Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]OP(CC(=O)C)(=O)OC.C([O-])([O-])=O.[K+].[K+].O=[CH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=1>CC#N.CO>[CH2:20]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=1)[CH2:19][C:18]#[CH:1]
Reactant: COP(=O)(CC(C)=O)OC
Reactant: COC(=O)Cc1ccc(CCC=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: C#CCCc1ccc(CC(=O)OC)cc1
Reaction time: 2 h

Procedure:
Dimethyl-2-oxopropylphosphonate (1.2 equiv, 1.5 g, 9.1 mmol) was added to a suspension of K2CO3 (3 equiv, 3.1 g, 23 mmol) and p-TsN3 (1.2 equiv, 1.8 g, 9.1 mmol) in MeCN (144 mL). The mixture was then stirred for 2 h. A solution of the methyl 2-(4-(3-oxopropyl)phenyl)acetate (1 equiv, 1.56 g, 7.6 mmol) in MeOH was then added in one portion and the reaction was stirred overnight. The solvent was evaporated under reduced pressure. The residue was partitioned between Et2O (100 mL) and water (100 mL). The aqueous phase was separated and extracted with Et2O (25 mL) twice. The organic phases were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column eluting with 0-30% EtOAc in hexanes to afford methyl 2-(4-(but-3-ynyl)phenyl)acetate in 980 mg (64%). LRMS: 202.5 (calc) 225.1 (found)(MNa)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH:13]([C:15]2([CH2:18][CH3:19])[CH2:17][CH2:16]2)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Br)(Br)[Br:21].[Br-].[Li+]>[Br-].[Zn+2].[Br-]>[CH2:18]([C:15](=[CH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:16][CH2:17][Br:21])[CH3:19]
Reactant: BrP(Br)Br
Reactant: CCC1(C(O)CCc2ccc(OC)c(OC)c2)CC1
Agent: [Br-]
Agent: [Li+]
Agent: [Zn+2]
Product: CCC(=CCCc1ccc(OC)c(OC)c1)CCBr

Procedure:
3-Ethyl-6-(3,4-dimethoxyphenyl)-3-hexenyl bromide [V; Ar is 3,4-(CH3O)2C6H3, R is C2H5 ] was prepared from 16 g. of 2-(3,4-dimethoxyphenyl)ethyl 1-ethylcyclopropyl carbinol (Preparation B4), 16.8 g. of phosphorus tribromide, 16.8 g. of lithium bromide and 17.6 g. of zinc bromide according to the procedure given above in Preparation C1. The product was used directly in the succeeding step (Preparation D4) without isolation.
Reaction SMILES: O/[C:2](=[CH:8]\[C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)/[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[CH:26]1([NH:32][NH2:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CCO.CCOC(C)=O>[CH:26]1([N:32]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:12][CH:11]=3)=[CH:8][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:33]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCOC(=O)/C(O)=C/C(=O)c1ccc(OCc2ccccc2)cc1
Reactant: NNC1CCCCC1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Yield: 98.6 %

Procedure:
The butenoate 1.2 (5.00 g, 15.3 mmol) and cyclohexylhydrazine hydrochloride (2.77 g, 18.4 mmol) were heated at refluxed in EtOH (60 ml) for 2 h. Concentration in vacuo resulted in formation of a solid which was suspended in EtOAc and filtered through a 1″ pad of SiO2, elution with ethyl acetate. The filtrate was concentrated to afford 6.10 g (98%) of the desired pyrazole ester 1.3. MS (ESI) 405.4 (M+H+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:8]([CH:13]=O)=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2].[CH2:15]([O:17][C:18]([C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[NH2:25])=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[NH:25][CH2:13][C:8]1[C:7]([O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:19])[CH3:16]
Reactant: CCOCCOc1cccnc1C=O
Reactant: CCOC(=O)c1[nH]ccc1N
Product: CCOCCOc1cccnc1CNc1cc[nH]c1C(=O)OCC
Yield: 71.1 %

Procedure:
The title compound (0.17 g, 73%) was prepared in accordance with general method A using 3-(2-ethoxyethoxy)pyridine-2-carbaldehyde (0.21 g, 1.08 mmol) and 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.11 g, 0.717 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]1[O:15][CH2:14][CH2:13][O:5]1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)c(C2OCCO2)c1

