Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:7]=[C:8]=[O:9]>C(#N)C>[C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=C=O
Reactant: c1ccccc1
Solvent: CC#N
Product: O=C=Nc1ccccc1

Procedure:
In the present invention, benzene is oxidized in acetonitrile to form a radical cation. The isocyanate anion (solubilized by the 18-crown-6 polyether) then attacks the activated ring to give a phenyl isocyanate radical which then loses a proton to give phenyl isocyanate. The 18-crown-6 acts as a solid to liquid phase transfer catalyst bringing the insoluble KOCN into the acetonitrile solution. A schematic is shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1.COC1C=CC([SH:29]2(=S)PP(=S)(C3C=CC(OC)=CC=3)S2)=CC=1.O>CN(C)P(=O)(N(C)C)N(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:29])[CH2:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1
Reactant: COc1ccc(P2(=S)P[SH](=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CCC(c2ccccc2F)c2cc(Cl)ccc2N1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Fc1ccccc1C1CCC(=S)Nc2ccc(Cl)cc21
Temperature: 25 °C

Procedure:
30 g of 7-chloro-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one are dissolved in 105 ml of hexamethylphosphoric acid triamide and treated with 22 g of 2,4-bis-(4-methoxyphenyl)-1,2,3,4-dithiadiphosphetane-2,4-disulphide. The mixture is heated to 100° for 1 hour, again cooled to room temperature and poured into 1.41 l of water. The mixture is extracted four times with ethyl acetate and the organic extracts are washed with water. The ethyl acetate solution is dried, filtered and evaporated in vacuo. After crystallization of the residue from ethanol, there is obtained 7-chloro-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1-benzazepine-2-thione of melting point 190°.
Reaction SMILES: C(S([C:8]1[C:13](S(C(C)(C)C)(=O)=O)=[C:12]2[CH2:21][C:9]=1[CH2:10][CH2:11]2)(=O)=O)(C)(C)C.[C:22]1([Li])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO>O1CCCC1>[C:22]1([C:13]2[C:8]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:9]3[CH2:21][C:12]=2[CH2:11][CH2:10]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: [Li]c1ccccc1
Reactant: CC(C)(C)S(=O)(=O)C1=C2CCC(=C1S(=O)(=O)C(C)(C)C)C2
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc(C2=C3CCC(=C2c2ccccc2)C3)cc1
Temperature: 25 °C
Yield: 27 %

Procedure:
First, the intermediate product 2,3-diphenylnorbornadiene was prepared as follows: A solution of 2,3-bis(tert-butylsulfonyl)norbornadiene (prepared according to the procedure of Riera, et al. Tetrahedron Letters 1990, volume 31, page 2173) (5.50 g, 19 mmol) in dry tetrahydrofuran (50 mL) was treated with 95 mmol of phenyl lithium at −78° C. under an argon atmosphere. After allowing the reaction mixture to gradually warm to room temperature overnight, methanol (25 mL) was added, and the solution was partially concentrated at reduced pressure. The resulting mixture was mixed with water (50 mL) and extracted with dichloromethane (2×50 mL). The combined organic extracts were dried over magnesium sulfate and concentrated to deposit a brown oil. The intermediate product was purified by column chromatography (silica gel, hexane/dichloromethane), followed by recrystallization from methanol to provide 1.25 g (27% yield) of 2,3-diphenylnorbornadiene as a white solid. 1H NMR (CDCl3) δ2.10 (m, 1 H), 2.40 (m, 1 H), 3.92 (m, 2 H), 7.01 (t, 2 H), 7.2-7.3 (m, 10 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[CH2:12]([Li])[CH2:13][CH2:14]C.CC1(C)CCCC(C)(C)N1>>[CH2:14]([C:7]1[C:2]([Cl:1])=[N:3][C:4]([O:10][CH3:11])=[N:5][C:6]=1[O:8][CH3:9])[CH:13]=[CH2:12]
Reactant: [Li]CCCC
Reactant: COc1cc(Cl)nc(OC)n1
Agent: CC1(C)CCCC(C)(C)N1
Product: C=CCc1c(Cl)nc(OC)nc1OC

