Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[OH:11])[C:5]([OH:7])=O.Cl.[CH3:15][O:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:19].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[CH3:15][O:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:19][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([Cl:12])[C:10]([OH:11])=[C:2]([Cl:1])[C:3]=1[OH:13]
Reactant: O=C(O)c1cc(Cl)c(O)c(Cl)c1O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1cc(Cl)c(O)c(Cl)c1O
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a solution of 3,5-dichloro-2,4-dihydroxybenzoic acid (17 g), L-phenylalanine methyl ester hydrochloride (19.8 g), WSC.HCl (17.6 g) and HOBT (12.4 g) in DMF (70 ml) was added dropwise triethylamine (12.8 ml) at room temperature, and the mixture was stirred for 16 hours. Then, the mixture was post-treated in the same manner as in the above Example 1, Step 5) to give the title compound (18.32 g, yield 57%).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:58][O:59][CH:60]([F:62])[F:61])[C:27]([NH:29][CH:30]2[C:56](=[O:57])[N:32]3[C:33]([C:40]([O:42][CH:43]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])=[C:34]([CH2:38]Cl)[CH2:35][S:36](=[O:37])[C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:63].[Na+]>CC(C)=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:58][O:59][CH:60]([F:62])[F:61])[C:27]([NH:29][CH:30]2[C:56](=[O:57])[N:32]3[C:33]([C:40]([O:42][CH:43]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])=[C:34]([CH2:38][I:63])[CH2:35][S:36](=[O:37])[C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)C(=NOC(F)F)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS(=O)[C@H]12)C(=NOC(F)F)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 2 h
Yield: 42.4 %

Procedure:
A mixture of benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate-1-oxide (syn isomer) (29 g), sodium iodide (14.6 g) and acetone (300 ml) was stirred for 2.0 hours at 0°-5° C. and evaporated. To the residue were added ethyl acetate (400 ml) and water (300 ml), and the organic layer was separated, dried and evaporated. The residue was subjected to column chromatography on silica gel (600 g) and the elution was carried out with a mixture of chloroform and ethyl acetate (15:1). The fractions containing the object compound were combined and evaporated. The residue was triturated with diisopropyl ether to give benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-iodomethyl-3-cephem-4-carboxylate-1-oxide (syn isomer) (13.57 g).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[CH3:18][N:19]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1)[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:21][C:20](=[O:26])[N:19]([CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])=[CH:33][CH:34]=1)[CH3:18])([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CN(CCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC(C)(C)C
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCN(C)C(=O)OC(C)(C)C)cc1
Yield: 59.5 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (2.4 g, 7.6 mmol) was reacted with tert-butyl methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)carbamate (4.2 g, 11 mmol) to afford the desired product (2.1 g, 40%) as a light brown solid: ESI MS m/z 465 [C26H28N2O4S+H]+.
Reaction SMILES: C(O)(C)(C)C.[Li].[CH3:7][C:8]1([CH3:17])[C@@H:10]([C:11](Cl)=[O:12])[C@@H:9]1[C:14](=[O:16])[CH3:15].[Cl-].[Na+]>O1CCCC1>[CH3:7][C:8]1([CH3:17])[C@@H:10]([CH:11]=[O:12])[C@@H:9]1[C:14](=[O:16])[CH3:15]
Reactant: CC(=O)[C@H]1[C@H](C(=O)Cl)C1(C)C
Agent: [Cl-]
Agent: [Li]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CC(=O)[C@H]1[C@H](C=O)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
36.6 g (0.495 mol) of tert.-butanol were added dropwise to a mixture of 6.3 g (0.165 mol) of lithium alanate and 100 ml of tetrahydrofuran at 20°-30° C. in the course of 1 hour. The mixture was subsequently stirred at room temperature for 2 hours and was then added dropwise to a solution of 26.1 g (0.15 mol) of trans-3,3-dimethyl-2-acetyl-cyclopropane-carboxylic acid chloride in 75 ml of tetrahydrofuran at -50° to -60° C. When the addition had ended, the mixture was subsequently stirred for 1 hour, without cooling, poured onto a mixture of 30 ml of concentrated sodium chloride and 300 g of ice and extracted twice by shaking with 400 ml of ether each time. The organic phases were first washed with 50 ml of saturated sodium bicarbonate solution and then with 100 ml of water, dried over sodium sulphate and evaporated in vacuo. Distillation of the residue in vacuo gave 12.7 g (62% of theory) of trans-3,3-dimethyl-2-acetyl-cyclopropane-carbaldehyde in the form of a colorless oil with a boiling point of 80°-86° C./10 mbars.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][CH:6]([NH:8][C:9](=[O:14])[C:10]([O:12]C)=O)[CH2:5][C:4]([CH3:16])([CH3:15])[NH:3]1.[C:18]([C:22]1[CH:23]=[C:24]([NH:33][C:34]([C:36]([NH:38][NH2:39])=[O:37])=[O:35])[CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])([CH3:21])([CH3:20])[CH3:19]>CO>[CH3:17][C:2]1([CH3:1])[CH2:7][CH:6]([NH:8][C:9](=[O:14])[C:10]([NH:39][NH:38][C:36](=[O:37])[C:34]([NH:33][C:24]2[CH:25]=[C:26]([C:29]([CH3:31])([CH3:32])[CH3:30])[C:27]([OH:28])=[C:22]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:23]=2)=[O:35])=[O:12])[CH2:5][C:4]([CH3:16])([CH3:15])[NH:3]1
Reactant: COC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1
Reactant: CC(C)(C)c1cc(NC(=O)C(=O)NN)cc(C(C)(C)C)c1O
Solvent: CO
Product: CC1(C)CC(NC(=O)C(=O)NNC(=O)C(=O)Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CC(C)(C)N1
Temperature: 15 °C

