Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([PH:5](=[O:9])[O:6][CH2:7][CH3:8])[CH2:2][CH2:3][CH3:4].C([Li])CCC.CCCCCC.C(OP(OCC)([C:26](=[CH2:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=O)C.[CH:36]1([CH:42]=O)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([P:5]([CH2:32]/[C:26](=[CH:42]\[CH:36]1[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1)/[C:27]([O:29][CH2:30][CH3:31])=[O:28])([O:6][CH2:7][CH3:8])=[O:9])[CH2:2][CH2:3][CH3:4]
Reactant: O=CC1CCCCC1
Reactant: C=C(C(=O)OCC)P(=O)(OCC)OCC
Reactant: CCCC[PH](=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCP(=O)(C/C(=C\C1CCCCC1)C(=O)OCC)OCC
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 22.1 %

Procedure:
Under a nitrogen atmosphere, a solution of 0.75 g (5.0 millimoles) of ethyl butylphosphinate in 5 ml of dry tetrahydrofuran was added dropwise over 10 minutes at -70° C. to a solution of 3.30 ml (5.1 millimoles) of 1.55 N butyllithium-hexane in 5 ml of dry tetrahydrofuran. The mixture was stirred at this temperature for 10 minutes, and then heated to -50 ° C. A solution of 1.18 g (5.0 millimoles) of ethyl 2-diethoxyphosphinoylpropenoate in ml of dry tetrahydrofuran was added dropwise over 10 minutes. The mixture was then stirred at 0° C. for hour. The mixture was cooled to -25° C., and a solution of 0.56 g (5.0 millimoles) of cyclohexanecarbaldehyde in 5 ml of dry tetrahydrofuran was added, and the mixture was stirred at this temperature for 2 hours and then at room temperature for 1 hour. To the reaction mixture was added 100 ml of a saturated aqueous solution of ammonium chloride, and the mixture was extracted twice with 80 ml of ethyl acetate each time. The combined organic layers were dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by medium-pressure liquid chromatography [Lobar column (a product of E. Merck & Co.), size C, Lichroprep SI 60, ethyl acetate)]. The first fraction was evaporated to give 0.38 g (yield 22%) of ethyl (Z)-2-(butylethoxyphosphinoyl)methyl-3-cyclohexylpropenoate as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[CH:9]1[CH:14]=[C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([CH:19]=O)[C:12]2=[CH:11][CH:10]=1.N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:8])[C:5]([C:6]#[N:7])=[CH:19][C:18]1[C:12]2[C:13](=[CH:14][CH:9]=[CH:10][CH:11]=2)[CH:15]=[CH:16][CH:17]=1)[CH3:2]
Reactant: CCOC(=O)CC#N
Reactant: O=Cc1cccc2ccccc12
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=Cc1cccc2ccccc12
Yield: 85.8 %

Procedure:
To a solution of 7.8 g of cyanoacetic acid ethyl ester and 10.0 g of 1-naphthylaldehyde in 150 ml of benzene were added 2 ml of piperidine and 2 ml of acetic acid, the mixture was heated under reflux for 3 hours while removing water formed during the reaction using a molecular sieve. After cooling, the reaction mixture was washed successively with a saturated sodium bicarbonate aqueous solution, water, diluted hydrochloric acid and water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from benzene-hexane to obtain 13.8 g of 2-cyano-3-(1-naphthyl)propenoic acid ethyl ester as light yellow crystals.
Reaction SMILES: [C:1]([NH:5][NH:6][PH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH2:16](N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OCC)C.CCCCCC>[C:1]([N:5]([C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[N:6]([PH:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8])[CH3:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccccc1[PH](=O)NNC(C)(C)C
Solvent: CCOCC
Solvent: CCCCCC
Product: CN(N(C(=O)c1ccccc1)C(C)(C)C)[PH](=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N'-t-butyl-N-(methylphenyl)phosphinylhydrazine (0.7 g) and triethylamine (3 ml) were stirred in diethyl ether (30 ml) at room temperature. Slowly, benzoyl chloride (1.2 g) was added dropwise to the reaction mixture. After stirring 1 hour at room temperature, the reaction mixture was diluted with hexane and the solid product filtered off. The white solid melted at 175°-178° C.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]([CH2:15][C:16]3[N:24]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:19]4=[N:20][CH:21]=[CH:22][CH:23]=[C:18]4[N:17]=3)[C:9](=[O:14])[N:10]([CH:11]([CH3:13])[CH3:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.[C:30]([Zn]C#N)#[N:31]>CN(C=O)C>[CH2:25]([N:24]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[N:17]=[C:16]1[CH2:15][N:8]1[C:7]2[C:2]([C:30]#[N:31])=[N:3][CH:4]=[CH:5][C:6]=2[N:10]([CH:11]([CH3:13])[CH3:12])[C:9]1=[O:14])[CH2:26][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccnc(Cl)c32)nc2cccnc21
Reactant: N#C[Zn]C#N
Solvent: CN(C)C=O
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccnc(C#N)c32)nc2cccnc21
Temperature: 25 °C