Procedure:
2-Chloro-5-nitrobenzaldehyde (18.6 g), ethylene glycol (18.6 ml), p-toluenesulfonic acid (monohydrate), (0.1 g), were refluxed in toluene (150 mL) for 3 hours. Water was removed azeotropically with a Dean-Stark trap. The reaction mixture was then transfered to seperatory funnel, washed with aqueous bicarbonate, water, dried (MgSO4), filtered and evaporated producing 22.2 g of 2-(2- chloro-5-nitrophenyl-1,3-dioxolane as a white solid, m.p. 78-81° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:25]=[CH:24][C:11]([O:12][CH:13]([CH3:23])[C:14]([O:21][CH3:22])=[CH:15][C:16](OCC)=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[H-].O>CCOCC>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:25]=[CH:24][C:11]([O:12][CH:13]([CH3:23])[C:14]([O:21][CH3:22])=[CH:15][CH2:16][OH:17])=[CH:10][CH:9]=2)=[CH:26][CH:27]=1
Reactant: CCOC(=O)C=C(OC)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: COC(=CCO)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 0.33 h

Procedure:
To a slurry of LiAIH4 (100 mg) in anhydrous ether (20 ml) is added dropwise at 0°, a solution of ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoate (500 mg) in ether. After addition is complete, the reaction mixture is stirred for about 20 minutes. Excess of the hydride is decomposed using wet ether and water. Filtration and evaporation of filtrate gives the C-1 alcohol, 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-penten-1-ol, MS m/e 440 (M+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([O:17]CC)=[O:16])=[CH:11]2.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][CH2:3][CH:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11]2
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC(C)COC)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(=O)O)[nH]c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
To a mixture of ethyl 7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (2.36 g), tetrahydrofuran (20 mL) and ethanol (20 mL) was added 1M aqueous sodium hydroxide solution (7.9 mL). The mixture was stirred at 50° C. for 2 h and at room temperature over night. To the mixture was added 1M aqueous sodium hydroxide solution (10.5 mL). The whole was stirred at 50° C. for further 1 h. The reaction mixture was concentrated in vacuo. The residue was acidified with 1M hydrochloric acid. Ethyl acetate and water were added to the mixture and the organic layer was separated. The organic layer was washed with water, dried (MgSO4), filtered, and concentrated in vacuo. The residue was triturated and washed with hexane to give the title compound (1.288 g, 58%) as a pink solid. The solid was recrystallized from ethyl acetate-hexane to give white crystals. mp 135.9-137.4° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([CH2:11][CH:12]([CH:20](O)[CH3:21])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:42](C(OCC)=O)=NC(OCC)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[NH2:42][CH:20]([CH3:21])[CH:12]([CH2:11][C:9]1[O:10][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: CCOC(=O)c1ccc(CC(C(=O)OC(C)(C)C)C(C)O)o1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CC(C(=O)OC(C)(C)C)C(C)N)o1
Temperature: 25 °C

Procedure:
To 1.65 g of tert-butyl (2RS,3SR)-2-{5-(ethoxycarbonyl)-2-furylmethyl}-3-hydroxybutanoate in 40 ml of tetrahydrofuran, 2.32 g of triphenylphosphine, 1.40 ml of diethyl azodicarboxylate and 2.43 g of diphenylphosphoryl azide were added successively under cooling with ice under stirring, and the resulting reaction solution was stirred at room temperature for 18 hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography [hexane/ethyl acetate=12/1→3/1]. The resulting azide was refluxed together with 2.33 g of triphenylphosphine in 33 ml of 10% hydrous tetrahydrofuran under heating for 3 hours. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=1/1→ethyl acetate/methanol=10/1] to give 686 mg of the title compound as a pale yellow oily substance.
Reaction SMILES: I.[Cl:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]([CH3:15])[NH:6][C:7](SC)=[N:8]2.[OH-].[NH4+:17]>C(#N)C.C(O)(C(F)(F)F)=O>[Cl:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]([CH3:15])[NH:6][C:7]([NH2:17])=[N:8]2
Reactant: [NH4+]
Reactant: CSC1=Nc2cccc(Cl)c2C(C)N1
Agent: I
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC1NC(N)=Nc2cccc(Cl)c21
Temperature: 130 °C
Yield: 62 %