Procedure:
Into a 3-necked 300 ml flask was introduced a 58% solution of methyl N-(2,2,6,6-tetramethyl-4-piperidinyl)oxamate in methanol (8.3 g, 0.02 mole), N-(3,5-di-t-butyl-4-hydroxyphenyl)-N'-aminooxamide (6.1 g, 0.02 mole) and 100 ml of anhydrous methanol. The flask was equipped with a magnetic stirrer, a thermometer and a Dean Stark trap containing a reflux condenser. The reaction mixture was heated in an oil bath to reflux for 31/2 hours. At this point, the Dean Stark trap was periodically drained until 40 ml of methanol was collected and solid material formed in the reaction mixture. An additional 10 ml of methanol was distilled from the reaction mixture. The reaction mixture was cooled to 15° C. and the resulting thick slurry was filtered. The filter cake was rinsed with 20 ml of cold methanol and air dried. The product was a white solid weighing 6.2 grams and had a melting range of 196°-202° C. The infrared scan (nujol mull) contained sharp carbonyl bands at 1665, 1585 and 1510 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9](OC3CCOCC3)[C:10]=2[N:11]=1.[CH:19]1([SH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([S:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:10]=2[N:11]=1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Reactant: SC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Clc1ccc2ncnc(SC3CCCCC3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.1 g, 0.500 mmol) in ACN (2.500 ml) were added cyclohexanethiol (0.058 g, 0.500 mmol) and K2CO3 (0.069 g, 0.500 mmol) at room temperature. After stirring overnight at room temperature, the reaction mixture was diluted with water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with 1N aq. NaOH and then washed with 1N aq. HCl. The organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=5:1) to give 6-chloro-4-(cyclo hexylthio)pyrido[3,2-d]pyrimidine (0.129 g, 92%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.36-1.42 (1H, m), 1.48-1.69 (5H, m), 1.80-1.86 (2H, m), 2.14-2.20 (2H, m), 4.10-4.16 (1H, m), 7.73 (1H, d, J=8.8 Hz), 8.19 (1H, d, J=8.8 Hz), 8.98 (1H, s).
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([O:12]CC)(=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>C(O)C>[C:4]([NH:2][NH2:3])(=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: NN
Reactant: CCCCCCC(=O)OCC
Solvent: CCO
Solvent: O
Product: CCCCCCC(=O)NN
Yield: 51.2 %

Procedure:
12.2 g of hydrazine hydrate was added to a solution of 15 g of ethyl heptanoate in 20 ml of ethanol, followed by heat-refluxing for 4.5 hours. After the reaction, the reaction mixture was cooled to precipitate a crystal. The crystal was recovered by filtration and recrystallized from 20 ml of ethanol to obtain 7 g of heptanohydrazide.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([CH2:13]Br)=[C:11]([O:15][CH2:16][CH3:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[O:18][CH2:19][CH3:20].[CH2:21]([O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[CH3:22]>CN(C)C=O>[CH2:21]([O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]2[CH2:13][C:12]3[C:11]([O:15][CH2:16][CH3:17])=[C:10]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]4=[C:4]([O:18][CH2:19][CH3:20])[C:3]=3[CH2:2]2)=[CH:30][CH:31]=1)[CH3:22]
Reactant: CCOc1c(CBr)c(CBr)c(OCC)c2ccccc12
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC)c4ccccc4c3OCC)C2)cc1
Yield: 35.8 %