Procedure:
Synthesis of 2,4-dichloro-7-aryl-6,7-dihydro-5H-cyclopenta[d]pyrimidines 33 could also be performed according to the pathway described on Scheme 9. 4-Chloro-2,6-dimethoxypyrimidine 40 could be deprotonated with a strong base, such as n-butyllithium or 2,2,6,6-tetramethylpiperidine, and quenched with allyl bromide to give 5-allyl-4-chloro-2,6-dimethoxypyrimidine 41. Nencka, R.; Votruba, I.; H{hacek over (r)}ebabecký, H.; Jansa, P.; Tlou{hacek over (s)}t'ová, E.; Horská, K.; Masojídková, M.; Holý, A. J. Med. Chem. 2007, 50, 6016-6023. The latter compound can react with α-styrylborinic acids in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium, to provide compounds of formula 42 which can undergo ring closure olefin metathesis under Grubbs conditions to form 2,4-dimethoxy-7-aryl-5H-cyclopenta[d]pyrimidines 43. Grubbs, R. H. Handbook of Metathesis, 2003, First Edition, Wiley-VCH. The double bond in compounds 43 can be reduced to give 2,4-dimethoxy-7-aryl-6,7-dihydro-5H-cyclopenta[d]pyrimidines 44, which upon acid-catalyzed hydrolysis, followed by chlorination with phosphorus oxychloride afford intermediates 33.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:23]4[C:18]([CH2:25][CH2:26]F)([CH2:19][CH2:20][C:21](=[O:24])[CH:22]=4)[CH2:17][C:14]=32)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+]>CN(C)C=O>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:23]4[C:18]5([CH2:19][CH:20]([C:21](=[O:24])[CH:22]=4)[CH2:26][CH2:25]5)[CH2:17][C:14]=32)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=C2c3ccc4nn(Cc5ccccc5)cc4c3CC2(CCF)CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C1C=C2c3ccc4nn(Cc5ccccc5)cc4c3CC23CCC1C3
Temperature: 150 °C

Procedure:
To a solution of 2-benzyl-9a-(2-fluoroethyl)-8,9,9a,10-tetrahydroindeno[2,1-e]indazol-7(2H)-one (1.0 g, 2.5 mmol) in 25 mL, of dimethylformamide was added lithium chloride (1.05 g, 25 mmol) and the stirred mixture was heated to 150° C. After heating for 89 hours, the reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The organic phase was washed thoroughly with water (3×) followed by brine and dried over MgSO4. The solution was concentrated under vacuum and the residue chromatographed on silica gel (elution with 15:85 to 75:25 EtOAc/hexanes) to yield 2-benzyl-2,9,10,11-tetrahydro-8,10a-methanoazuleno[2,1-e]indazol-7(8H)-one as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([OH:12])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][CH2:23][O:24][CH3:25]>CC#N>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH:5]=1
Reactant: COCCCBr
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCCOc1cc(C(=O)OC)ccc1OC
Temperature: 25 °C

Procedure:
A solution of methyl-3-hydroxy-4-methoxybenzoate (Aldrich) (89.3 g, 0.49 mol), K2CO3 (100.5 g, 0.727 mol) and 1-bromo-3-methoxy-propane (80 g, 0.523 mol) in CH3CN (1100 mL) is refluxed for 6 h. After completion of the reaction, the mixture is cooled to RT and concentrated under reduced pressure. The residue is taken up into AcOEt (500 mL) and washed with water. The aqueous layer is back-extracted twice with AcOEt, and the combined organic extracts are dried over MgSO4, filtered and concentrated to afford the title compound which is further used in the next step without purification. tR (HPLC, CC 70/4 Nucleosil 3 C18HD column, 20 to 100% CH3CN in H2O in 2, then 4 min with 100% CH3CN, CH3CN and H2O with 0.1% TFA, flow: 1.5 mL/min): 3.07 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([F:10])[C:5]([Br:11])=[CH:4][CH:3]=1>ClCCl.[O-2].[Mn+4].[O-2]>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([F:10])[C:5]([Br:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)c(F)c1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Nc1ccc(Br)c(F)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A suspension mixture of (6-amino-3-bromo-2-fluorophenyl)methanol (8.3 g, 37.72 mmol) and manganese(IV) oxide (19.68 g, 226.32 mmol) in dichloromethane (400 mL) was stirred at room temperature overnight. The solid was filtered off, and the filtrate was concentrated to give the title product as a light yellow solid (6.0 g, 73%), which was directly used in the next step without further purification. MS (ES+) C7H5BrFNO requires: 217, found: 218, 220 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:11][CH:10]=2)[C:5]([C:28]2[CH:47]=[CH:46][C:31]([O:32][C@H:33]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]([O:36]CC)=[O:35])=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.[OH-].[K+].Cl>C1COCC1.CO>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][CH:14]=2)[C:5]([C:28]2[CH:47]=[CH:46][C:31]([O:32][C@H:33]([CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]([OH:36])=[O:35])=[CH:30][CH:29]=2)=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCOc1ccc(CCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCCCOc1ccc(CCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a mixed solution of ethyl (2R)-2-{4-[5-methyl-1-(4-dodecyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate (461 mg, 0.722 mmol) in THF (10 ml) and methanol (5 ml) was added 1N aqueous potassium hydroxide solution (2.16 ml, 2.16 mmol) and the mixture was stirred for 1 hour at room temperature. The reaction solution was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the object compound as an oily substance. 360 mg (yield: 81.6%)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:23][C:24](=[O:39])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([N:34]5[CH:38]=[CH:37][N:36]=[CH:35]5)[CH:29]=4)[CH2:25][C:24](=[O:39])[NH:23][C:9]=3[CH:10]=2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnc3)c2)=Nc2ccc(C#Cc3ccc(F)cc3)cc2N1

