Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][SH:2].CN(C=O)C.Cl[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[C:18]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([CH3:28])[N:21]=[C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:19]=1>O1CCCC1>[CH3:28][C:22]1[N:21]=[C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:19]=[C:18]([C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[S:2][CH3:1])[C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1c(C)nc(-c2ccccc2)nc1-c1cc([N+](=O)[O-])ccc1Cl
Reactant: CS
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)nc(-c2ccccc2)nc1-c1cc([N+](=O)[O-])ccc1SC
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.9 %

Procedure:
To a solution of methyl mercaptan-DMF solution (methylmercaptan 66 g/DMF 306 g) (3.8 ml) and methyl 4-(2-chloro-5-nitrophenyl)-6-methyl-2-phenyl-5-pyrimidinecarboxylate (1.5 g) in tetrahydrofuran (25 ml) was added and the mixture was stirred for 3 hours at ambient temperature. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of water (50 ml) and ethyl acetate (100 ml). The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give a residue, which was chromatographed on silicagel eluting with a mixture of n-hexane and ethyl acetate (10:1). The fractions containing the desired product were combined and concentrated in vacuo. The crystalline residue was recrystallized from n-hexane to afford methyl 6-methyl-4-(2-methylthio-5-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate (0.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][SiH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:14]Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][SiH:11]([Cl:14])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: ClCl
Reactant: Fc1ccc(C2CC[SiH2]CC2)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(C2CC[SiH](Cl)CC2)cc1

Procedure:
In the same manner as in Example 9, 21.0 g of 4-(p-fluorophenyl)-1,1-dichloro-1-silacyclohexane was obtained from 4-(p-fluorophenyl)-1,1-diphenyl-1-silacyclohexane obtained in Preparatory Example 5. A mixture of 50.0 g of methanol and 30 g of triethylamine was added to the solution obtained above, followed by agitation under reflux for 1 hour. The resultant solution was concentrated, to which 200 ml of hexane was added thereby permitting secondarily produced hydrochloride to be precipitated. The precipitate was removed by filtration and the resulting filtrate was concentrated to obtain a mixture of 4-(p-fluorophenyl)-1,1-dimethoxy-1-silacyclohexane and acetophenone. The mixture was subjected to distillation under reduced pressure to remove the acetophenone therefrom. The resultant residue was dissolved in 100 ml of THF and added to a solution of 10.0 g of lithium aluminium hydride in 100 ml of THF. The reaction mixture was agitated under reflux for 1 hour, which was poured into 200 ml of 5% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried and concentrated by a usual manner, followed by purification through silica gel chromatography to obtain 14.7 g of 4-(p-fluorophenyl)-1-silacyclohexane. Subsequently, 14.0 g of 4-(p-fluorophenyl)-1-silacyclohexane was added to 100 ml of toluene, into which chlorine gas was blown to obtain 4-(p-fluorophenyl)-1-chloro-1-silacyclohexane. This solution was dropped in 100 ml of a THF solution of 1 mole/liter of trans-2-(4-n-propylcyclohexyl)ethylmagnesium bromide at room temperature. The reaction mixture was charged into 200 ml of 5% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried and concentrated, followed by purification through silica gel chromatography to obtain 20.8 g of the intended product. The thus obtained product exhibited nematic liquid crystal properties at a temperature between 49.1° C. and 62.9° C. and was found to be very useful as a liquid crystal substance.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][CH:17]([OH:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:20][C@@H:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([NH2:24])=[O:23]>>[C:22]([C@@H:21]([NH:20][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][CH:17]([OH:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:23])[NH2:24]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(O)c1ccc(N2CC(O)C2)c(OCC2CC2)n1
Product: CC(C)C[C@H](NC(=O)c1ccc(N2CC(O)C2)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3-hydroxy-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 75 a) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=377.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19](=[O:26])[C@@H:20]([NH2:25])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:13]([OH:27])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[O:42]1[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[CH:44]=[C:43]1[C:51](O)=[O:52]>ClCCl.CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19](=[O:26])[C@@H:20]([NH:25][C:51]([C:43]2[O:42][C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[CH:44]=2)=[O:52])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:13]([OH:27])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](N)C(=O)NC1CCCN(C(=O)OCc2ccccc2)CC1O
Reactant: O=C(O)c1cc2ccccc2o1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CO
Product: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CCCN(C(=O)OCc2ccccc2)CC1O