Procedure:
A solution of 2,3-bis(bromomethyl)-1,4-diethoxy-naphthalene (41 mg, 0.1 mmol) and 4-aminophenylacetic acid ethyl ester (20 mg, 0.11 mmol) in N,N-dimethylformamide (1 ml) was heated at 60° C. under nitrogen for 14 h. The solvent was removed in vacuo and the residue taken up in ethyl acetate (10 ml) and washed with 8% aqueous sodium bicarbonate solution (5 ml). The organic layer was dried over magnesium sulphate and the solvent removed in vacuo. Purification by flash column chromatography on silica gel eluting with 90% cyclohexane/ethyl acetate gave the product as a white solid (15 mg, 36%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH:8]([F:10])[F:9])=[CH:5][C:6]=1[Cl:7].C([Li])CCC.CN(C)[CH:18]=[O:19]>O1CCCC1>[Cl:7][C:6]1[CH:5]=[C:4]([CH:8]([F:10])[F:9])[S:3][C:2]=1[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: FC(F)c1cc(Cl)c(Cl)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1sc(C(F)F)cc1Cl
Reaction time: 2 h

Procedure:
2.47 g of the product of Stage B were cooled to -60° C. in 20 ml of tetrahydrofuran and 9.2 ml of n-butyllithium were added. The mixture was stirred for 2 hours and 1.4 ml of dimethylformamide and 3 ml of tetrahydrofuran were added. The mixture was stirred for 30 minutes at -60° C., allowed to return to room temperature and the synthesis was continued as shown in Stage A to obtain 0.9 g of the expected product.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:28])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][Si](C(C)(C)C)(C)C)[CH:15]=2)=[N:8][C:7]=1[CH3:29])=[O:5])C.O.[OH-].[Li+]>C1COCC1.O>[OH:20][C:16]1[CH:15]=[C:14]([CH2:13][C:12]([NH:11][C:9]2[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([CH3:29])[N:8]=2)=[O:28])[CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1sc(NC(=O)Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(NC(=O)Cc2cccc(O)c2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
A mixture of 2-{2-[3-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-acetylamino}-4-methyl-thiazole-5-carboxylic acid ethyl ester (1.02 g, 2.347 mmol) and lithium hydroxide monohydrate (1 g, 23.83 mmol) in THF (21 mL) and water (7 mL)) was stirred at 25° C. for 16 h. The reaction was quenched by addition of aqueous 2N HCl (25 mL) followed by addition of sodium chloride. The resultant biphasic solution was extracted with 7:3 ethyl acetate/THF (3×125 mL). The organic layers were combined, washed with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give 2-[2-(3-Hydroxy-phenyl)-acetylamino]-4-methyl-thiazole-5-carboxylic acid (0.62 g, 90.4%) as a white solid. MS m/e 293.3 (M+H+).
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([F:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:17][O:18][C:19](=[O:30])[C:20]1[CH:25]=[C:24]([Cl:26])[C:23]([F:27])=[C:22]([CH2:28][NH2:29])[CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:15][C@H:14]([F:16])[CH2:13][C@H:9]1[C:10](=[O:12])[NH:29][CH2:28][C:22]1[CH:21]=[C:20]([C:19]([O:18][CH3:17])=[O:30])[CH:25]=[C:24]([Cl:26])[C:23]=1[F:27])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)O
Reactant: COC(=O)c1cc(Cl)c(F)c(CN)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(Cl)c(F)c(CNC(=O)[C@@H]2C[C@@H](F)CN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-boc-trans-4-fluoro-L-proline (143 mg, 0.61 mmol), 3-aminomethyl-5-chloro-4-fluoro-benzoic acid methyl ester (prepared as described in Part C, 275 mg, 0.61 mmol) and HATU (0.35 g, 0.92 mmol) in DMF (4 mL) was added DIPEA (430 μl, 2.45 mmol) and the resulting solution was stirred overnight at ambient temperature. The reaction mixture was splitted in two batches and the crude product was purified without aqueous workup by RP-preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 ml/min) to give the title compound. MS (LC-MS): 333.0 [M−100]+; tR (HPLC conditions c): 5.05 min.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][N:25]([CH3:30])[S:26]([CH3:29])(=[O:28])=[O:27])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>Cl.O1CCOCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][N:25]([CH3:30])[S:26]([CH3:29])(=[O:28])=[O:27])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Product: CN(Cc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1)S(C)(=O)=O
Reaction time: 3 h