Procedure:
The mixture of compound 25 (0.075 g, 0.182 mmol), tetrakis(triphenyl-phosphine)palladium (41 mg, 0.036 mmol) and dicyanozinc (0.042 g, 0.363 mmol) in DMF (3 mL) under nitrogen atmosphere was irradiated for 30 minutes in a microwave reactor at 170° C. The resulting mixture was allowed to cool down to room temperature then filtered through an acrodisk filter and evaporated to dryness. The residue was purified by column chromatography using EtOAc. The title compound 29 was isolated as a white solid (60 mg, 81%).
Reaction SMILES: CO[S:3]([O-])(=O)=O.[CH3:7][N+:8]1[S:9][C:10]([Cl:15])=[C:11]([Cl:14])[C:12]=1Cl>C(O)C>[Cl:14][C:11]1[C:12](=[S:3])[N:8]([CH3:7])[S:9][C:10]=1[Cl:15]
Reactant: COS(=O)(=O)[O-]
Reactant: C[n+]1sc(Cl)c(Cl)c1Cl
Solvent: CCO
Product: Cn1sc(Cl)c(Cl)c1=S
Reaction time: 8 h
Yield: 77.9 %

Procedure:
2-Methyl-3,4,5-trichloroisothiazolium methylsulfate (10.7 g) thiourea (2.6 g) were added to 100 ml of ethanol at room temperature. After stirring overnight the product which had precipitated from solution was collected by filtration and recrystallized from ethanol to yield 5.3 g (78%) of 4,5-dichloro-2-methyl-4-isothiazolin-3-thione, mp 143-144. Analysis: Calculated for C4H3ClNS2 : C, 24.00; H, 1.50; N, 7.00; Cl, 35.45; S, 32.05. Found: C, 24.07; H, 1.45; N, 7.00; Cl, 35.67; S, 31.78.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[NH:32]1[C:40]2C(=CC=CC=2)[C:34](CCCC(O)=O)=[CH:33]1.C(OC(=O)CSC1SC(N)=NC=1)C>>[NH:32]1[C:33]2[C:2](=[CH:7][CH:6]=[CH:5][CH:34]=2)[C:3]([CH2:4][CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:40]1
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCCc2c[nH]c3ccccc23)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexy)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-(1H-indol-3-yl)-butyric acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH:13]([CH3:15])[CH3:14])/[C:8]([OH:10])=O)[N:6]=1.[NH2:16][C@@H:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH2:24][O:25][C:26](=[O:31])[CH2:27][C:28](=[O:30])[CH3:29])[CH2:22][S:23][C@H:18]12>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH:13]([CH3:15])[CH3:14])/[C:8]([NH:16][C@@H:17]2[C:35](=[O:36])[N:19]3[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH2:24][O:25][C:26](=[O:31])[CH2:27][C:28](=[O:30])[CH3:29])[CH2:22][S:23][C@H:18]23)=[O:10])[N:6]=1
Reactant: CC(C)O/N=C(\C(=O)O)c1csc(N)n1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Product: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OC(C)C)c3csc(N)n3)[C@H]2SC1