Procedure:
To a solution of 4-((S)-2-amino-4-methyl-pentanoylamino)-3-hydroxy-azepane-1-carboxylic acid benzyl ester of Example 78a (3.2 g) in dichloromethane (200 mL) was added EDC (1.48 g), HOBt (1.05 g), TEA (1.29 mL) and benzofuran-2-carboxylic acid. The reaction was stirred until complete. Workup and column chromatography (2% methanol:dichloromethane) provided the title compound (3.78 g): MS(EI) 521 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([CH3:11])[CH3:10].C1CCN2C(=NCCC2)CC1>O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:16][CH2:17][N:12]([CH:9]([CH3:11])[CH3:10])[CH2:13][CH2:14]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)N1CCNCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(C)N1CCN(c2ccc(Br)cn2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution containing 12.1 g of 2,5-dibromopyridine (51.1 mmol), 8.8 ml of 1-isopropyl-piperazine (61.5 mmol) and 9.2 ml of DBU (61.5 mmol) is stirred overnight at 100° C. The reaction mixture is returned to ambient temperature and the solution is diluted with water and extracted with ethyl acetate. The organic phases are collected, washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue is chromatographed on an SiO2 column, eluting with a mixture of CH2Cl2/MeOH 98/2 and then 96/4, to yield the title product.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22](I)[CH:23]=3)[N:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1.[CH:29]([O-])=[O:30].[Na+].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>[F:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH:29]=[O:30])[CH:23]=3)[N:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1
Reactant: O=C[O-]
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4ccc(I)cc34)cc2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)cc3)c2c1
Temperature: 80 °C
Yield: 77.8 %

Procedure:
In 100 ml of dimethylformamide was dissolved 4-(4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline hydrochloride (III-1, 5.0 g), and 1.25 g of sodium formate, dichlorobis(triphenylphosphine)palladium (324 mg), and triethylamine (3.2 ml) were added. The reaction mixture was degassed, and stirred under heating at 80° C. for 3 hours under the carbon monoxide atmosphere. Thereafter, the reaction mixture was poured into ice water, and extracted with ethyl acetate. The extract was washed with water and sodium chloride solution, and dried with magnesium sulfate. The dried solution was filtered with Celite, concentrated, and powdered with an ethyl acetate-hexane (1:2) to obtain 4-(4-(3-fluorobenzyloxy)phenylamino)-6-formylquinazoline (IV-1, 2.86 g) as a yellow solid.
Reaction SMILES: C[Mg]Br.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([C:23]3[N:28]=[CH:27][C:26]([C:29]4[O:33][N:32]=[C:31](C(OCC)=O)[CH:30]=4)=[CH:25][CH:24]=3)([CH3:22])[CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)[CH:9]=[N:10][CH:11]=1>C1(C)C=CC=CC=1.C1COCC1.C1COCC1>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([C:23]3[N:28]=[CH:27][C:26]([C:29]4[O:33][N:32]=[C:31]([C:6]([OH:5])([CH3:7])[CH3:11])[CH:30]=4)=[CH:25][CH:24]=3)([CH3:22])[CH:19]([CH3:20])[CH3:21])=[CH:14][CH:13]=2)[CH:9]=[N:10][CH:11]=1
Reactant: CCOC(=O)c1cc(-c2ccc(C(C)(c3ccc(-c4cncc(OC)c4)cc3)C(C)C)nc2)on1
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cncc(-c2ccc(C(C)(c3ccc(-c4cc(C(C)(C)O)no4)cn3)C(C)C)cc2)c1
Reaction time: 3 h