Procedure:
Prepared from {4-(4-fluoro-phenylethynyl)-2-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-phenyl}-carbamic acid tert.-butyl ester (Example K33) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a beige solid (89 mg).
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.C1(S([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22]Br)=[N:20][CH:21]=2)(=O)=O)C=CC=CC=1>O>[CH3:1][O:2][CH2:22][C:19]1[N:20]=[CH:21][C:16]([OH:15])=[CH:17][CH:18]=1
Reactant: C[O-]
Reactant: O=S(=O)(Oc1ccc(CBr)nc1)c1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCc1ccc(O)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
Sodium methoxide (393 mg) was added to a methanol (20 ml) solution containing 5-(benzenesulfonyloxy)-2-(bromomethyl)pyridine (Beilstein Registry No. 7430370, 800 mg), followed by stirring at room temperature for 4 hours. Water was added to the reaction solution, followed by extraction with EtOAc. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: EtOAc) to obtain 6-(methoxymethyl)pyridin-3-ol (200 mg).
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][C:25]([O:27]CC)=O)=[O:22])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CC(C)([O-])C.[K+].Cl>C1COCC1.CN(C=O)C>[CH2:1]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([O:23][CH2:24][C:25]=2[OH:27])=[O:22])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccc(CC(=O)OCC(=O)OCC)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1ccc(C2=C(O)COC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
In a mixture of THF (50 ml) and DMF (10 ml) was dissolved ethoxycarbonylmethyl 4-dodecyloxyphenylacetate (5.0 g, 0.013 mol.). To the solution was added at room temperature potassium tertiary butoxide (2 g, 0.017 mol.). The mixture was stirred at room temperature for one hour, after which was added 2N HCl (20 ml). The resultant mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure The resultant crude crystals were recrystallized from IPE-ethyl acetate to give 2-(4-dodecyloxyphenyl)-3-hydroxy-2-buten-4-olide (4-h, 3.0 g, 70%). By a procedure analogous to the above, compounds (4-a to 4-c, 4-f, 4-j to 4-m) were synthesized. Physico-chemical properties and NMR spectra of these compounds are shown in Table 7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]#[N:18])=[C:12]3[NH:11][CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([SiH](CC)CC)C.[OH-].[K+]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]#[N:18])=[C:12]3[NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cnn2c1NCC=C2c1cccc(Cl)c1
Agent: CC[SiH](CC)CC
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cnn2c1NCCC2c1cccc(Cl)c1
Temperature: 55 °C

