Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[S:11]1[C:15]([S:16](Cl)(=[O:18])=[O:17])=[CH:14][C:13]2[CH:20]=[CH:21][CH:22]=[CH:23][C:12]1=2>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][S:16]([C:15]2[S:11][C:12]3[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=3[CH:14]=2)(=[O:18])=[O:17])=[C:4]([NH:10][S:16]([C:15]2[S:11][C:12]3[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=3[CH:14]=2)(=[O:17])=[O:18])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: Nc1cc(F)c(Cl)cc1N
Product: O=S(=O)(Nc1cc(F)c(Cl)cc1NS(=O)(=O)c1cc2ccccc2s1)c1cc2ccccc2s1
Yield: 59.2 %

Procedure:
N,N′-(4-chloro-5-fluoro-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide) (0.108 g) was prepared by using 4-chloro-5-fluoro-benzene-1,2-diamine (0.054 g, 0.33 mmol) and Benzo[b]thiophene-2-sulfonyl chloride (0.157 g, 0.67 mmol), following the procedure as in Example 32.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[O:6]1[C:8]([CH3:10])([CH3:9])[CH2:7]1>>[CH2:1]([NH:5][CH2:7][C:8]([CH3:10])([CH3:9])[OH:6])[CH:2]([CH3:4])[CH3:3]
Reactant: CC1(C)CO1
Reactant: CC(C)CN
Product: CC(C)CNCC(C)(C)O

Procedure:
Isobutylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-isobutyl-N-(2,2-dimethyl-2-hydroxyethyl)amine. N-Isobutyl-N-(2,2-dimethyl-2-hydroxyethyl)amine was reacted with SOCl2 followed by 2,4-dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,4-1-dichlorophenylimino)-3-isobutyl-5,5-dimethyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[CH:15]\[C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)/[C:12]([OH:14])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[Cl:46][C:47]1[S:51][C:50]([NH2:52])=[N:49][CH:48]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:46][C:47]1[S:51][C:50]([NH:52][C:12](=[O:14])/[C:11](/[C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=2)=[CH:15]/[C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[N:49][CH:48]=1
Reactant: CS(=O)(=O)c1ccc(/C(=C\c2cccs2)C(=O)O)cc1
Reactant: Nc1ncc(Cl)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(/C(=C\c2cccs2)C(=O)Nc2ncc(Cl)s2)cc1
Temperature: 60 °C
Reaction time: 0.03 h

Procedure:
A solution of (E)-2-(4-methanesulfonylphenyl)-3-thiophen-2-ylacrylic acid (Preparation 2, 309 mg, 1.0 mmol), HATU (813 mg, 2.1 mmol), 5-chlorothiazol-2-ylamine hydrochloride (258 mg, 1.5 mmol), and DIPEA (0.71 mL, 4.0 mmol) in anhydrous DMF (5 mL) was heated under microwave irradiation with stirring at 60° C. for 2 min. The solvents were evaporated off under reduced pressure, then the remainder was partitioned between CH2Cl2 (60 mL) and 1M HCl (60 mL). The organic layer was separated and washed with 1M HCl (60 mL), H2O (60 mL), saturated aqueous Na2CO3 (2×60 mL), H2O (60 mL), and brine (60 mL), before being dried (Na2SO4). Filtration, solvent evaporation, and flash chromatography (IH-EtOAc, 4:1 to 2:3) gave the title compound: RTA=3.77 min; m/z (ES+)=466.1 [M+MeCN+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]3[CH2:14][CH2:15][CH2:16][N:8]3[C:7](=O)[C:6]=2[CH:18]=1.B>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]3[CH2:14][CH2:15][CH2:16][N:8]3[CH2:7][C:6]=2[CH:18]=1
Reactant: CN1C(=O)C2CCCN2C(=O)c2cc(F)ccc21
Agent: B
Product: CN1C(=O)C2CCCN2Cc2cc(F)ccc21

