Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1(=[O:8])(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:19][C:20]1[CH:47]=[CH:46][C:23]([CH2:24][N:25]2[C:30](=[O:31])[C:29]3[C:32]([O:41][CH3:42])=[C:33]4[C:38](=[O:39])[N:37]([CH3:40])[CH2:36][CH2:35][N:34]4[C:28]=3[C:27]([CH:43](Cl)[CH3:44])=[N:26]2)=[CH:22][CH:21]=1>CN(C=O)C.C1COCC1>[F:19][C:20]1[CH:47]=[CH:46][C:23]([CH2:24][N:25]2[C:30](=[O:31])[C:29]3[C:32]([O:41][CH3:42])=[C:33]4[C:38](=[O:39])[N:37]([CH3:40])[CH2:36][CH2:35][N:34]4[C:28]=3[C:27]([CH:43]([N:2]3[CH2:3][CH2:4][CH2:5][CH2:6][S:1]3(=[O:8])=[O:7])[CH3:44])=[N:26]2)=[CH:22][CH:21]=1
Reactant: COc1c2n(c3c(C(C)Cl)nn(Cc4ccc(F)cc4)c(=O)c13)CCN(C)C2=O
Reactant: O=S1(=O)CCCCN1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1c2n(c3c(C(C)N4CCCCS4(=O)=O)nn(Cc4ccc(F)cc4)c(=O)c13)CCN(C)C2=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a cold (0° C.) solution of 1,2-thiazinane 1,1-dioxide (32 mg, 0.24 mmol) in anhydrous DMF (2 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (0.18 mL, 1M) was added. After stirred at room temperature for 20 minutes, solid 2-(4-fluorobenzyl)-10-methoxy-4-(1-chloroethyl)-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (50 mg. 0.12 mmol) was added and the reaction mixture was stirred at room temperature overnight. The product mixture was concentrated under vacuum. The residue was partitioned between dichloromethane and dilute hydrochloric acid. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to afford the title compound. ES MS M+1=518
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+]([O-])=O)[CH:6]=1.[SH:25][CH2:26][P:27](=[O:32])([O:30][CH3:31])[O:28][CH3:29]>>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=2[Cl:1])=[CH:6][C:7]=1[S:25][CH2:26][P:27](=[O:32])([O:30][CH3:31])[O:28][CH3:29])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Reactant: COP(=O)(CS)OC
Product: COP(=O)(CSc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])OC

Procedure:
In like manner, 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene and dimethyl sulfhydrylmethylphosphonate is reacted together to yield dimethyl 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylthiomethylphosphonate.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH3:27].[CH3:28][C:29]1([CH3:41])[CH2:33][C:32]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:31]=2[O:30]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:28][C:29]1([CH3:41])[CH2:33][C:32]2[CH:34]=[C:35]([C:2]3[C:7](=[O:8])[N:6]([CH2:9][C:10]4[CH:15]=[CH:14][C:13]([C:16]5[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=5)=[CH:12][CH:11]=4)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=3[CH3:27])[CH:36]=[CH:37][C:31]=2[O:30]1
Reactant: CCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC1(C)Cc2cc(B(O)O)ccc2O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(-c2ccc3c(c2)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 88.8 %

Procedure:
To a solution of 4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (1.0 g) and 2,2-dimethyl-2,3-dihydro-1-benzofuran-5-ylboronic acid (0.68 g) in 1,4-dioxane (20 mL) were added 2 M aqueous cesium carbonate solution (4 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1.03 g, 89%) as a colorless solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[Br-].[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:11])=[O:10]>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:9]([OH:11])=[O:10]
Reactant: O=C(O)CCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccs1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCC=Cc1cccs1
Yield: 46 %

Procedure:
This compound was synthesized from 2-thiophenecarboxaldehyde (2.24 g, 20 mmol) and 9-carboxynonyltriphenylphosphonium bromide (10.27 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization (hexanes-ethyl acetate) afforded the product (2.45 g, 46%) as white crystals (mp 61-62° C.); IR: 3450-2500, 1715 cm-1 ; 1H-NMR: 1.31 (m, 8 H), 1.45 (m, 2 H), 1.65 (m, 2 H), 2.34 (t, 2 H), 2.38 (t, 2 H), 5.55 (m, 1 H), 6.50 (d, 1 H), 6.95 (m, 2 H), 7.23 (d, 2 H), 10.05 (bs, 1 H). Anal. Calcd. for C15H22O2S: C, 67.63, H, 8.32%; Found: C, 67.60, H, 8.34%. Z:E=19:81.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]2[C:16](=O)[C:15]3[C:10](=[CH:11][C:12]([C:18]([O:20]C)=[O:19])=[CH:13][CH:14]=3)[O:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[Cl:23][C:24]1[CH:31]=[C:30]([NH:32][NH2:33])[CH:29]=[CH:28][C:25]=1[C:26]#[N:27].O1CCCC1.CN(C)C=O>CO>[Cl:23][C:24]1[CH:31]=[C:30]([N:32]2[CH:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]3[CH2:8][O:9][C:10]4[CH:11]=[C:12]([C:18]([OH:20])=[O:19])[CH:13]=[CH:14][C:15]=4[C:16]3=[N:33]2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: COC(=O)c1ccc2c(c1)OCC(=CC1CCCC1)C2=O
Reactant: N#Cc1ccc(NN)cc1Cl
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4OCC3C2C2CCCC2)cc1Cl