Procedure:
Starting from 2-(2-aminothiazol-4-yl)-2(Z)-isopropoxyiminoacetic acid and 7β-amino-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid, the titled compound is obtained by the procedure of Reference Example 3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[CH3:8].CO>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ncc(CO)cc1F
Solvent: CO
Solvent: ClCCl
Product: Cc1ncc(C=O)cc1F
Temperature: 35 °C
Reaction time: 4 h
Yield: 31.2 %

Procedure:
To a solution of (5-fluoro-6-methyl-3-pyridinyl)methanol (468 mg, 3.32 mmol) in DCM (4 ml) was added CrO2 (Magtrieve) (4.2 g, 49.7 mmol). The mixture was stirred at 35° C. for 4 h. TLC (5% MeOH in DCM) showed starting material remaining. An excess of CrO2 (Magtrieve) (2.8 g, 33.3 mmol) was added. The mixture was stirred at 35° C. for 48 h. The solids were filtered off and the solvent evaporated to afford 144 mg (28%) of the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:38])[CH:15]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][C:18]=2[CH2:26][CH2:27][CH3:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH2:39][C:40]1[N:41]([CH3:46])[CH2:42][C:43](=[O:45])[N:44]=1.C(N(CC)CC)C>C1COCC1>[CH3:46][N:41]1[CH2:42][C:43](=[O:45])[N:44]=[C:40]1[NH:39][C:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH:15]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[C:14]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])=[O:38])=[C:18]([CH2:26][CH2:27][CH3:28])[CH:19]=1)=[O:24]
Reactant: CN1CC(=O)N=C1N
Reactant: CCCc1cc(C(=O)O)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1cc(C(=O)NC2=NC(=O)CN2C)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Yield: 60.5 %

Procedure:
To a solution of 200 mg (0.370 mmol) of N-(4-isopropylbenzenesulfonyl)-α-(4-carboxy-2-n-propylphenoxy)-3,4-methylenedioxyphenylacetamide (from Step D) in 1 mL of dry THF was added 90 mg (0.556 mmol) of 1,1-carbonyldiimidazole. The solution was stirred at reflux under N2 for 2 hours. The cooled solution was evaporated to dryness. The residue was dissolved in 1 mL of acetonitrile and treated with 63 mg (0.556 mmol) of 2-amino-4,5-dihydro-1-methyl-1H-imidazol-4-one (creatinine) and 129 μL (93.7 mg; 0.925 mmol) of triethylamine. The mixture was stirred at reflux overnight. The cooled reaction mixture was quenched by addition of 1N HCl and extracted twice with EtOAc. The combined organic extracts were dried over MgSO4, and filtered. The filtrate was concentrated, and the residue was flash chromatographed (silica gel, 27×3.5 cm; elution with 500 mL of 99:1:1 CHCl3 -MeOH-concentrated NH4OH followed by 1 L of 85:15:1 CHCl3 -MeOH-concentrated NH4OH) to give 142 mg (60%) of the title compound as a yellow solid, mp 137°-139 ° C.; homogeneous by TLC in 85:15:1 CHCl3 -MeOH-concentrated NH4OH. ESI mass spectrum m/e 635 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL), and the solution was added with benzylamine (0.011 mL, 0.10 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) followed by stirring at room temperature for 16 hours. The reaction mixture was added with 3 mol/L aquous sodium hydroxide solution, extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The mixture was added with aldehyde resin and stirred at room temperature for 16 hours. The resin was filtered off and the solvent of the filtrate was evaporated under reduced pressure. The residue was dissolved in chloroform, and the solution was filtered through a column filled with SCX (positive-ion-exchange resin). The resulting SCX was washed with 7 mol/L ammonia-methanol solution and the solvent of the filtrate was evaporated under reduced pressure to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(benzylaminomethyl)indol-2-yl]isoindolinone.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:37]([CH3:39])[CH3:38])[C:6]2[O:10][C:9]([C:11]3[CH:35]=[CH:34][C:14]([C:15]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22](B5OC(C)(C)C(C)(C)O5)=[CH:21][CH:20]=4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:36]=1)#[N:2].Br[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[CH:43]=1.C(B(O)O)(C)=C>>[C:1]([C:3]1[CH:4]=[C:5]([CH:37]([CH3:39])[CH3:38])[C:6]2[O:10][C:9]([C:11]3[CH:35]=[CH:34][C:14]([C:15]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([CH2:41][C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:49])([F:50])[F:51])[CH:43]=5)=[CH:21][CH:20]=4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:36]=1)#[N:2]
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCc4ccc(B5OC(C)(C)C(C)(C)O5)cc4)cc3)oc12
Agent: C=C(C)B(O)O
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCc4ccc(Cc5cccc(C(F)(F)F)c5)cc4)cc3)oc12