Procedure:
5-Chloro-4-methyl-2-methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (100 mg, 0.28 mmol) was suspended in a mixture of ammonium hydroxide (1 ml, 25% in H2O) and acetonitrile (1 ml) and heated in a microwave oven to 130° C. (15 min) and subsequently to 170° C. (30 min). The title compound (35 mg, 62%) was isolated from the reaction mixture by preparative, reverse-phase HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min) as a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].O[CH:7]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:8][N:9]1[CH2:14][CH2:13][C:12]([N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19](=[O:22])[CH2:20][CH3:21])([CH2:15][O:16][CH3:17])[CH2:11][CH2:10]1>ClCCl>[ClH:3].[Cl:5][CH:7]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:8][N:9]1[CH2:14][CH2:13][C:12]([N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19](=[O:22])[CH2:20][CH3:21])([CH2:15][O:16][CH3:17])[CH2:11][CH2:10]1
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCN(CC(O)c2ccccc2)CC1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(CC(Cl)c2ccccc2)CC1
Yield: 61.7 %

Procedure:
To 4.5 parts of sulfinyl chloride is added dropwise a mixture of 13 parts of N-[1-(2-hydroxy-2-phenylethyl)-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide hydrochloride and 260 parts of dichloromethane. Upon completion, the whole is stirred and refluxed for a few hours. The reaction mixture is cooled and the solvent is evaporated. The residue is taken up in 2-propanone. The mixture is filtered and the filtrate is treated with activated charcoal. The latter is filtered off and the filtrate is evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 9.2 parts (61.7%) of N-[1-(2-chloro-2-phenylethyl)-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide monohydrochloride; mp. 145.3° C.
Reaction SMILES: C(C1C=CC(C(NC2C(C)=C(C3N=C(NC4C=CC(C(N(C(C)C)C)C(O)=O)=CC=4)C(=O)N(C)C=3)C=CC=2)=O)=CC=1)(C)(C)C.[CH2:45]([N:47]1[CH2:52][CH2:51][N:50]([CH:53]([C:59]2[CH:64]=[CH:63][C:62]([NH:65][C:66]3[C:71](=[O:72])[N:70]([CH3:73])[CH:69]=[C:68]([C:74]4[CH:79]=[CH:78][CH:77]=[C:76]([NH:80][C:81]([C:83]5[S:87][C:86]6[CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][C:85]=6[CH:84]=5)=[O:82])[C:75]=4[CH3:93])[N:67]=3)=[CH:61][CH:60]=2)[C:54]([O:56]CC)=[O:55])[CH2:49][CH2:48]1)[CH3:46]>>[CH2:45]([N:47]1[CH2:52][CH2:51][N:50]([CH:53]([C:59]2[CH:60]=[CH:61][C:62]([NH:65][C:66]3[C:71](=[O:72])[N:70]([CH3:73])[CH:69]=[C:68]([C:74]4[CH:79]=[CH:78][CH:77]=[C:76]([NH:80][C:81]([C:83]5[S:87][C:86]6[CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][C:85]=6[CH:84]=5)=[O:82])[C:75]=4[CH3:93])[N:67]=3)=[CH:63][CH:64]=2)[C:54]([OH:56])=[O:55])[CH2:49][CH2:48]1)[CH3:46]
Reactant: CCOC(=O)C(c1ccc(Nc2nc(-c3cccc(NC(=O)c4cc5c(s4)CCCCC5)c3C)cn(C)c2=O)cc1)N1CCN(CC)CC1
Agent: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(C(=O)O)N(C)C(C)C)cc2)n1
Product: CCN1CCN(C(C(=O)O)c2ccc(Nc3nc(-c4cccc(NC(=O)c5cc6c(s5)CCCCC6)c4C)cn(C)c3=O)cc2)CC1
Yield: 97 %