Procedure:
Methyl magnesium bromide (300 μL of a 1.4M solution in toluene:THF (75:25), 0.420 mmol) was added to a stirred solution of 3b (40.0 mg, 0.0850 mmol) in THF (2.00 mL) at 0° C. After approximately 3 h, the reaction was quenched with saturated aqueous ammonium chloride and extracted three times with EtOAc. The combined organic extracts were washed with water and brine, dried (magnesium sulfate) and concentrated in vacuo. The crude residue was purified by preparative thin-layer chromatography on silica gel (60% EtOAc/hexanes as eluent) to afford the title compound 3c. m/z (ES) 458 (MH)+. 1HNMR (500 MHz, CDCl3): δ 9.02 (m, 1H), 8.46 (m, 1H), 8.29 (m, 1H), 7.96 (m, 1H), 7.51 (m, 4H), 7.38 (m, 2H), 6.62 (s, 1H), 3.92 (s, 3H), 3.18 (m, 1H), 1.78 (s, 3H), 1.69 (s, 6H), 0.91 (d, 3H, J=6.6 Hz), 0.88 (d, 3H, J=6.9 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].N1C=CC=CC=1.[Cl:24][C:25]1[CH:26]=[C:27]([S:32](Cl)(=[O:34])=[O:33])[CH:28]=[CH:29][C:30]=1[Cl:31].O>C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([S:32]([NH:1][C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(=[O:33])=[O:34])[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCCC2
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)c1c(NS(=O)(=O)c2ccc(Cl)c(Cl)c2)sc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (12.26 g, 48.4 mmol) was dissolved in DCM (150 ml), and pyridine (6.0 ml, 74 mmol) was added thereto. A solution of 3,4-dichlorobenzenesulfonyl chloride (8.4 ml, 54 mmol) was then added, and the mixture was heated for 17 h under reflux and then cooled to room temperature. Water was added (100 ml), and stirring was carried out overnight at room temperature. The phases were then separated (pH organic phase≈2), washed with saturated NaHCO3 solution, dried (sodium sulfate) and concentrated in vacuo.
Reaction SMILES: [N:1]#[C:2]Br.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[C:6]=1[NH2:12]>C(#N)C.O>[Cl:4][C:5]1[C:6]2[N:12]=[C:2]([NH2:1])[NH:11][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1cccc(Cl)c1N
Reactant: N#CBr
Solvent: CC#N
Solvent: O
Product: Nc1nc2c(Cl)cccc2[nH]1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Cyanogen bromide was added to a solution of 3-chlorobenzene-1,2-diamine (0.81 g, 0.570 mmol) in acetonitrile (10 mL) and water (2 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 14 hours. The reaction was quenched with saturated aqueous sodium hydrogen carbonate (50 ml) and shaken. The resulting solid was filtered off, was washed with water and dried at reduced pressure to 0.49 g of 4-chloro-1H-benzo[d]imidazol-2-amine (yield, 49%). MS (EI): 168 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=O)[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.O.C([NH2:16])=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:8])[NH:16][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: NC=O
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Solvent: O
Product: O=C1NC(=O)c2cc(Cl)ccc21
Temperature: 20 °C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
A solution of 10.0 g of 4-chlorophthalic anhydride in 24.6 g of formamide is heated at a temperature in the region of 120° C. with stirring for 3 hours and is then cooled to a temperature in the region of 20° C. and poured into 100 cm3 of water. After stirring for 30 minutes, the mixture is filtered and the precipitate is then dried under vacuum at a temperature in the region of 60° C. 10.4 g of 4-chlorophthalimide are thus obtained in the form of a solid melting at 171° C. Rf=0.07 (thin layer chromatography on silica gel, eluent: dichloromethane).
Reaction SMILES: C(OC1C=CC(F)=CC=1C1C(CN)=CC2C(=C(Cl)C=CC=2)N=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C.ClC1N=CN=C2C=1NC=N2.N1C(N)=C2C(NC=N2)=NC=1.[Cl:58][C:59]1[CH:60]=[CH:61][CH:62]=[C:63]2[C:68]=1[N:67]=[C:66]([C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[CH:70]=1)[C:65]([C@H:76]([NH:78][C:79]1[N:87]=[CH:86][N:85]=[C:84]3[C:80]=1[N:81]=[CH:82][NH:83]3)[CH3:77])=[CH:64]2>C(O)CCC>[Cl:58][C:59]1[CH:60]=[CH:61][CH:62]=[C:63]2[C:68]=1[N:67]=[C:66]([C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[CH:70]=1)[C:65]([C@@H:76]([NH:78][C:79]1[N:87]=[CH:86][N:85]=[C:84]3[C:80]=1[N:81]=[CH:82][NH:83]3)[CH3:77])=[CH:64]2
Reactant: C[C@@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2nc1-c1cccc(F)c1
Agent: Clc1ncnc2nc[nH]c12
Agent: NCc1cc2cccc(Cl)c2nc1-c1cc(F)ccc1OCc1ccccc1
Agent: Nc1ncnc2[nH]cnc12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2nc1-c1cccc(F)c1