Procedure:
To an 8.0 g portion of 7-(3-chlorophenyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (prepared as described in Ex. 30) in 65 ml of trifluoroacetic acid, stirred under nitrogen and heated to 55° C. was added 7.3 ml of triethylsilane. The reaction mixture was stirred and heated at 60° C. for 71/2 hours. The mixture was then carefully poured into an ice cooled beaker containing 100 ml of 25% aqueous potassium hydroxide. The precipitate which formed was collected by filtration and dissolved in chloroform. The chloroform solution was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give 6.8 g of white crystals. The crystals were triturated with ether. The ether was collected and crystals formed. The crystals were washed with ether and gave 2.8 g of white crystals. The crude product, 2.8 g, was chromatographed on a liquid chromatograph using a silica gel column and eluting with 5% ethyl acetate/chloroform. The fraction containing the desired product was collected and evaporated in vacuo and gave crystals, mp 148°-150° C.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[C:24]([C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=[CH:21]5)[CH:14]=[CH:15][C:16]=3[OH:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[CH3:34]I.O>CN(C=O)C>[C:1]12([C:11]3[CH:12]=[C:13]([C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[C:24]([C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=[CH:21]5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:34])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CI
Reactant: COC(=O)c1cccc2cc(-c3ccc(O)c(C45CC6CC(CC(C6)C4)C5)c3)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc2cc(-c3ccc(OC)c(C45CC6CC(CC(C6)C4)C5)c3)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
Methyl 6-(3-adamantyl-4-hydroxyphenyl)naphtoate (506 mg, 1.23 mmol) was added to an ice-cooled suspension of NaH (80 mg, 60%) in dry DMF, the mixture stirred 1 h at 0° C., then added with 245 mg (1.7 mmol) of CH3I, and left 90 min at r.t. Taking up with 80 ml of cold water, repeated extraction with CH2Cl2, then with EtOAc, drying and evaporating the joined organic phases, and chromatography (silicagel, hexane/EtOAc 9/1) gave 300 mg of methyl 6-(3-adamantyl-4-methoxyphenyl)naphtoate. This compound (235 mg) was suspended in a 1M solution of NaOH in MeOH and the mixture was refluxed 8 h. Evaporation, taking up with water, addition of HCl and filtration gave 227 mg of 6-(3-adamantyl-4-methoxyphenyl)naphtoic acid, mp >300° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)(=[O:4])=[O:3].[N:13]#[C:14]Br>O>[NH2:13][C:14]1[NH:12][C:7]2[CH:6]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:10]=[CH:9][C:8]=2[N:11]=1
Reactant: N#CBr
Reactant: CS(=O)(=O)c1ccc(N)c(N)c1
Solvent: O
Product: CS(=O)(=O)c1ccc2nc(N)[nH]c2c1
Reaction time: 4 h

Procedure:
One mole, 186.1 g., of 4-methylsulfonyl-o-phenylenediamine was suspended in 1.2 l. of water with stirring. One mole, 106 g., of cyanogenbromide was added portionwise to the reaction mixture. The reaction mixture was stirred for 4 hours and then filtered. Sodium hydroxide, 39 g. (1 m.) in 500 ml. of water, was added to the filtrate. The aqueous mixture was cooled in an ice bath and the product crystallized. The product was collected and dried before crystallization from ethanol-ether; yield 200 g., m.p. 233°-238° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][OH:4].[C:15]1(=O)OCC[O:16]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:5]([CH:2]1[CH2:3][O:4][C:15](=[O:16])[NH:1]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C1OCCO1
Reactant: CCCCCCCCCCC(N)CO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCC1COC(=O)N1
Yield: 91.5 %

Procedure:
26.465 g of 2-aminododecanol and 12.32 g of ethylene carbonate were heated at approximately 110° C. for 48 hours (preparation of the cyclic urethanes can be carried out without a solvent or in toluene solution)as a solvent. The reaction was followed by tlc and at the completion of the reaction the contents were cooled, dissolved in ethyl acetate and the organic solution was washed with brine and water. After drying, the filtrate was concentrated and the oily residue was kugelrohr distilled to give 27.33 g (96.56%) of colorless liquid, which slowly solidified, m.p. 31.5-32.5° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C@H:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]([C@:18]34[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:19]3[C@@H:20]3[C@@:33]([CH3:36])([CH2:34][CH2:35]4)[C@@:32]4([CH3:37])[C@@H:23]([C@:24]5([CH3:41])[C@@H:29]([CH2:30][CH2:31]4)[C:28]([CH3:39])([CH3:38])[C@@H:27]([OH:40])[CH2:26][CH2:25]5)[CH2:22][CH2:21]3)=[O:17])[CH2:11]2)[CH2:5][CH2:4]1)[CH3:2].N1C=CC=CC=1.[CH3:54][C:55]1([CH3:62])[CH2:59][C:58](=[O:60])[O:57][C:56]1=[O:61]>C(OCC)(=O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C@H:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]([C@:18]34[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:19]3[C@@H:20]3[C@@:33]([CH3:36])([CH2:34][CH2:35]4)[C@@:32]4([CH3:37])[C@@H:23]([C@:24]5([CH3:41])[C@@H:29]([CH2:30][CH2:31]4)[C:28]([CH3:38])([CH3:39])[C@@H:27]([O:40][C:58](=[O:60])[CH2:59][C:55]([CH3:62])([CH3:54])[C:56]([OH:61])=[O:57])[CH2:26][CH2:25]5)[CH2:22][CH2:21]3)=[O:17])[CH2:11]2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCN(CC)CC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)CC(=O)OC1=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCN(CC)CC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-N-((1R,3S)-3-((4-ethylpiperazin-1-yl)methyl)cyclopentyl)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamide (Example 35, 0.24 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.32 g, 0.48 mmol) and 3,3-dimethyldihydrofuran-2,5-dione (1.3 ml) were added and the contents were refluxed for about 16 hours and completion of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, washed with water followed by brine solution, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.1 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.80-0.95 (m, 16H) 1.23-1.90 (m, 41H); 2.03-3.08 (m, 16H), 4.13-4.18 (m, 1H), 4.46 (s, 1H), 4.58 (s, 1H), 4.72 (s, 1H); 5.61-5.63 (m, 1H); ES Mass: [M+1] 778 (100%); HPLC: 78.4%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([S:26][CH2:27][CH3:28])=[N:24][CH:25]=3)=[CH:16][CH:15]=2)[N:13]=1.ClC1C=CC=C(C(OO)=[O:37])C=1>ClC(Cl)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][C:23]([S:26]([CH2:27][CH3:28])=[O:37])=[N:24][CH:25]=3)=[CH:18][CH:19]=2)[N:13]=1
Reactant: CCSc1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(Cl)Cl
Product: CCS(=O)c1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cn1

