered off with suction. 227 g of product having a melting point of 98° C. were obtained. This corresponds to a crude yield of 95% of theory.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][N:12]1[C:34](=[O:35])[N:15]2[N:16]=[CH:17][C:18]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[C:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C:14]2=[N:13]1)(=O)C.O(C)[Na].C(O)(=O)C>CO>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][N:12]1[C:34](=[O:35])[N:15]2[N:16]=[CH:17][C:18]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[C:19]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C:14]2=[N:13]1
Reactant: CC(=O)Oc1ccccc1Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Agent: CO[Na]
Solvent: CC(=O)O
Solvent: CO
Product: O=c1n(Cc2ccccc2O)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reaction time: 8 h
Yield: 79 %

Procedure:
2-((7,8-Bis(4-chlorophenyl)-3-oxo-[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl)methyl)phenyl acetate, prepared as described in 25A, (1.13 g), was dissolved in 25 mL of CH3OH. A solution of NaOCH3 (121 mg, 2.24 mmol) in a small amount of CH3OH (2 mL) was added to the reaction, and then, the reaction was stirred overnight. After this time, 0.3 mL of acetic acid was added to the reaction. The reaction was stirred for an additional 10 min, and then the resultant solution was concentrated under reduced pressure. The crude residue was purified using silica gel column chromatography using an automated system, eluting with a gradient of 0% to 60% EtOAc/hexanes for 30 min followed by 60% EtOAc/hexanes for an additional 15 min. The title compound, 2-(2-hydroxybenzyl)-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (818 mg, 79% yield) was obtained as yellow solid. MS [M+H]+=463; 1H NMR (CDCl3, 400 MHz) δ 8.54 (s, 1H), 8.14 (s, 1H), 7.32-7.17 (m, 8H), 7.04-7.00 (m, 2H), 6.94 (dd, 1H), 6.81 (td, 1H), 5.13 (s, 2H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13](O)[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:19](=[O:22])([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(CC)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:13]([O:22][CH2:19][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)c(O)c2)cc1
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CS(=O)(=O)c1ccc(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Temperature: 40 °C
Yield: 85 %

Procedure:
4′-methanesulfonyl-biphenyl-3,4-diol (30 mg) and potassium carbonate (38 mg) were dissolved in methylethylketone. Afterward, benzylbromide (60 mg) and tetrabutylammoniumiodide (2-3 mg) were added one after another and heated for 24 hours at 40° C. After filtering just potassium carbonate, the residue was separated through a silica gel attributed chromatography (an eluting agent: ethylacetate/n-hexane=1/1, v/v). As a result, the present compound (42 mg, productive yield 85%) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[S:15](Cl)(=[O:18])(=[O:17])[OH:16].CCN(C(C)C)C(C)C>ClCCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][CH:11]([S:15]([OH:18])(=[O:17])=[O:16])[C:12]([OH:14])=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)CCCSSc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(O)C(CCSSc1ccccn1)S(=O)(=O)O
Yield: 48.7 %

Procedure:
4-(pyridin-2-yldisulfanyl)butanoic acid (102 mg, 0.445 mmol) was coevaporated with 1,2-dichloroethane, (2×6 ml) (to remove moisture) and re-dissolved in 6 ml of 1,2-dichloroethane. The resulting solution was then placed in a preheated oil bath (75˜80° C.). To this solution, sulfurochloridic acid (100 μL, ˜3 eq) was added and the resulting mixture was stirred for 5˜8 min. DIPEA (117 μL, 1.5 eq) was then added (to precipitate the product) and the resulting mixture was stirred for 5 min. Another portion of sulfurochloridic acid (40 ul, 1.33 eq) was added and the mixture was stirred for ˜15 min, followed by addition of DIPEA (63 μL, 0.81 eq) and stirred for 5 min. A third portion of sulfurochloridic acid (40 ul, 1.33 eq) was added and the mixture was stirred for 15˜20 min. The resulting mixture was removed from the oil bath and cooled (on ice bath). Aqueous NaOH (0.5 M) or concentrated Na2CO3 was added to raise the pH ˜12 and the reaction mixture was stirred for 10 min. The organic phase was separated, washed with water (2×10 ml), and neutralized with H3PO4 to pH 7. The organic phase was then concentrated to ˜5 ml and acidified with HCl to pH ˜4. The crude product was purified by passing through a C-18 column using eluting with a gradient of 100% water (containing 0.5% HAc) to 75% of water (containing 0.5% HAc)/25% of MeOH. Fractions containing the desired product (eluted out at 5˜10% of MeOH) were pooled, evaporated to afford 4-(pyridin-2-yldisulfanyl)-2-sulfobutanoic acid (67 mg, 0.217 mmol, 48.7% yield). 1H NMR (D2O) 8.41 (dd, 1H, J=1.5, 4.9 Hz), 7.89 (m, 2H), 7.31 (m, 1H), 3.75 (dd, 1H, J=5.1, 9.6), 2.97 (m, 1H), 2.82 (m, 1H), 2.28 (m, 2H); 13C NMR 176.60, 160.28, 150.60, 140.27, 123.39, 122.92, 69.07, 37.56, 29.45; ESI MS m/z—307.8 (M-H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH2:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>[Cu]I.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.C1COCC1>[CH3:11][Si:10]([C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([C:25]#[C:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=2)=[CH:3][CH:4]=1)([CH3:13])[CH3:12]
Reactant: C#Cc1ccc(CCCC)cc1
Reactant: C[Si](C)(C)C#Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCc1ccc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.7 %