Procedure:
Using the same procedure as described for the preparation of 29, saponification of 45 (1.29 g) gave a 97% yield (1.20 g) of 46 as an off-white solid: mp 168-170° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.79 (s, 1H), 9.25 (s, 1H), 7.96 (d, 2H, J=7.5 Hz), 7.70 (s, 1H), 7.29 (m, 6H), 3.86 (m, 1H), 3.71 (s, 3H), 3.37 (q, 2H, J=7.2 Hz), 2.81 (m, 2H), 2.69 (m, 2H), 2.42 s, 8H), 2.19 (s, 3H), 1.83 (br s, 2H), 1.61 (br s, 4H), 0.95 (t, 3H, J=7.2 Hz); MS (ESI+), m/z 655 (M+H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1.C([O-])(=[O:17])C.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[O:8]([C:5]1[CH:6]=[CH:7][C:2](=[O:17])[NH:3][N:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1ccc(Oc2ccccc2)nn1
Reactant: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1ccc(Oc2ccccc2)n[nH]1
Temperature: 110 °C
Yield: 84.8 %

Procedure:
A mixture of 3-chloro-6-phenoxy-pyridazine (1.01 g, 4.89 mmol) and sodium acetate (1.40 g, 17.06 mmol) in glacial acetic acid (50 mL, 0.1M) was heated to 110° C. overnight. After this time the reaction was cooled to 25° C. and was diluted with water (450 mL). The reaction was brought to pH=5-6 by the addition of a 5N aqueous sodium hydroxide solution. The resulting solution was extracted with ethyl acetate (3×100 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with ethyl acetate and concentrated in vacuo. The resulting oil was azeotroped with methanol four times and dried in vacuo to afford 6-phenoxy-2H-pyridazin-3-one (0.78 g, 86%) as a white solid. 1H-NMR (300 MHz, DMSO-d6) δ ppm 7.00 (d, J=10.0 Hz, 1H), 7.13-7.27 (m, 3H), 7.34-7.46 (m, 3H), 12.29 (br s, 1H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:15]([O:16][CH3:17])=[CH:14][C:8]([CH:9]=[CH:10][C:11](O)=[O:12])=[CH:7][C:6]=1[O:18][CH3:19])(=[O:3])[CH3:2].O1C=CN=C1[Cl:25]>CN(C)C=O.O1CCCC1>[C:1]([O:4][C:5]1[C:15]([O:16][CH3:17])=[CH:14][C:8]([CH:9]=[CH:10][C:11]([Cl:25])=[O:12])=[CH:7][C:6]=1[O:18][CH3:19])(=[O:3])[CH3:2]
Reactant: Clc1ncco1
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1OC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(C=CC(=O)Cl)cc(OC)c1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture o 4-acetoxy-3,5-dimethoxycinnamic acid (638 mg), dimethylformamide (2 drops) and tetrahydrofuran (8 ml) was added oxazolyl chloride (0.25 ml). The mixture was stirred at room temperature for one hour and then the solvent was distilled off to obtain 4-acetoxy-3,5-dimethoxycinnamic acid chloride as crystals. To a solution of the crystals in dichloromethane (15 ml) were added 5-amino-4-(2-chlorophenyl)-2-ethylthieno[2,3-b]pyridine (576 mg) and N,N-dimethylaniline (0.25 ml) with ice cooling. After warming to room temperature, the mixture was stirred for 5 hours, washed in turn with water, aqueous saturated NaHCO3 solution and water, and then dried over MgSO4. The solvent was distilled off and the residue was crystallized from ethanol (729 mg, 67.4%). 5-(4-Acetoxy-3,5-dimethoxycinnamoylamino)-4-(2-chloropheny ethylthieno[2,3-b]pyridine was obtained as colorless prisms by recrystallization from acetone, mp: 133°-135° C.
Reaction SMILES: COC1C=CC(C[NH:8][CH2:9][C:10]2[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])=CC=1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>CC#N.O>[CH3:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[N:12]=[C:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:28])[F:29])[C:10]([CH2:9][NH2:8])=[CH:19]2
Reactant: COc1ccc(CNCc2cc3cccc(C)c3nc2-c2ccccc2C(F)(F)F)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: Cc1cccc2cc(CN)c(-c3ccccc3C(F)(F)F)nc12