Procedure:
The title compound was prepared from 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]benzamide (26 mg, EXAMPLE 8) and 1-(bromomethyl)-3-(trifluoromethyl)benzene (24 mg) following the procedure described in EXAMPLE 3 (26 mg, 93%) Mass spectrum (ESI) 554.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.33 (d, J=8.2 Hz, 2H), 7.97 (d, J=8.3 Hz, 2H), 7.94 (s, 1H), 7.51 (s, 1H), 7.41 (m, 4H), 7.33 (d, J=8.0 Hz, 2H), 7.20 (d, J=7.8 Hz, 2H), 6.42 (bs, 1H), 4.67 (d, J=5.5 Hz, 2H), 4.04 (s, 2H), 3.38 (sept, J=6.9 Hz, 1H), 1.46 (d, J=6.8, 6H).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]=[C:17]([C:19]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[O:20])[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:29][S:30]([C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:18]=[C:17]([C:19]([N:21]4[CH2:26][CH2:25][N:24]([S:39]([C:35]5[CH:36]=[CH:37][CH:38]=[C:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:34]=5)(=[O:41])=[O:40])[CH2:23][CH2:22]4)=[O:20])[CH:16]=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)=[CH:27][CH:28]=1
Reactant: O=C(c1cccc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)N1CCNCC1
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(S(=O)(=O)N2CCN(C(=O)c3cccc(-c4ccc(Oc5ccc(F)cc5)cc4)n3)CC2)c1
Yield: 84 %