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-(3-{[methyl(methylsulfonyl)amino]methyl}-1,2,4-oxadiazol-5-yl)hexanoate (preparation 6) (264 mg, 0.60 mmol) in 4M HCl in dioxan (2 ml) was stirred at room temperature for 20 hours. Further 4M HCl in dioxan (2 ml) was added and stirred for a further 3 hours. A few drops of concentrated HCl was added and the reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure to afford the title compound (245 mg—contained some dioxan as impurity).
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([Cl:17])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][S:27]([NH2:30])(=[O:29])=[O:28].C(=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1>[CH2:26]([S:27]([NH:30][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([Cl:17])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:28])=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: CCCCCCCCS(N)(=O)=O
Reactant: O=C1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: CCCCCCCCS(=O)(=O)Nc1cccc2c1C(=O)c1cccc(Cl)c1C2=O

Procedure:
1,5-dichloroanthraquinone (1.0g), n-octanesulfonamide (0.77g), potassium carbonate (1.0g), cupric acetate monohydrate (1.0g) and chlorobenzene (15ml) were refluxed for 4 hours. The solvent was evaporated at reduced pressure and the residue was extracted with toluene. After filtration the extract was separated by chromatography on silica using toluene as eluent to give the desired product as the second fraction.
Reaction SMILES: Cl[C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:7])=[CH:4][N:3]=1.[CH3:25][C:26]1[CH:39]=[CH:38][C:29]([C:30]([NH:32][N:33]2[NH:37][CH:36]=[CH:35][S:34]2)=[O:31])=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1>>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:6](=[O:7])[C:5]2[CH:23]=[CH:24][C:2]([C:27]3[CH:28]=[C:29]([C:30](=[O:31])[NH:32][N:33]4[NH:37][CH:36]=[CH:35][S:34]4)[CH:38]=[CH:39][C:26]=3[CH3:25])=[N:3][CH:4]=2)[CH2:17][CH2:18]1
Reactant: CN1CCN(Cc2ccccc2NC(=O)c2ccc(Cl)nc2)CC1
Reactant: Cc1ccc(C(=O)NN2NC=CS2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)NN2NC=CS2)cc1-c1ccc(C(=O)Nc2ccccc2CN2CCN(C)CC2)cn1

Procedure:
N-[2-(4-Methylpiperazin-1-ylmethyl)phenyl]-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide (Intermediate 5) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B. LCMS: retention time 2.43 min, MH+ 528. NMR: δH [2H6]-DMSO 13.07,(1H, b), 11.74,(1H, s), 9.26,(1H, s), 9.21,(1H, s), 8.43,(1H, d), 8.34,(1H, d), 8.29,(1H, s), 8.12,(1H, d), 7.93,(1H, d), 7.56,(1H, d), 7.36,(1H, t), 7.29,(1H, d), 7.11,(1H, t), 3.78,(2H, s), 2.67-2.26,(11H, m), 2.11,(3H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][O:9][CH2:10][CH2:11][S:12][CH2:13][CH2:14]C1OCCO1.[CH:20](O)=[O:21]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][O:9][CH2:10][CH2:11][S:12][CH:13]([CH3:14])[CH:20]=[O:21]
Reactant: c1ccc(CCOCCSCCC2OCCO2)nc1
Reactant: O=CO
Product: CC(C=O)SCCOCCc1ccccn1
Reaction time: 22 h