Procedure:
2-(2,6-Difluorophenyl)-4-[4-(2-ethylthiopyridin-5-yl)phenyl]oxazoline (Ex. No. 39; 0.60 g, 1.5 mmol) was stirred for 5 hours at 20° C. with 3-chloroperbenzoic acid (0.41 g, 1.7 mmol) in dichloroethane (10 ml). After extraction and chromatography, 2-(2,6-difluorophenyl)-4-[4-(2-ethylsulfinylpyridin-5-yl)phenyl]oxazoline was obtained, 0.21 g, colorless oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:15])[C:10]#[C:11][CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:22][O:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Br)[CH:26]=1>CN(C=O)C>[CH3:22][O:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[I:1])[C:9](=[O:15])[C:10]#[C:11][CH:12]([CH3:13])[CH3:14])[CH:26]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CC(C)C#CC(=O)Nc1ccccc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN(C(=O)C#CC(C)C)c2ccccc2I)c1
Reaction time: 0.17 h
Yield: 51.4 %

Procedure:
A mixture of 4-methyl-pent-2-ynoic acid (2-iodo-phenyl)-amide (21 g, 67.1 mmol) and cesium carbonate (33.0 g, 100.7 mmol) in DMF (170 ml) was stirred for 10 minutes. 3-bromomethyl-benzoic acid methyl ester (16.9 g, 73.8 mmol) was added. Then the mixture was stirred for 12 hours at room temperature. After removal of the solids, the filtrate was treated with water and extracted with ether. The organic layer was dried over sodium sulfate and concentrated to give the residue which was purified by flash chromatography, eluting with ethyl acetate/hexane=1:4 to afford the product 3-{[(2-iodo-phenyl)-(4-methyl-pent-2-ynoyl)-amino]-methyl}-benzoic acid methyl ester as yellow solid (15.9 g, 51%). MS calcd. for C21H20ClNO3 461.3, obsd. (ESI+) [(M+H)+] 461.9.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([C:15]#[N:16])=[C:8]2O)(=[O:3])[CH3:2].O=P(Cl)(Cl)[Cl:20]>>[C:1]([NH:4][C:5]1[N:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([C:15]#[N:16])=[C:8]2[Cl:20])(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Nc1ccc2ncc(C#N)c(O)c2n1
Product: CC(=O)Nc1ccc2ncc(C#N)c(Cl)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
A solution of 6-acetamido-4-hydroxyl-[1,5]naphthyridine-3-carbonitrile (1.0 g, 4.386 mmol) was heated at reflux in POCl3 (20 ml) under nitrogen for 5 hrs. After cooling, the solvent was removed by rotary evaporation. Ice water was added to the black residue, which was cooled (ice bath) and stirred for 1 hr. The mixture was warmed to room temperature and stirred at room temperature for 1 hr. The mixture was cooled with ice bath, and made basic with NH4OH. The aqueous layer was extracted with CH2Cl2. The combined extracts were washed with water, dried (Na2SO4) and concentrated to give the title compound as a dark blue solid (200 mg, 19%).