Procedure:
According to the methodology described in Example 7, compound 6 (100 mg, 0.24 mmol), 3-methylsulfonylbenzenesulfonyl chloride (60 mg, 0.24 mmol), DIEA (0.1 mL, 0.7 mmol) and DCM (5 mL) were reacted to give compound 8 in 84% yield (LC/MS (m/z+H)=596; 1H NMR (CDCl3) δ ppm: 6.8-8.5 (m, 15H); 4.0 (m, 4H); 3.3 (m, 4H); 3.2 (s, 3H)).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([CH2:9][OH:10])=[N:7][CH:6]=[N:5]1.Cl[C:12]1[C:13]([N:27]2[CH2:32][CH:31]=[CH:30][CH2:29][CH2:28]2)=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)[N:17]=1.O>CN(C=O)C>[N:27]1([C:13]2[C:12]([O:10][CH2:9][C:8]3[N:4]([CH3:3])[N:5]=[CH:6][N:7]=3)=[N:17][N:16]3[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:19][N:20]=[C:15]3[CH:14]=2)[CH2:28][CH:29]=[CH:30][CH2:31][CH2:32]1
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1N1CC=CCC1
Reactant: Cn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncnc1COc1nn2c(-c3ccccc3)nnc2cc1N1CC=CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
Sodium hydride (60% dispersion in oil, 23 mg, 0.58 mmol) was added to a solution of (2-methyl-2H-1,2,4-triazol-3-yl)methanol (EP-A-421210) (57 mg, 0.53 mmol) in dry DMF (2 ml) at room temperature under nitrogen. After 1 hour at room temperature a solution of 6-chloro-7-(3,6-dihydro-2H-pyridin-1-yl)-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (150 mg) in dry DMF (2 ml) was added via syringe. The mixture was stirred at room temperature for 16 hours. Water (20 ml) was added and the solid filtered and dried in vacuo. Recrystallisation from ethyl acetate/petroleum ether afforded the title pyridaziite as a white solid (131 mg, 70%). 1H NMR (250 MHz, CDCl3) 8.29 (2H, m), 7.94 (1H, s), 7.52 (3H, m), 7.23 (1H, s), 5.91 (1H, m), 5.80 (1H, m), 5.63 (2H, s), 3.96 (3H, s), 3.71 (2H, m), 3.40 (2H, m), 2.23 (2H, m). MS (ES+) 389 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[C:30]([O:31][CH3:32])=[CH:29][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]4[CH:20]=[C:19]([O:21][CH2:22][CH2:23]Cl)[C:18]([O:25][CH3:26])=[CH:17][C:14]=4[CH:15]=3)[N:10]=[CH:9][C:8]=2[C:27]#[N:28])=[C:4]([CH3:33])[CH:3]=1.[Cl:34][C:35]1[C:63]([O:64][CH3:65])=[CH:62][C:38]([NH:39][C:40]2[C:49]3[C:44](=[CH:45][C:46]4[CH:53]=[C:52]([O:54][CH3:55])[C:51]([O:56][CH2:57][CH2:58]Cl)=[CH:50][C:47]=4[CH:48]=3)[N:43]=[CH:42][C:41]=2[C:60]#[N:61])=[C:37]([CH3:66])[CH:36]=1.C([O-])(=O)C.[Na+].[NH:72]1[CH2:77][CH2:76][O:75][CH2:74][CH2:73]1>>[Cl:1][C:2]1[C:30]([O:31][CH3:32])=[CH:29][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]4[CH:20]=[C:19]([O:21][CH2:22][CH2:23][N:72]5[CH2:77][CH2:76][O:75][CH2:74][CH2:73]5)[C:18]([O:25][CH3:26])=[CH:17][C:14]=4[CH:15]=3)[N:10]=[CH:9][C:8]=2[C:27]#[N:28])=[C:4]([CH3:33])[CH:3]=1.[Cl:34][C:35]1[C:63]([O:64][CH3:65])=[CH:62][C:38]([NH:39][C:40]2[C:49]3[C:44](=[CH:45][C:46]4[CH:53]=[C:52]([O:54][CH3:55])[C:51]([O:56][CH2:57][CH2:58][N:72]5[CH2:77][CH2:76][O:75][CH2:74][CH2:73]5)=[CH:50][C:47]=4[CH:48]=3)[N:43]=[CH:42][C:41]=2[C:60]#[N:61])=[C:37]([CH3:66])[CH:36]=1
Reactant: COc1cc(Nc2c(C#N)cnc3cc4cc(OC)c(OCCCl)cc4cc23)c(C)cc1Cl
Reactant: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCCl)c(OC)cc4cc23)c(C)cc1Cl
Reactant: C1COCCN1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OC)c(OCCN5CCOCC5)cc4cc23)c(C)cc1Cl
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCN5CCOCC5)c(OC)cc4cc23)c(C)cc1Cl
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
A mixture of 318 mg (0.66 mmol) of 4-(4-chloro-5-methoxy-2-methylanilino)-7-methoxy-8-(chloroethoxy)benzo[g]quinoline-3-carbonitrile and 4-(4-chloro-5-methoxy-2-methylanilino)-8-methoxy-7-(chloroethoxy)benzo[g]quinoline-3-carbonitrile (1:1 mixture), 100 mg of sodium acetate and 5 mL of morpholine is stirred and heated to 130° C. using an oil bath. After 30 minutes the reaction is allowed to cool to room temperature. The reaction mixture is concentrated in vacuo and the residue purified by silica gel chromatography, eluting with 95:5 methylene chloride/methanol to yield 82 mg (23%) of 4-(4-chloro-5-methoxy-2-methylanilino)-7-methoxy-8-[2-(4-morpholinyl)ethoxy]benzo[g]quinoline-3-carbonitrile as a yellow wax and 153 mg of 4-(4-chloro-5-methoxy-2-methylanilino)-8-methoxy-7-[2-(4-morpholinyl)ethoxy]benzo[g]quinoline-3-carbonitrile as a yellow solid, mp 191–194° C. dec.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[C:23]1([C:29]#[C:30][CH:31]=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:31][C:30]#[C:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: O=CC#Cc1ccccc1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCC#Cc4ccccc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.2 %