Procedure:
The title compound was prepared from methyl 3-(cyclopentylmethylene)-4-oxochroman-7-carboxylate, Preparation 31 (573 mg, 2.0 mmol) and 2-chloro-4-hydrazinylbenzonitrile hydrochloride; Preparation 1 (612 mg, 3.0 mmol) according to Method B and Method C. The crude precipitate was formed from dimethylformamide and methanol to give 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid (yellow solid, 237 mg, 0.563 mmol, 28% yield). The title compound was largely present as (±)-(3RS,3aSR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.20 (s, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.58 (dd, J=8.2, 1.6 Hz, 1H), 7.47 (d, J=1.2 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.20 (dd, J=8.8, 2.1 Hz, 1H), 4.95 (dd, J=9.4, 7.0 Hz, 1H), 4.78 (dd, J=10.2, 5.9 Hz, 1H), 4.31 (dd, J=13.3, 10.5 Hz, 1H), 4.00 (ddd, J=13.2, 9.7, 5.7 Hz, 1H), 2.03-2.16 (m, 1H), 1.13-1.68 (m, 8H). ES-MS m/z 422 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]#[N:18])=[N:9]2)=[CH:5][CH:4]=1.C[O-].[Na+].[Cl-].[NH4+:25].C(O)(=O)C>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17](=[NH:25])[NH2:18])=[N:9]2)=[CH:19][CH:20]=1
Reactant: [NH4+]
Reactant: COc1ccc(Cn2nc(C#N)c3ccccc32)cc1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(Cn2nc(C(=N)N)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
9.25 g of 1-(4-methoxybenzyl)-1H-indazole-3-carbonitrile (1-1-1, 35.1 mmol, 1 eq.) were suspended in 128 ml of dry methanol under a nitrogen atmosphere. 0.949 g (17.6 mmol, 0.5 eq.) of sodium methanolate were added. The reaction mixture was stirred for 18 hours at room temperature. To the resulting mixture were added 2.82 g (52.7 mmol, 1.5 eq.) of ammonium chloride and 1.0 ml (17.6 mmol, 0.5 eq.) of 100% acetic acid and stirred for 5 hours at 50° C. After cooling down at room temperature the mixture was concentrated in vacuo. The residue was partitioned between aq. half saturated sodium hydrogen carbonate solution and dichloromethane/isopropanol 4:1. The aqueous layer was extracted three times with dichloromethane/isopropanol 4:1. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography to yield 6.45 g (23 mmol, 65.5%) of the analytically pure target compound.
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:26][C@H:25]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[C@H:24]4[C@@H:15]([CH2:16][CH:17]=[C:18]5[C@@H:23]4[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.Cl.C(=O)(O)[O-:37].[Na+]>CC(C)=O>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C@H:25]2[CH2:26][C@@:4]3([CH3:5])[C@@H:6]([CH2:7][CH2:8][C:3]3=[O:2])[C@H:15]3[C@H:24]2[C@@H:23]2[C:18]([CH2:17][CH2:16]3)=[CH:19][C:20](=[O:37])[CH2:21][CH2:22]2)=[CH:28][CH:29]=1
Reactant: COc1ccc([C@H]2C[C@@]3(C)[C@@H](CC45OCCOC43OCCO5)[C@@H]3CC=C4CCCC[C@@H]4[C@H]32)cc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc([C@H]2C[C@]3(C)C(=O)CC[C@H]3[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]32)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
17,17-bis-(ethylenedioxy)-11β-(4-methoxyphenyl)-5-estrene is dissolved in 50 ml of acetone and mixed under protective gas with 2.5 ml of 4 n aqueous hydrochloric acid. After three hours of stirring at room temperature and one hour at 40° C., the reaction mixture is poured on cold saturated sodium bicarbonate solution and the aqueous phase is extracted several times with methylene chloride. The combined organic phases are dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel-with a mixture of ethyl acetate/hexane. 683 mg of 11β-(4-methoxyphenyl)-4-estrene-3,17-dione is obtained as white foam.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N(CC)CC)C.Br[C:18]1[S:19][C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=1.O1CCCC1>>[CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:18]2[S:19][C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(S)c1
Reactant: FC(F)(F)c1nnc(Br)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(Sc2nnc(C(F)(F)F)s2)c1
Yield: 94.9 %