Procedure:
A mixture of (2-(2-(benzyloxy)-5-fluorophenyl)-8-chloroquinolin-3-yl)-methanamine (0.120 g, 0.40 mmol) in n-butanol (5 mL) was treated with DIEA (0.80 mmol, 2.0 eq) followed with 6-chloropurine (0.075 g, 0.48 mmol, 1.2 eq) at 100° C. for 8 h. The reaction mixture was concentrated and purified by column chromatography on a Redi-Sep™ column using 0 to 100% gradient of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 as eluent to provide the mixture of N-(S)-1-(8-chloro-2-(3-fluorophenyl)quinolin-3-yl)ethyl)-9H-purin-6-amine and N-((R)-1-(8-chloro-2-(3-fluorophenyl)quinolin-3-yl)ethyl)-9H-purin-6-amine. Further separation by chiral HPLC with IA column at IPA/Hexane (10%) provides N-((S)-1-(8-chloro-2-(3-fluorophenyl)quinolin-3-yl)ethyl)-9H-purin-6-amine [PI3Kδ IC50=6 nM] as a white solid. 1H-NMR (MeOD) δ ppm 8.43 (s, 1H), 8.05 (s, 1H), 7.98 (s, 1H), 7.73-7.80 (m, 2H), 7.48-7.53 (m, 1H), 7.44-7.49 (m, 1H), 7.35-7.44 (m, 2H), 7.04-7.11 (m, 1H), 1.44-1.47 (d, 3H), Mass Spectrum (ESI) m/e=419 (M+1), and N—((R)-1-(8-chloro-2-(3-fluorophenyl)-quinolin-3-yl)ethyl)-9H-purin-6-amine [PI3Kδ IC50=424 nM] as a white solid. 1H-NMR (MeOD) δ ppm, 8.56 (s, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 7.84-7.93 (m, 2H), 7.45-7.66 (m, 4H), 7.14-7.23 (m, 1H), 3.89-3.98 (m, 1H), 1.57-1.60 (d, 3H) Mass Spectrum (ESI) m/e=419 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]([OH:17])=O)[CH:7]=[CH:6]2.S(Cl)([Cl:20])=O>CN(C)C=O.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]([Cl:20])=[O:17])[CH:7]=[CH:6]2
Reactant: O=S(Cl)Cl
Reactant: COc1cc2ccc(C(=O)O)cc2cc1OC
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COc1cc2ccc(C(=O)Cl)cc2cc1OC

Procedure:
To a solution containing 15.0 g. of 6,7-dimethoxy-2-naphthoic acid and one drop of dimethylformamide in 200 ml. of benzene was added 25 ml. of thionyl chloride. After heating one hour under reflux the mixture was evaporated to dryness in vacuo. Additional benzene was added and evaporation repeated to give 6,7-dimethoxy-2-naphthoyl chloride which was used directly in the preparation of 6,7-dimethoxy-2-naphthamide as described hereinabove in Example 113.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:13][NH:14][CH3:15]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8]([N:14]([CH3:15])[CH3:13])(=[O:10])=[O:9])[CH:7]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: CNC
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(F)cc1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A mixture of 5-fluoro-2-methylbenzene sulfonylchloride (2.1 mL, 14.3 mmol) in THF (18 mL) and 2 M dimethylamine in methanol (18 mL), was stirred at room temperature for 0.5 h. The resulting mixture was concentrated under reduced pressure to give a crude product as a mixture of white solid and colourless oil. The crude product was purified by column (30% EtOAc in Hexane) to give the titled compound as a colourless oil (3.09 g, 99% yield).
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[CH2:16][S:17][C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:13][C:12]([OH:18])=[CH:11][CH:10]=4.N1C=CN=C1.[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C=O)C>[C:25]([Si:28]([CH3:30])([CH3:29])[O:18][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[S:17][CH2:16][C:15]2=1)([CH3:27])([CH3:26])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2[nH]c3c(c2c1)CSc1ccccc1-3
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c3c(c2c1)CSc1ccccc1-3
Reaction time: 2 h

Procedure:
6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol (820 mg, 3.24 mmoL) in DMF (10 mL) was treated with imidazole (331 mg, 4.862 mmoL) followed by TBSCl (733 mg, 4.862 mmoL) at room temperature. The reaction was stirred for 2 hours. The reaction mixture was then partitioned between CH2Cl2 and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the oil) was then purified by column chromatography (silica gel; hexanes:EtOAc 4:1 as eluent) to yield the title compound as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])C)[C:19]([OH:21])=O)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:7])([CH3:4])(C)C.[CH2:26]([NH:33][NH2:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[N:35]1([CH2:40][C:41]([OH:43])=O)[CH:39]=[CH:38][N:37]=[N:36]1>>[CH2:26]([N:33]([C:41](=[O:43])[CH2:40][N:35]1[CH:39]=[CH:38][N:37]=[N:36]1)[NH:34][C:19](=[O:21])[C@@H:18]([C@@H:8]([C:6]([O:5][CH:1]1[CH2:4][CH2:9][CH2:8][CH2:6][O:5]1)=[O:7])[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)[CH2:22][CH2:23][CH3:25])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](CCCC1CCCCC1)C(=O)OC(C)(C)C
Reactant: O=C(O)Cn1ccnn1
Reactant: NNCc1ccccc1
Product: CCC[C@@H](C(=O)NN(Cc1ccccc1)C(=O)Cn1ccnn1)[C@H](CCCC1CCCCC1)C(=O)OC1CCCCO1