Procedure:
When 7-fluoro-1,2,3,11a-tetrahydro-10-methyl-5 H-pyrrolo [2,1-c] [1,4] benzodiazepin- 5,11(10H)-dione (prepared from proline and 5-fluoro N-methylisatoic anhydride as described in Example 1) and borane are reacted as described in Example 1, the above compound is obtained.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].Br[C:7]1[C:11](OC)([CH3:12])[CH2:10][CH2:9][C:8]=1[CH3:15].O>CCOCC>[CH2:1]([C:7]1[C:11]([CH3:12])=[CH:10][CH2:9][C:8]=1[CH3:15])[C:2]1[C:3]([CH3:4])=[CH:2][CH2:1][C:3]=1[CH3:4]
Reactant: COC1(C)CCC(C)=C1Br
Reactant: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC1=CCC(C)=C1CC1=C(C)CC=C1C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
One equivalent of n-butyl lithium was added to a solution in which 7.038 g (34.3 mmol) of 2-bromo-3-methoxy-1,3-dimethyl-cyclopentene compound prepared in the example 3 was dissolved in 38 ml of ether at −25° C. nitrogen atmosphere. When white solid was precipitated, the temperature was elevated to 10° C. and the reaction was continued for further 10 minutes. The temperature was lowered to −25° C. and the fulvene compound prepared in the example 2 was added. Completion of reaction is determined by the development of yellow color of the reaction mixture. 50 ml of water was added to the reaction mixture and the solvent was removed using the rotatory evaporator. 50 ml of 2N HCl solution was added to the organic layer extracted with 50 ml of ethyl acetate, and the resulting mixture was vigorously shaked for 2 minutes. Water layer was removed by layer separation and the organic layer was neutralized with 50 ml of a saturated sodium bicarbonate solution. Isolated organic layer was dried over magnesium sulfate, and then the vacuum distillation was preformed to give 4.17 g of yellow 2,2′-methylenebis(1,3-dimethyl-1,3-cyclopentadiene) compound. Yield: 61%.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]([CH3:25])[C:20](=[O:26])[CH2:19][CH2:18]4)[CH:11]=[N:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.[CH2:34]([S:36](Cl)(=[O:38])=[O:37])[CH3:35].O>C(Cl)Cl>[CH3:25][N:21]1[C:22]2[C:17](=[CH:16][C:15]([C:10]3[CH:11]=[N:12][CH:13]=[C:14]4[C:9]=3[CH2:8][CH2:7][CH2:6][N:5]4[CH2:4][CH2:3][NH:2][S:36]([CH2:34][CH3:35])(=[O:38])=[O:37])=[CH:24][CH:23]=2)[CH2:18][CH2:19][C:20]1=[O:26]
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCCN4CCN)ccc21
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)NCCN1CCCc2c(-c3ccc4c(c3)CCC(=O)N4C)cncc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28.8 %

Procedure:
To a solution of 6-[1-(2-amino-ethyl)-1,2,3,4-tetrahydro-[1,7]naphthyridin-5-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 12, 0.03 g, 0.081 mmol) in DCM (1 mL) were added triethylamine (0.020 g, 0.201 mmol) and ethanesulfonylchloride (0.011 g, 0.089 mmol) and the reaction mixture was stirred at room temperature for 1.5 h. The mixture was diluted with DCM, poured into H2O (5 mL) and extracted with DCM (2×10 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (0.01 g, 29%) as a yellow oil. MS: 429.2 (M+H+).
Reaction SMILES: CC(C)(OC([NH:7][CH:8]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH:9]([OH:16])[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=O)C>C(Cl)Cl>[NH2:7][CH:8]([CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)[CH:9]([OH:16])[C:10]([O:12][CH:13]([CH3:14])[CH3:15])=[O:11]
Reactant: CC(C)OC(=O)C(O)C(CC1CCCCC1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)OC(=O)C(O)C(N)CC1CCCCC1
Temperature: 0 °C
Yield: 73 %

Procedure:
β-[[(1,1-dimethylethoxy)carbonyl]amino]-α-hydroxycyclohexanebutanoic acid, 1-methylethyl ester (mixture of [R-(R*,S*)] and [S-(R*,R*)]isomers) (Example F), 3.4 g (10 mmol), is dissolved in methylene chloride, cooled to 0° C. and hydrochloric acid gas is bubbled in for five minutes every 15 minutes for two hours. The solution is diluted with ethyl acetate (50 ml) washed with saturated sodium bicarbonate solution (100 ml) and then with saturated brine solution (100 ml). The organics are separated, dried over magnesium sulfate and evaporated to dryness in vacuo to give 1.75 g (73%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:6](Cl)([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:5]=[N:4][N:3]=1.N1C=CC=CC=1.O.[NH2:30][NH2:31]>O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:30][NH2:31])=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: ClC1=NN=CC(Cl)(c2ccc(Cl)cc2)C1c1ccc(Cl)cc1
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: NNc1nnc(Cl)c(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a r.b. flask was added 3,5-dichloro-4,5-bis(4-chlorophenyl)pyridazine (4.5 gm, 12.2 mmol), pyridine (20 ml) and hydrazine monohydrate (1.494 gm, 30.49 mmol). The reaction mixture was stirred at 120° C. for 1 h. After this time, the reaction mixture was cooled to RT Water (400 ml) was then added and a solid precipitated. The solution was filtered and the solid was collected and air dried overnight to give the title compound, 1-(6-chloro-4,5-bis(4-chlorophenyl)pyridazin-3-yl)hydrazine (3.7 gm, 83% yield) as a solid. MS (M+H)=364.9.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][N:7]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH:3]=1.[CH3:37][N:38]1[CH:43]2[CH2:44][CH2:45][CH:39]1[CH2:40][C:41](=O)[CH2:42]2>>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:4]1[CH:3]=[C:2]([NH:1][CH:41]2[CH2:42][CH:43]3[N:38]([CH3:37])[CH:39]([CH2:45][CH2:44]3)[CH2:40]2)[CH:11]=[C:10]2[C:5]=1[CH2:6][N:7]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:8](=[O:20])[N:9]2[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19]
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(N)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Reactant: CN1C2CCC1CC(=O)C2
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(NC4CC5CCC(C4)N5C)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1