Procedure:
To 10 mL of a chloroform solution containing 500 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 1940 mg of phenylpropargylaldehyde, 100 mg of acetic acid were added, and stirred at room temperature for 2 hours. To the reaction mixture, 526 mg of sodium triacetoxyborohydride was added, and stirred for 14 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 0.27 g of 7-methoxy-1-(2-(4-(3-phenyl-2-propyn-1-ylamino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as a brown oil and 0.23 g of 1-(2-(4-(bis(3-phenyl-2-propyn-1-ylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a brown oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.[CH3:31][O:32][C:33]1[C:38]([CH3:39])=[CH:37][C:36]([CH:40]2[CH2:45][N:44]3[CH:46]=[C:47]([C:49](O)=[O:50])[N:48]=[C:43]3[CH2:42][CH2:41]2)=[CH:35][C:34]=1[CH3:52].[F:53][C:54]([F:68])([F:67])[C:55]1[CH:56]=[C:57]([N:61]2[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[CH:58]=[CH:59][CH:60]=1>CN(C=O)C>[CH3:31][O:32][C:33]1[C:38]([CH3:39])=[CH:37][C:36]([CH:40]2[CH2:45][N:44]3[CH:46]=[C:47]([C:49]([N:64]4[CH2:63][CH2:62][N:61]([C:57]5[CH:58]=[CH:59][CH:60]=[C:55]([C:54]([F:67])([F:68])[F:53])[CH:56]=5)[CH2:66][CH2:65]4)=[O:50])[N:48]=[C:43]3[CH2:42][CH2:41]2)=[CH:35][C:34]=1[CH3:52]
Reactant: COc1c(C)cc(C2CCc3nc(C(=O)O)cn3C2)cc1C
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1c(C)cc(C2CCc3nc(C(=O)N4CCN(c5cccc(C(F)(F)F)c5)CC4)cn3C2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TBTU (240 mg; 0.75 mmol) and N-methylmorpholine (206 μl; 189 mg; 1.87 mmol) were added to a solution of 6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (210 mg; 0.63 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then 1-(3-trifluoromethylphenyl)piperazine (140 μl; 172 mg; 0.75 mmol) was added. The reaction mixture was stirred for 4 h at room temperature, then poured onto water and extracted with chloroform. The organic phase was dried over MgSO4, filtered and concentrated to small volume. The raw product was purified by column chromatography on silica gel (chloroform). Yield: 198 mg (62%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2Br)[CH:6]=1)[CH3:2].[F:19][C:20]([F:40])([F:39])[C:21]1[CH:22]=[CH:23][C:24]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[C:25](B(O)O)[CH:26]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:23]2[CH:22]=[C:21]([C:20]([F:40])([F:19])[F:39])[CH:26]=[CH:25][C:24]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH:6]=1)[CH3:2]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1
Reactant: CCOC(=O)c1cc(F)cc(C2=C(Br)CCC2)c1
Product: CCOC(=O)c1cc(F)cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccc(F)cc3)CCC2)c1

Procedure:
Prepared by general procedure B(iii) but using 3-(2-bromocyclopent-1-enyl)-5-fluorobenzoic acid ethyl ester instead of 3-(2-bromo-cyclopent-1-enyl)-6-methyl benzoic acid ethyl ester and using [5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]boronic acid instead of (5-chloro-2-benzyloxyphenyl)boronic acid.