Procedure:
4-iodophenytrimethyl silylacetylene (5.0 g, 16.6 mmol), 4-n-butylphenylacetylene (2.67 g, 16.0 mmol), CuI (32 mg, 0.16 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.35 g, 0.48 mmol), triethylamine (50 mL) and THF (50 mL) were added together and stirred at ambient temperature under N2 for 18 h. The reaction mixture was filtered to remove solids and concentrated to dryness, redissolved in CHCl3, washed with water (2×), brine, dried with MgSO4, filtered, concentrated and the solid recrystallized from hexanes to give 2.10 g (40%) product. The crude product could also be purified by washing with MeOH. This gave 1.94 g additional product for a total yield of 79%. 1H NMR (CDCl3) δ: 7.46 (m, 6H), 7.20 (d, J=8.1 Hz, 2H); 2.63 (t, J=7.6 Hz, 2H); 1.62 (m, 2H); 1.38 (m, 2H); 0.95 (t, J=7.2 Hz, 3H); 0.28 (s, 9H). 13C{1H} NMR (CDCl3): 143.7, 131.9, 131.6, 131.3, 128.5, 123.6, 122.7, 120.1, 104.7, 96.1, 91.6, 88.4, 35.6, 33.4, 22.3, 14.0, −0.1 ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:18]([OH:20])=O)[CH:4]=1.[NH2:21][C:22]1[NH:26][N:25]=[N:24][N:23]=1>S(Cl)(Cl)=O>[NH:23]1[C:22]([NH:21][C:18]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=3)[N:6]=2)=[O:20])=[N:26][N:25]=[N:24]1
Reactant: Nc1nnn[nH]1
Reactant: COc1cc(C(=O)O)nc(-c2ccc([N+](=O)[O-])cc2)c1
Solvent: O=S(Cl)Cl
Product: COc1cc(C(=O)Nc2nnn[nH]2)nc(-c2ccc([N+](=O)[O-])cc2)c1
Yield: 65.8 %

Procedure:
In the same manner as described in Example 13-(1), 4-methoxy-6-(4-nitrophenyl)-2-pyridinecarboxylic acid (2.54 g), thionyl chloride (30 ml) and 5-aminotetrazole (1.2 g) are treated to give N-(5-tetrazolyl)-4-methoxy-6-(4-nitrophenyl)-2-pyridinecarboxamide (2.08 g). M.P. 279°-281° C. (decomp.) (recrystallized from dimethylformamide)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[CH2:15](I)[CH3:16]>>[CH2:15]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1)[CH3:16]
Reactant: O=[N+]([O-])c1ccc(-c2ncc[nH]2)cc1
Reactant: CCI
Product: CCn1ccnc1-c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-(imidazol-2-yl)-nitrobenzene and ethyl iodide
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]2[C:13](=[O:14])[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:29]([O:33][CH2:34][CH3:35])(=[O:32])[CH:30]=O.[BH3-]C#N.[Na+]>C1COCC1.CCO.CC(O)=O>[CH2:34]([O:33][C:29](=[O:32])[CH2:30][NH:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]2[C:13](=[O:14])[NH:12][C:11]3=[CH:15][CH:16]=[CH:17][CH2:18][C:10]3=[CH:9][CH2:8]2)=[CH:4][C:3]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:35]
Reactant: CCOC(=O)C=O
Reactant: Nc1ccc(OC2CCc3ccccc3NC2=O)cc1OCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CNc1ccc(OC2CC=C3CC=CC=C3NC2=O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 3-(4-amino-3-benzyloxyphenoxy)-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (7.4 mmol) and ethyl glyoxylate (1.44 mL, 7.4 mmol) in THF (5 mL) is stirred at RT for 5 h. The mixture is diluted with 38 mL of EtOH/HOAc (9:1) then NaCNBH3 (0.91 g, 14 mmol) is added and stirring is continued for 18 h. The solvent is removed under reduced pressure and the residue triturated with water. The solid is purified by column chromatography using a gradient of 33-50% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:12]2[OH:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]([F:37])([F:36])[CH2:32][CH2:33][CH2:34]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:12]2[O:29][CH2:34][CH2:33][CH2:32][C:31]([F:37])([F:36])[F:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Reactant: OCCCC(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(OCCCC(F)(F)F)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a solution of ethyl 6-benzyloxy-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (5.93 g, 15 mmol), 4,4,4-trifluorobutanol (2.31 g, 18 mmol) and tributylphosphine (7.5 ml, 30 mmol) in tetrahydrofuran (50 mL) was added 1,1′-(azodicarbonyl)dipiperidine (7.57 g, 30 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give ethyl 6-benzyloxy-2-isobutyl-1-oxo-4-(4,4,4-trifluorobutoxy)-1,2-dihydro-3-isoquinolinecarboxylate (6.71 g, 88.5%) as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH2:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2Cl)[CH3:2].[C:13]1([Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCOCC>[CH2:1]([C:3]1[CH2:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: Br[Mg]c1ccccc1
Reactant: CCC1=Cc2cccc(Cl)c2C1
Solvent: CCOCC
Product: CCC1=Cc2cccc(-c3ccccc3)c2C1
Yield: 80 %