Procedure:
8.5 g (0.061 mole) of 3,5-dimethylthiophenol, 6.2 g (0.061 mole) of triethylamine and 14.3 g (0.061 mole) of 2 -bromo-5-trifluoromethyl-1,3,4-thiadiazole in 150 mole of tetrahydrofuran were stirred for 30 minutes under reflux. The salt (by-product) which had precipitated was filtered off and washed thoroughly with tetrahydrofuran. After distilling off the solvent in vacuo, a colorless oil passed over on distillation. 16.8 g (95% of theory) of 2-(3',5'-dimethylphenylthio)-5-trifluoromethyl-1,3,4-thiadiazole of boiling point 107°-108° C/10.2 mm Hg were obtained. 22.8 g (0.201 mole) of hydrogen peroxide (30% strength) in 100 ml of glacial acetic acid were added thereto and the reaction mixture was stirred for 15 hours at 60° C, and poured onto ice water. The precipitate was filtered off and recrystallized from ethanol. 12.7 g (54% of theory) of 2-(3',5'-dimethylphenylsulfonyl)-5-trifluoromethyl-1,3,4-thiadiazole of melting point 110° C were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[N:10][CH:11]=[C:12]([C:15]#[N:16])[C:13]=3[S:14][C:4]=2[CH:3]=1.[CH3:27][S:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)(=[O:30])=[O:29].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(CC)CC>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][NH:17][C:9]2[C:8]3[C:5]4[CH:6]=[CH:7][C:2]([C:34]5[CH:35]=[CH:36][C:31]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:32][CH:33]=5)=[CH:3][C:4]=4[S:14][C:13]=3[C:12]([C:15]#[N:16])=[CH:11][N:10]=2)=[CH:20][CH:21]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COc1ccc(CNc2ncc(C#N)c3sc4cc(Br)ccc4c23)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COc1ccc(CNc2ncc(C#N)c3sc4cc(-c5ccc(S(C)(=O)=O)cc5)ccc4c23)cc1
Temperature: 150 °C

Procedure:
To a suspension of 7-bromo-1-[(4-methoxybenzyl)amino][1]benzothieno[3,2-c]pyridine-4-carbonitrile (Example 12, Step 9) and [4-(methylsulfonyl)phenyl]boronic acid (1.5 equiv) in 1-PrOH/H2O (4.5/1) (0.11 M) was added Pd2(dba)3 (0.03 equiv), Ph3P (0.06 equiv) and Et2NH (1.2 equiv). The mixture was degassed and heated to 150° C. for 10 min in a microwave reactor. The mixture was diluted with H2O and filtered. The crude product was swished with hot EtOH to give the title compound.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:16][CH2:17][CH2:18][CH3:19])=[C:6](B(O)O)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[CH:20]([C:22]1[S:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:30](I)[C:24]=2[CH:23]=1)=[O:21].C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:20]([C:22]1[S:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:30]([C:6]3[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=3[O:16][CH2:17][CH2:18][CH3:19])[C:24]=2[CH:23]=1)=[O:21]
Reactant: CCCOc1c(B(O)O)cc(C(C)C)cc1C(C)C
Reactant: O=Cc1cc2c(I)cccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCOc1c(-c2cccc3sc(C=O)cc23)cc(C(C)C)cc1C(C)C