Procedure:
The material from step b) (0.850 g) was dissolved in 80% formic acid (10 ml) and left to stand at room temperature for 22 hours. The mixture was partitioned between ether and water. The layers were separated and the aqueous layer extracted with ether. The ethereal extracts were combined, washed with brine, dried (MgSO4) and evaporated is under reduced pressure to yield the subtitled compound as an oil (0.70 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C1CCC(N=C=NC2CCCCC2)CC1.[F:25][C:26]1[CH:27]=[C:28]([N:38]2[CH:42]=[C:41]([CH2:43][NH2:44])[N:40]=[N:39]2)[CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][S:35][CH2:34][CH2:33]1.O>C(#N)C>[F:25][C:26]1[CH:27]=[C:28]([N:38]2[CH:42]=[C:41]([CH2:43][NH:44][C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[O:9])[N:40]=[N:39]2)[CH:29]=[CH:30][C:31]=1[N:32]1[CH2:33][CH2:34][S:35][CH2:36][CH2:37]1
Reactant: O=C(O)c1cnccn1
Reactant: NCc1cn(-c2ccc(N3CCSCC3)c(F)c2)nn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: CC#N
Product: O=C(NCc1cn(-c2ccc(N3CCSCC3)c(F)c2)nn1)c1cnccn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of pyrazine-2-carboxylic acid (127 mg, 1.02 mmol) and DCC (211 mg, 1.02 mmol) in acetonitrile (5 mL) was added to a stirring solution of C-[1-(3-fluoro-4-thiomorpholin-4-yl-phenyl)-1H-[1,2,3]triazol-4-yl]-methylamine (200 mg, 0.68 mmol), obtained in Example 19, in dry acetonitrile (10 mL) and allowed to stir at room temperature for 6 h. The reaction mixture was then poured into ice-cooled water and extracted with ethyl acetate (20 mL×2). The organic portion was washed with water followed by brine and dried over sodium sulfate. Upon concentration and purification by silica gel column chromatography (acetone/chloroform, 15:85) the title compound was obtained (245 mg, 90%). Mp. 216-218° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]3[C:20](=[O:26])[N:21]([CH:23]([CH3:25])[CH3:24])[CH2:22][C:9]=23)=[CH:4][CH:3]=1.I[CH3:28]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]3[C:20](=[O:26])[N:21]([CH:23]([CH3:24])[CH3:25])[CH:22]([CH3:28])[C:9]=23)=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(C)N1Cc2c(nn(-c3ccccc3Cl)c2-c2ccc(Cl)cc2)C1=O
Solvent: C1CCOC1
Product: CC(C)N1C(=O)c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2C1C
Reaction time: 0.17 h
Yield: 16 %

Procedure:
To a solution of 3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one 3A-1 (19 mg, 0.05 mmol) in THF (0.5 ml) at −78° C. was added LiHMDSi (55 μl, 0.055 mmol). A deep blue-black solution was formed. The reaction mixture was stirred for 0.17 hour and then iodomethane (4.4 μl, 0.07 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 0.25 h (until a yellow color formed) and at room temperature for 2 hours, quenched with sat'd aq NH4Cl, and extracted with EtOAc. The organic solution was washed with sat'd aq NaCl, dried, and concentrated in vacuo. The residue was purified on 1 mm chromatotron plates using a 1:1 EtOAc/hexane solution to give 6A-1 as a white solid (3.2 mg, 14%); +ES MS (M+1) 400.3; 1H NMR (CDCl3): δ 7.4–7.3 (m, 4H), 7.28–7.24 (m, 2H), 7.1-7.06 (m, 2H), 4.84–4.77 (m, 1H), 4.37–4.27 (m, 1H), 1.48–1.4 (m, 9H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][N:10]1[C:15](=[O:16])[C:14]2[CH:17]=[CH:18][S:19][C:13]=2[C:12]([CH2:20][CH:21]([CH3:23])[CH3:22])=[N:11]1.O.Cl.[C:26]1([CH:36]=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>O1CCCC1>[OH:37][CH:36]([C:18]1[S:19][C:13]2[C:12]([CH2:20][CH:21]([CH3:23])[CH3:22])=[N:11][N:10]([CH3:9])[C:15](=[O:16])[C:14]=2[CH:17]=1)[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)Cc1nn(C)c(=O)c2ccsc12
Reactant: O=Cc1cccc2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cc1nn(C)c(=O)c2cc(C(O)c3cccc4ccccc34)sc12
Reaction time: 2 h

Procedure:
Lithium diisopropylamide (6.75 mmol) in tetrahydrofuran (8 ml) and 1-naphthaldehyde (0.7 ml) in tetrahydrofuran (5 ml) were added alternately to a solution of 5-methyl-7-(2-methylpropyl)thieno[2,3-d]pyridazin-4(5H)-one (1 g) prepared in b) above in tetrahydrofuran (20 ml) at 0° C. After 2 hours, water (10 ml) was added, the reaction mixture was acidified with dilute hydrochloric acid and then extracted with ethyl acetate. The organic phase was washed once with dilute hydrochloric acid, twice with saturated sodium hydrogen carbonate solution and once with brine, before being dried and evaporated. Purification by chromatography eluting with isohexane/ethyl acetate (1:1), and subsequent HPLC eluting with the same gave the title compound (0.4 g).