Procedure:
In a manner analogous to that described in Example 1, parts (iii)-(vii) and Example 8, from 2(R)-[1(S)-(tert-butoxycarbonyl)-4-cyclohexylbutyl]-4-methylvaleric acid and benzylhydrazine and using 1,2,3-triazole-1-acetic acid in place of N-tert.butoxycarbonyl-β-alanine in Example 8, there was obtained 2′-benzyl-2(R)-[4-cyclohexyl-1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbonyl]butyl]-2′-[2-(1,2,3-triazol-1-yl)acetyl]valerohydrazide in the form of a white solid.
Reaction SMILES: O[CH:2]=[C:3]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])[C:4]#[N:5].[CH3:15][S:16](Cl)(=[O:18])=[O:17].O>N1C=CC=CC=1>[CH3:15][S:16]([CH:2]=[C:3]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])[C:4]#[N:5])(=[O:18])=[O:17]
Reactant: Cc1cc(C)c(C(C#N)=CO)c(C)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(C)c(C(C#N)=CS(C)(=O)=O)c(C)c1
Reaction time: 1 h
Yield: 105.1 %

Procedure:
A solution of intermediate 1 (1 g) in 10 ml pyridine was cooled to 0° C. under nitrogen and then treated with methanesulfonyl chloride (0.67 g) with good stirring. The solution was allowed to come to room temperature and stirred for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with 1M HCl, water and brine, dried (MgSO4) and concentrated to give 3-methanesulfonyl-2-(2,4,6-trimethylphenyl)acrylonitrile (intermediate 2) as a brown solid (1.4 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[Cl:9][S:10]([C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([CH3:23])=[CH:16][N:17]=[CH:18]2)(=[O:12])=[O:11]>>[ClH:9].[ClH:9].[CH3:1][CH:2]1[CH2:8][CH2:7][N:6]([S:10]([C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[C:15]([CH3:23])=[CH:16][N:17]=[CH:18]3)(=[O:11])=[O:12])[CH2:5][CH2:4][NH:3]1
Reactant: CC1CCNCCN1
Reactant: Cc1cncc2cccc(S(=O)(=O)Cl)c12
Product: Cc1cncc2cccc(S(=O)(=O)N3CCNC(C)CC3)c12
Product: Cl
Yield: 77 %

Procedure:
Using 0.29 g of hexahydro-5-methyl-1H-1,4-diazepine synthesized in accordance with U.S. Pat. No. 3,040,029 and 0.48 g of 5-chlorosulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.3 g of the objective compound (white crystals).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18](O)=O)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.C(OP(C#N)(OCC)=O)C.C(N(CC)CC)C.[NH2:38][C:39]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:40]=1[OH:46]>COCCOC.CCOC(C)=O>[NH2:1][C:2]1[C:3]([C:18]2[NH:38][C:39]3[C:40]([OH:46])=[CH:41][CH:42]=[CH:43][C:44]=3[N:45]=2)=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: Nc1cccc(O)c1N
Reactant: CS(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)O)n2)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: COCCOC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2cnc(N)c(-c3nc4cccc(O)c4[nH]3)n2)cc1
Temperature: 170 °C
Yield: 73.7 %

Procedure:
A mixture of 3-amino-6-(4-methylsulfonylphenyl)pyrazine-2-carboxylic acid (120 mg, 0.4091 mmol), diethoxyphosphorylformonitrile (73.40 mg, 0.4500 mmol), triethylamine (124.2 mg, 171.1 μL, 1.227 mmol) and 2,3-diaminophenol (50.79 mg, 0.4091 mmol) in DME (5 mL) was heated in the microwave at 170° C. for 1 hour. The mixture was diluted with EtOAc, washed with water and brine and concentrated in vacuo The residue was then dissolved in DCM and triturated with ether to give the desired product as a yellow solid (115 mg, 74% Yield). 1H NMR (400 MHz, DMSO) 3.6 (3H, s), 6.65 (1H, d), 7.1-7.18 (2H, m), 8.0-8.1 (4H, m), 8.6 (2H, d), 8.9 (1H, s), 9.05 (1H, br s), 9.9 (1H, s), 12.9 (1H, b rs) ppm; MS (ES+) 382