Procedure:
A mixture of 1.08 mmol of 3,5-di-iso-propyl-2-n-propoxy phenylboronic acid, 1.62 mmol of 2-formyl-4-iodo-benzo[b]thiophene and 62 mg (0.05 mmol) of Pd(PPh3)4, 1 mL of 2N aqueous sodium carbonate in 9 mL of toluene and 4 mL ethanol was heated to reflux. After complexion (TLC), water was added and the solution was extracted with ethyl acetate. The organic layer is dried over MgSO4 and after evaporation of the solvents, the crude oil was purified over a short silica plug (eluent: 10/90=ethyl acetate/hexane) to afford 2-formyl-4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thiophene.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]2[N:9]([CH:10]=1)[CH2:8][CH2:7][S:6]2(=[O:12])=[O:11]>C(#N)C.[O-2].[O-2].[Mn+4]>[S:6]1(=[O:12])(=[O:11])[CH2:7][CH2:8][N:9]2[CH:10]=[C:3]([CH:2]=[O:1])[N:4]=[C:5]12
Reactant: O=S1(=O)CCn2cc(CO)nc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC#N
Product: O=Cc1cn2c(n1)S(=O)(=O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-Dihydro-6-hydroxymethylimidazo[2,1-b]thiazole-1,1-dioxide (207 mg, 1.1 mmol) was dissolved in acetonitrile (minimum volume) and treated with manganese dioxide (621 mg, 3 wt. equivalents) and the mixture stirred vigorously at ambient temperature. After 1 h, more manganese dioxide (621 mg) was added and the mixture sitrred for a further 18 h. The mixture was filtered through Celite, the filter bed washed with acetonitrile, the filtrate and washings combined and evaporated to dryness under reduced pressure. The residue was triturated under dichloromethane and the resulting solid collected by filtration, washed with dichloromethane and dried in air (108 mg, 53%) (Found: M+ 186.0103. C6H6N2O3S requires M 186.0099); nmax (Nujol) 1691, 1320 and 1132 cm-1 ; dH [250 MHz; (CD3)2SO] 4.25 (2H, t, J 7 Hz), 4.68 (2H, t, J 7 Hz), 8.32 (1H, s), 9.81 (1H, s).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1>>[F:23][C:22]1[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(C(=O)c2cn(-c3cccc(-c4c(F)cccc4OC)c3)cn2)cc1

Procedure:
This compound is prepared by method C using compound 12g and 4-bromoanisole
Reaction SMILES: [C:1]1([O:7][C:8](=[O:20])[CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)=O.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26].CCCCCC>O1CCCC1>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([CH:9]([C:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])[C:8]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:20])[CH:11]=[C:12]([O:18][CH3:19])[CH:13]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1cc(CC(=O)Oc2ccccc2)cc(OC)c1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(OC)cc(C(C(=O)Oc2ccccc2)C(=O)Oc2ccccc2)c1
Temperature: -70 °C
Reaction time: 2.5 h

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (400 mL, 1M in tetrahydrofuran obtained commercially from Aldrich Chem. Co.) was added a solution of 3,5-dimethoxybenzeneacetic acid phenyl ester (53.1 g) in tetrahydrofuran (65 mL) dropwise over 20 min while cooling in a dry ice bath at −70° C. The resulting slurry was stirred at dry ice temperature for 45 min Phenyl chloroformate (26 mL) was added all at once followed by 50 mL of tetrahydrofuran. The resulting thick slurry was stirred for 2.5 h at 0° C. while cooling in an ice bath before quenching with diluted aqueous HCl (50 mL of conc. HCl diluted to 150 mL with water). The bulk of tetrahydrofuran was removed under vacuum and diethyl ether (550 mL) and water (80 mL) were added. The aqueous layer was separated and extracted with diethyl ether (50 mL). The combined ether layers were dried over magnesium sulfate and concentrated under vacuum to yield a crude solid which was stirred with hexane (250 mL) for 24 h. The solid was then collected by filtration, washed with hexane (100 mL), and vacuum dried to yield 62 g of the title compound. 1H NMR (CDCl3) δ 7.37 (t, 2H), 7.26 (q, 1H), 7.13 (d, 2H), 6.73 (s, 2H), 6.45 (s, 1H), 5.02 (s, 1H), 3.82 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[C:20]([O:21][CH3:22])=[CH:19][C:5]([NH:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]3[N:12]=[C:13]([S:15][CH3:16])[S:14][C:10]=3[CH:9]=2)=[C:4]([N+:23]([O-])=O)[CH:3]=1.CC(O)=O.CO>CCO.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:23])[C:5]([NH:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]3[N:12]=[C:13]([S:15][CH3:16])[S:14][C:10]=3[CH:9]=2)=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1cc(NCc2ccc3nc(SC)sc3c2)c([N+](=O)[O-])cc1Br
Agent: [Zn]
Solvent: CCO
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(NCc2ccc3nc(SC)sc3c2)c(N)cc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.5 %