Procedure:
The 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-7-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino]-3,4-dihydroquinazolin-2(1H)-one was prepared from 7-amino-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (COMPOUND CCC4, STEP A) and 8-methyl-8-azabicyclo[3.2.1]octan-3-one by a procedure analogous to that described in EXAMPLE CCC18, STEP A. Mass spectrum (ESI) 661 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:17]2=[CH:18][CH:19]=[N:20][CH:21]=[C:16]2[C:5]2[C:6]([OH:15])=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:9][C:4]=2[O:3]1.[ClH:23].[N:24]1([CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:23].[CH3:22][C:2]1([CH3:1])[C:17]2=[CH:18][CH:19]=[N:20][CH:21]=[C:16]2[C:5]2[C:6]([O:15][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:9][C:4]=2[O:3]1
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: O=C(O)CCCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCc1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-(1-pentyl)-10-[4-(piperidino)butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(1-pentyl)-5H-[1]benzopyrano[3,4-d]pyridine and γ-piperidinobutyric acid hydrochloride in the presence of dicyclohexylcarbodiimide.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30]#[C:31][CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[OH:33]>C(OCC)C>[C:34]1([C:32](=[O:33])[C:31]#[C:30][C:26]2[S:25][CH:29]=[CH:28][CH:27]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: OC(C#Cc1cccs1)c1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(C#Cc1cccs1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Place pyridinium dichromate (0.75 g, 2 mmol) and methylene chloride (15 mL) under argon atmosphere and cool to 0° C. Add α-[(2-thiophenyl)ethynyl]-benzenemethanol (321 mg, 1.5 mmol). Stir overnight while slowly warming to room temperature. Dilute with ethyl ether and filter the chromium salts. Purify by silica gel chromatography to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]2[O:11][CH:9]([CH:10]=1)[CH:8]1[CH:4]2[C:5](=[O:22])[CH:6]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[C:7]1=[O:12].[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]3[O:11][CH:9]([CH:10]=2)[CH:8]2[CH:4]3[C:5](=[O:22])[CH:6]([C:13]3[C:14]([CH3:21])=[CH:15][C:16]([CH3:20])=[CH:17][C:18]=3[CH3:19])[C:7]2=[O:12])=[CH:26][CH:25]=1
Reactant: Cc1cc(C)c(C2C(=O)C3C4C=C(Br)C(O4)C3C2=O)c(C)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: Cc1cc(C)c(C2C(=O)C3C4C=C(c5ccc(F)cc5)C(O4)C3C2=O)c(C)c1
Temperature: 150 °C

Procedure:
A mixture of (1RS,2RS,6SR,7SR)-8-bromo-4-(2,4,6-trimethylphenyl)-10-oxatricyclo-[5.2.1.02,6]dec-8-en-3,5-dione (300 mg, 0.82 mmol), 4-fluorophenylboronic acid (171 mg, 1.22 mmol), sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenyl-3-sulfonate hydrate (17 mg, 0.03 mmol), potassium phosphate (522 mg, 2.5 mmol) and palladium acetate (4 mg, 0.02 mmol) in water (8 ml) are heated for 150° C. for 25 minutes under microwave irradiation. The mixture is cooled to room temperature and dilute aqueous hydrochloric acid is added. The mixture is filtered and the filtrate is extracted with ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure. Purification by column chromatography on silica gel gives (1RS,2SR,6RS,7RS)-8-(4-fluorophenyl)-4-(2,4,6-trimethylphenyl)-10-oxatricyclo[5.2.1.02,6]dec-8-en-3,5-dione.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@@:8]2([CH3:19])[NH:13][C:12](=S)[C:11]([CH3:16])([CH3:15])[S:10](=[O:18])(=[O:17])[CH2:9]2)[CH:7]=1.[NH3:21]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:9][S:10](=[O:18])(=[O:17])[C:11]([CH3:16])([CH3:15])[C:12]([NH2:21])=[N:13]2)[CH:7]=1
Reactant: CC1(C)C(=S)N[C@](C)(c2cc(Br)ccc2F)CS1(=O)=O
Reactant: N
Product: CC1(C)C(N)=N[C@](C)(c2cc(Br)ccc2F)CS1(=O)=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 81.6 %