Procedure:
Prepared according to Procedure G using N-(4-methoxybenzyl)(8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methanamine (1.1427 g, 2.62 mmol, 1 eq) and ammonium cerium(iv) nitrate (3.59 g, 6.55 mmol, 2.5 eq) in CH3CN—H2O (2:1, 12 mL). After purification, (8-methyl-2-(2-(trifluoromethyl)phenyl)quino-lin-3-yl)methanamine was obtained as brown syrup. 1H NMR (DMSO-d6) δ ppm 8.47 (1 H, s), 7.91 (1 H, d, J=7.4 Hz), 7.84 (1 H, d, J=7.4 Hz), 7.67-7.81 (2 H, m), 7.47-7.62 (3 H, m), 3.46-3.70 (2 H, m), 2.61 (3 H, s), 1.86 (2 H, br. s.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Cl[C:17]1([C:29]2[C:30]([O:35][CH2:36][CH3:37])=[N:31][CH:32]=[CH:33][CH:34]=2)[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=2)[NH:19][C:18]1=[O:28].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>ClCCl>[CH2:36]([O:35][C:30]1[C:29]([C:17]2([NH:15][C:12]3[CH:13]=[CH:14][C:9]([CH2:8][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:10][CH:11]=3)[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=3)[NH:19][C:18]2=[O:28])=[CH:34][CH:33]=[CH:32][N:31]=1)[CH3:37]
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: CCOc1ncccc1C1(Cl)C(=O)Nc2ccc(C#N)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ncccc1C1(Nc2ccc(CN3CCN(C)CC3)cc2)C(=O)Nc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.1 %

Procedure:
4-(4-Methyl-piperazin-1-ylmethyl)phenylamine (425 mg, 2.07 mmol) was added to a solution of 3-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile (500 mg, 1.59 mmol) in dichloromethane (50 ml) and DIPEA (0.27 ml, 159 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h and then an aqueous NaHCO3 solution was added. The aqueous reaction mixture was extracted with dichloromethane. The combined organic phase was dried over magnesium sulfate, filtered and concentrated at reduced pressure. Purification by chromatography (silica gel, 0-20% methanol in dichloromethane) afforded 791 mg of the title compound (99% yield).
Reaction SMILES: CN(C)[C:3](=[O:22])[CH2:4][CH2:5][C:6]12[C:21]3[N:10]([C:11]4[C:16]([C:17]=3[CH2:18][CH2:19][O:20]1)=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:9][CH2:8][CH2:7]2.[OH-:24].[K+]>>[CH2:9]1[N:10]2[C:21]3[C:6]([CH2:5][CH2:4][C:3]([OH:22])=[O:24])([O:20][CH2:19][CH2:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:7][CH2:8]1
Reactant: CN(C)C(=O)CCC12CCCn3c1c(c1ccccc13)CCO2
Reactant: [OH-]
Agent: [K+]
Product: O=C(O)CCC12CCCn3c1c(c1ccccc13)CCO2

Procedure:
A solution of 1,2,3,3a,5,6-hexahydro-N,N-dimethyl-4-oxa-10b-azafluoranthene-3a-propionamide (described in Example 8, 25 g, 0.08 mole) in a 10% potassium hydroxide solution (500 ml) is stirred at reflux for 18 hr. The solution is cooled, washed with diethyl ether, acidified and extracted with diethyl ether. The organic phase is dried over sodium sulfate, evaporated and crystallized to give 1,2,3,3a,5,6-hexahydro-4-oxa-10b-azafluoranthene-3a-propionic acid (21.5 g), mp 153°-155° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([NH2:19])=[NH:18])=[CH:16][C:10]=3[N:9]=2)=[CH:6][C:5]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)=[CH:4][C:3]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH2:32])[C:26]=1[OH:33].C(N(CC)CC)C.[O-:41][C:42]#[N:43].[K+].Cl>CO>[OH:1][C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([NH2:19])=[NH:18])=[CH:16][C:10]=3[N:9]=2)=[CH:6][C:5]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)=[CH:4][C:3]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH:32][C:42]([NH2:43])=[O:41])[C:26]=1[OH:33]
Reactant: N#C[O-]
Reactant: N=C(N)c1ccc2[nH]c(-c3cc(-c4nnn[nH]4)cc(-c4cccc(CN)c4O)c3O)nc2c1
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CCN(CC)CC
Product: N=C(N)c1ccc2[nH]c(-c3cc(-c4nnn[nH]4)cc(-c4cccc(CNC(N)=O)c4O)c3O)nc2c1
Temperature: 50 °C
Reaction time: 72 h
Yield: 8.3 %