Procedure:
A 5L flask was equipped as in Example 3. 178 g 2-ethyl-7-chloroindene (1 mol), 1L ether and 10.8 g Ni(dpp) (0.02 mol, 2 mol %) added, followed by 355 mL of 3.1M phenylmagnesium bromide in ether (1.1 mol, 10% excess). After quenching and work-up by the method described in Example 3, 176 g 2-ethyl-7-phenylindene (0.8 mol) was obtained by vacuum distillation at 140° C. in 80% yield.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]4[NH:22][CH:23]=[C:24]([C:26]([O:28]C)=[O:27])[N:25]=4)=[CH:16][CH:15]=3)[C:10]([CH2:30][CH3:31])=[C:9]([CH3:32])[N:8]=2)=[CH:4][CH:3]=1.[Li+].[OH-].O.C1COCC1.Cl>O.CO>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]4[NH:22][CH:23]=[C:24]([C:26]([OH:28])=[O:27])[N:25]=4)=[CH:18][CH:19]=3)[C:10]([CH2:30][CH3:31])=[C:9]([CH3:32])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(Cc2nc(C(=O)OC)c[nH]2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(Cc2nc(C(=O)O)c[nH]2)cc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A 8-mL vial was charged with methyl 2-[[4-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]methyl]-1H-imidazole-4-carboxylate (8 mg, 0.017 mmol, 1 eq.), LiOH/H2O (19 mg, 0.44 mmol, 26 eq.), THF (1 ml), MeOH (0.2 ml) and water (0.2 ml). The resulting mixture was stirred at 55° C. overnight. After cooling to room temperature, the mixture was added 2N HCl aq. to pH 6˜7. The precipitate was collected by filtration and washed with water. After drying, the title compound was obtained as a solid (4.8 mg, 62% yield). MW=453.94. 1H NMR (400 MHz, DMSO-d6) δ 8.52 (brs, 1H), 7.65 (m, 3H), 7.55 (d, J=4.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 2H), 7.16 (d, J=4.0 Hz, 1H), 3.97 (s, 2H), 2.73 (q, J=7.2 Hz, 2H), 2.49 (s, 3H), 1.09 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=O)=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=1>>[CH3:15][O:16][C:17]1[C:22]([NH:23][CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=2)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: COc1ncccc1N
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Product: COc1ncccc1NCCc1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 33, step 1, (4-trifluoromethyl-phenyl)-acetic acid (commercially available) was coupled with 2-methoxy-pyridin-3-ylamine (commercially available) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([O:16]CC)[CH3:15])[S:10][C:9]2=[S:19])=[CH:4][CH:3]=1.O.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([OH:16])[CH3:15])[S:10][C:9]2=[S:19])=[CH:6][CH:7]=1
Reactant: CCOC(C)=C1SC(=S)N(c2ccc(Cl)cc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(O)=C1SC(=S)N(c2ccc(Cl)cc2)C1=O

Procedure:
To a mixture of 32 g. (0.1 m.) of 3-(4'-chlorophenyl)-5-(1'-ethoxyethylidene)-rhodanine in 400 ml. of water and 250 ml. of methanol is added 85 ml. of 5% sodium hydroxide solution and the resulting suspension is stirred at room temperature for 5 hours. The reaction mixture is filtered and the filtrate is decolorized, then acidified with dilute hydrochloric acid to give 3-(4'-chlorophenyl)-5-(1'-hydroxyethylidene)-rhodanine, m.p. 200°-205°C.