Procedure:
A mixture of (R)-5-(5-bromo-2-fluoro-phenyl)-2,2,5-trimethyl-1,1-dioxo-1λ6-thiomorpholin-3-thione (1.28 g, 3.37 mmol, Eq: 1.00) and ammonia (7 N in MeOH) (38.5 ml, 269 mmol, Eq: 80) was stirred in a sealed tube for 20 hours at 60° C. Extracted with ethyl acetate/sat. NaHCO3-sol., dried the organic layer over Na2SO4, filtered and evaporated. The residue was chromatographed with ethyl acetate to give (R)-5-(5-bromo-2-fluoro-phenyl)-2,2,5-trimethyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (1 g, 2.75 mmol, 81.8% yield) as a white solid. MS (ISP): m/z=363.3 [M+H]+ and 365.3 [M+2+H]+.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:15]([O:19][C:20]([N:22]1[CH2:26][C@@H:25]([OH:27])[CH2:24][C@H:23]1[C:28]([O:30][CH3:31])=[O:29])=[O:21])([CH3:18])([CH3:17])[CH3:16].[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:26][C@@H:25]([O:27][C:34]2[CH:33]=[CH:32][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)[CH2:24][C@H:23]1[C:28]([O:30][CH3:31])=[O:29])=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: Oc1ccc2ccccc2c1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](Oc2ccc3ccccc3c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 84.1 %

Procedure:
DIAD (3.72 ml, 18.9 mmol) was added to a solution of methyl (2S,4S)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarboxylate (4.22 g, 17.2 mmol), 2-naphthol (2.73 g, 18.9 mmol) and triphenylphosphine (4.96 g, 18.9 mmol) in THF (80 ml) under stirring at room temperature in a nitrogen gas stream. The mixture was stirred overnight at room temperature. The residue, which had been obtained by concentrating the reaction mixture under reduced pressure, was purified by chromatography on a silica gel column (silica gel: 600 g), whereby from chloroform/ethyl acetate (10/1) eluate fractions, the title compound (5.37 g) was obtained as an amorphous substance (this compound was provided for the subsequent reaction without further purification).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:21])=[C:7]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N+:22]([O-:24])=[O:23].C(=O)(O)[O-].[Na+].[I-].[Na+].Cl.Cl[CH2:34][CH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][N:37]1[CH3:42]>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:21][CH2:34][CH2:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][N:37]3[CH3:42])=[C:7]([C:13]3[CH:14]=[C:15]([CH3:20])[CH:16]=[C:17]([CH3:19])[CH:18]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N+:22]([O-:24])=[O:23]
Reactant: CN1CCCCC1CCCl
Reactant: Cc1cc(C)cc(-c2c(O)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
A mixture of 7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-6-nitro-1H-quinolin-2-one (100 mg) and sodium bicarbonate (54 mg) was suspended in 2 mL dry N,N-dimethylformamide and heated to 80° C. on an oil bath. After 30 minutes, sodium iodide (48 mg) was added followed by 2-(2-chloroethyl)-1-methylpiperidine hydrochloride (64 mg) and the mixture stirred at 80° C. for 7 hours. At this time the reaction was cooled to room temperature and quenched by the addition of 25 mL ice/water. The mixture was filtered and the residue washed (1×) with ice water then dried at 40° C. Purification of the crude product by flash chromatography on silica gel (chloroform:10% ammonium hydroxide in methanol, 95:5) gave the title compound (67 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:5]2[NH:6][CH2:7][CH2:8][S:9][C:4]=2[CH:3]=1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([S:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]3)=[N:23]2)=[CH:18][CH:17]=1>>[Cl:1][C:2]1[C:11]([CH2:12][NH:35][CH:32]2[CH2:31][CH2:30][N:29]([CH2:28][CH2:27][S:26][C:22]3[CH:21]=[N:20][C:19]4[C:24](=[CH:25][C:16]([O:15][CH3:14])=[CH:17][CH:18]=4)[N:23]=3)[CH2:34][CH2:33]2)=[CH:10][C:5]2[NH:6][CH2:7][CH2:8][S:9][C:4]=2[CH:3]=1
Reactant: O=Cc1cc2c(cc1Cl)SCCN2
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Product: COc1ccc2ncc(SCCN3CCC(NCc4cc5c(cc4Cl)SCCN5)CC3)nc2c1