Procedure:
2-(2,2′-Dihydroxy-5-(1H-tetrazol-5-yl)-3′-aminomethylbiphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine (0.2 g 0.2 mmol), prepared as in Example 7, was dissolved in methanol (10 mL). The solution was treated with triethylamine (0.2 mL, 1.5 mmol) and then potassium cyanate (0.09 g, 1.1 mmol aqueous solution, 0.5 mL) was added in 3 portions over 1 hour. 1N hydrochloric acid (5 mL) was added and the mixture was stirred at 50° C. over 3 days. Drying afforded crude product, which was subjected to purification by reverse phase HPLC to give 2-(2,2′-dihydroxy-5-(1H-tetrazol-5-yl)-3′-ureidomethylbiphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine (0.008 g) as a brown solid. LCMS calcd. 484.47, obsrvd. (M+H) 485.1, (M−H) 483.1.
Reaction SMILES: [Na].[CH3:2][CH2:3][C@@H:4]([C:25]([C@H:27]([C@@H:29]([OH:45])[C@H:30]([C@H:32]1[O:37][C@@H:36]([CH2:38][C:39]([O:41][OH:42])=[O:40])[C@H:35]([CH3:43])[CH2:34][C@@H:33]1[CH3:44])[CH3:31])[CH3:28])=[O:26])[C@H:5]1[O:9][C@@:8]([C@:11]2([OH:23])[O:15][C@@:14]([C@@H:18]([OH:21])[CH2:19][CH3:20])([CH2:16][CH3:17])[CH2:13][C@H:12]2[CH3:22])([CH3:10])[CH2:7][C@@H:6]1[CH3:24].O.O.C([O-])(=O)C.[Co+2:52].C([O-])(=O)C.O>C(O)C>[Co:52].[CH3:2][CH2:3][C@@H:4]([C:25]([C@H:27]([C@@H:29]([OH:45])[C@H:30]([C@H:32]1[O:37][C@@H:36]([CH2:38][C:39]([O:41][OH:42])=[O:40])[C@H:35]([CH3:43])[CH2:34][C@@H:33]1[CH3:44])[CH3:31])[CH3:28])=[O:26])[C@H:5]1[O:9][C@@:8]([C@:11]2([OH:23])[O:15][C@@:14]([C@@H:18]([OH:21])[CH2:19][CH3:20])([CH2:16][CH3:17])[CH2:13][C@H:12]2[CH3:22])([CH3:10])[CH2:7][C@@H:6]1[CH3:24]
Reactant: [Co+2]
Agent: CC(=O)[O-]
Agent: CC[C@@H](C(=O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H]1O[C@@H](CC(=O)OO)[C@H](C)C[C@@H]1C)[C@H]1O[C@](C)([C@]2(O)O[C@](CC)([C@@H](O)CC)C[C@H]2C)C[C@@H]1C
Agent: [Na]
Solvent: O
Solvent: CCO
Product: [Co]
Reaction time: 18 h

Procedure:
A mixture of 13.0 g (0.02 mole) of sodium lysocellin and 2.5 g of cobalt acetate dihydrate in 150 ml of ethanol was stirred and held at ambient temperature for approximately 18 hours. Two volumes of water were added to the reaction mixture slowly. A tacky semi-solid precipitate formed. On continued stirring and trituration with fresh water, a filtrable solid was obtained. The removed cobalt salt was isolated and dried (13.1 g). The product had a melting point at 119.2° C. Analysis: Calculated % Co (4.48), Found (4.54).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:22].O1CCOCC1>CO>[ClH:22].[CH3:20][S:17]([C:13]1[CH:12]=[C:11]([C:8]2([NH2:7])[CH2:10][CH2:9]2)[CH:16]=[CH:15][N:14]=1)(=[O:19])=[O:18]
Reactant: CC(C)(C)OC(=O)NC1(c2ccnc(S(C)(=O)=O)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CS(=O)(=O)c1cc(C2(N)CC2)ccn1
Reaction time: 8 h

Procedure:
To a solution of [1-(2-methanesulfonyl-pyridin-4-yl)-cyclopropyl]-carbamic acid tert-butyl ester (606 mg, 1.94 mmol) in methanol (10 mL) is added a solution of 4 N HCl in dioxane (2 mL, 8 mmol). The mixture stirred overnight and is then concentrated and the residue is triturated with ether-ethanol. The solid is collected by filtration to afford the title compound.