Procedure:
To a stirred suspension of 4-bromo-5-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline (212 mg, 0.5 mmol) from Step 1 of this Example in EtOH (4 mL) and HOAc (2 mL) at 0° C. under argon was added zinc powder (160 mg, 2.4 mmol) in one portion. After 1.5 h at 0° C., MeOH (5 mL), additional HOAc (2 mL), and zinc powder (160 mg, 2.4 mmol) were added. The mixture was allowed to warm to rt and stirred for 18 h. The mixture was filtered and the filtrate was cooled to 0° C. The pH of the filtrate was adjusted to pH˜9 by addition of solid Na2CO3. The mixture was then partitioned between EtOAc (150 mL) and water (100 mL). The EtOAc layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% hexanes to 100% EtOAc to afford 4-bromo-5-methoxy-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine (120 mg, 61%). LCMS (ESI) m/z 410 and 412 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:6]([O:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1)([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=1)[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].CN(C=O)C.[H-].[Na+].[CH3:43][O:44][C:45]1[CH:50]=[C:49]([CH3:51])[N:48]=[C:47](S(C)(=O)=O)[N:46]=1>O>[CH3:43][O:44][C:45]1[CH:50]=[C:49]([CH3:51])[N:48]=[C:47]([O:1][CH:2]([C:6]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=2)[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)[C:3]([OH:5])=[O:4])[N:46]=1
Reactant: CCc1ccc(C(OCCc2ccc(OC)c(OC)c2)(c2ccc(CC)cc2)C(O)C(=O)O)cc1
Reactant: COc1cc(C)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(C(OCCc2ccc(OC)c(OC)c2)(c2ccc(CC)cc2)C(Oc2nc(C)cc(OC)n2)C(=O)O)cc1
Reaction time: 0.25 h
Yield: 23.7 %

Procedure:
1.8 g (3.8 mmol) of 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-ethylphenyl)propionic acid were introduced into 20 ml of DMF, and 554 mg of NaH (50% suspension) were added. After the mixture had stirred for 15 minutes, 855 mg (4.2 mmol) of 4-methoxy-6-methyl-2-methylsulfonylpyrimidine were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the mixture, which was then extracted with ether. The aqueous phase was acidified with 1 N aqueous HCl, extracted with ether and dried over magnesium sulfate. The solvent was distilled off and 540 mg (23%) of colorless powder were isolated after recrystallization from ether/n-hexane.
Reaction SMILES: C([C:3]([N:17]1CCOCC1)([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[CH2:4][CH:5](C)[C:6](OC)=[O:7])#N.C(C(N1CCOCC1)(C1CCNCC1)CCC(OCC)=O)#[N:24]>>[N:14]1[CH:15]=[CH:16][C:11]([C:3]2[CH2:4][CH2:5][C:6](=[O:7])[NH:24][N:17]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)C(C)CC(C#N)(c1ccncc1)N1CCOCC1
Reactant: CCOC(=O)CCC(C#N)(C1CCNCC1)N1CCOCC1
Product: O=C1CCC(c2ccncc2)=NN1

Procedure:
Following the procedure described in Example 1 but using in place of methyl 4-cyano-2-methyl-4-(4-morpholinyl)-4-(4-pyridinyl)butanoate a molar equivalent quantity of ethyl 4-cyano-4-(4-morpholinyl)-4-(4-piperidinyl)butanoate [McEvoy et al., J. Org. Chem. 44, 4597 (4600)(1979)], it is contemplated that there can be obtained 4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone.
Reaction SMILES: [C:1]([C:4]1[C@@H:5]([C:29]2[CH:30]=[CH:31][CH:32]=[C:33]3[C:38]=2[O:37][C:36]([CH3:39])=[CH:35][C:34]3=[O:40])[C:6]([C:12]([O:14][C@H]2CC(=O)N(CC3C=CC=CC=3)C2=O)=[O:13])=[C:7]([CH3:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].C1CCN2C(=NCCC2)CC1.O.Cl>C(OCC)(=O)C>[C:1]([C:4]1[C@@H:5]([C:29]2[CH:30]=[CH:31][CH:32]=[C:33]3[C:38]=2[O:37][C:36]([CH3:39])=[CH:35][C:34]3=[O:40])[C:6]([C:12]([OH:14])=[O:13])=[C:7]([CH3:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)NC(C)=C(C(=O)O[C@H]2CC(=O)N(Cc3ccccc3)C2=O)[C@@H]1c1cccc2c(=O)cc(C)oc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)O)[C@@H]1c1cccc2c(=O)cc(C)oc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
300 mg (0.555 mmol) of (3S)-1-benzyl-2,5-dioxopyrrolidin-3-yl (4R)-5-acetyl-2,6-dimethyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-1,4-dihydropyridine-3-carboxylate are dissolved in 10 ml of ethyl acetate, and 295.7 mg (1.942 mmol) of DBU are added. The mixture is stirred at room temperature for 8 h. Water is then added, and the pH is adjusted to pH 4-5 with 1 N hydrochloric acid. The aqueous phase is separated off and extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution. After drying over magnesium sulfate, the solvent is removed in vacuo. The product obtained in this way is reacted further without purification.