Procedure:
The title compound is prepared as a yellow waxy solid (23 mg, 34% yield) following Scheme 3 and in analogy to Example 40 using 7-chloro-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde (27 mg, 0.12 mmol 1.0 eq) and 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (40 mg, 0.12 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[N:13][O:14][CH2:15][CH3:16])=[C:10]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[I-].[Li+]>N1C=CC=CC=1>[Cl:1][C:2]1[C:11]([CH:12]=[N:13][O:14][CH2:15][CH3:16])=[C:10]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCON=Cc1c(S(C)(=O)=O)ccc(C(=O)OC)c1Cl
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CCON=Cc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Reaction time: 2 h
Yield: 88.3 %

Procedure:
A solution of 4.37 g (0.0137 mol) of methyl 2-chloro-3-ethoxyiminomethyl-4-methylsulfonylbenzoate was slowly added dropwise to 7.29 g (0.055 mol) of lithium iodide in 50 ml of dry pyridine. After stirring for 2 hours at reflux, the reaction mixture was cooled and the solvent was removed under reduced pressure. The residue was taken up in water and adjusted to pH=1-2 with dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with water, dried and concentrated under reduced pressure. 3.70 g of 2-chloro-3-ethoxyiminomethyl-4-methylsulfonylbenzoic acid were obtained. (Yield 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[O:13]1CCOCC1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[O:13])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(Cl)ccc2n1
Reactant: C1COCCO1
Product: O=Cc1ccc2cc(Cl)ccc2n1
Temperature: 80 °C

Procedure:
A suspension of 6-chloro-2-methyl-quinoline (355 mg) and SeO2 (233 mg) in 1,4-dioxane (3 mL) was heated at 80° C. for 16 h. The resulting black mixture was filtered through diatomaceous earth. Concentration of the filtrate gave the title compound as a yellow powder (324 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([CH:36]1[CH2:38][CH2:37]1)(=[O:35])=[O:34]>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33]([CH:36]3[CH2:38][CH2:37]3)(=[O:35])=[O:34])=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1Br)C1CC1
Reactant: CC1(C)OB(c2ccc(-c3ncc(N)nc3C#N)c(F)c2)OC1(C)C
Product: N#Cc1nc(N)cnc1-c1ccc(-c2ccccc2S(=O)(=O)C2CC2)cc1F

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile and 1-bromo-2-(cyclopropylsulfonyl)benzene. MS (ESI): mass calcd. for C20H15FN4O2S, 394.09; m/z found, 395.0 [M+H]+. 1H NMR (600 MHz, DMSO-δ6) δ 8.26 (s, 1H), 8.07 (dd, J=8.0, 1.3, 1H), 7.82-7.77 (m, 1H), 7.74-7.69 (m, 1H), 7.66-7.62 (m, 1H), 7.52 (dd, J=7.6, 1.3, 1H), 7.44 (dd, J=10.8, 1.7, 1H), 7.41-7.36 (m, 3H), 2.47-2.41 (m, 1H), 0.99-0.91 (m, 2H), 0.90-0.83 (m, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][C:10](=O)[CH2:9][C:8](=[O:13])[CH2:7]1.Cl.[NH2:15][CH2:16][C:17]#[C:18][CH3:19].O1CCCC1>C(N(CC)CC)C>[CH3:19][C:18]1[C:9]2[C:8](=[O:13])[CH2:7][CH:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH2:11][C:10]=2[N:15]=[CH:16][CH:17]=1
Reactant: O=C1CC(=O)CC(c2cccs2)C1
Reactant: CC#CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccnc2c1C(=O)CC(c1cccs1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
To a mixture of 5-(2-thienyl)cyclohexane-1,3-dione (1.5 g), 1-amino-2-butyne hydrochloride (0.82 g), molecular sieves 4A (3 g) and tetrahydrofuran (30 ml) was added triethylamine (0.78 g). The mixture was stirred at room temperature for 1 hour, refluxed for refluxed for 12 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and to the residue was added diphenylether (80 ml), and the mixture was stirred at 250° C. for 6 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give colorless crystals of 4-methyl-7-(2-thienyl)-5,6,7,8-tetrahydroquinolin-5-one (0.67 g).