Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[C:3]=1[F:10].ClC(Cl)(Cl)C[O:14][C:15](=O)[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:27])[N:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15](=[O:14])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:24]([CH3:26])[CH3:25])=[O:27])=[CH:19][CH:18]=2)=[C:4]([F:9])[C:3]=1[F:10]
Reactant: Nc1ccc(Br)c(F)c1F
Reactant: CN(C)C(=O)c1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(Br)c(F)c2F)cc1
Temperature: 105 °C
Yield: 36.6 %

Procedure:
To a 50 mL round bottom flask, 4-bromo-2,3-difluoroaniline (0.5 g, 0.0024 mol), 2,2,2-trichloroethyl(4-(dimethylcarbamoyl)phenyl)carbamate (0.978 g, 0.00288 mol; from Preparation 5), TEA (1.01 mL, 0.0072 mol) and toluene (20 mL) were added. The reaction mixture was maintained at 105° C. for 12 h. The cooled reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the crude product. The crude was purified by column chromatography using 3% MeOH in chloroform to get the title compound [0.35 g, 36%]. 1H NMR (300 MHz, DMSO-d6): δ 9.30 (s, 1H), 8.96 (s, 1H), 8.0-7.92 (m, 1H), 7.52-7.42 (m, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.20-7.06 (m, 1H), 2.96 (s, 6H); LC-MS (ESI): Calculated mass: 397.0; Observed mass: 400.0 (RT: 1.49 min).
Reaction SMILES: [C:1](OC)(=O)CC[C@H]([C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)C(CCCC2)CC3)CC1)C.C(Cl)(=O)C.[CH3:32][C@@H:33]([C@@H:39]1[C@@:43]2([CH3:60])[C@@H:44]([OH:59])[CH2:45][C@@H:46]3[C@@:51]4([CH3:57])[CH2:52][CH2:53][C@@H:54]([OH:56])[CH2:55][C@H:50]4[CH2:49][C@@H:48]([OH:58])[C@H:47]3[C@@H:42]2[CH2:41][CH2:40]1)[CH2:34][CH2:35][C:36]([OH:38])=[O:37]>CO>[CH3:32][C@@H:33]([C@@H:39]1[C@@:43]2([CH3:60])[C@@H:44]([OH:59])[CH2:45][C@@H:46]3[C@@:51]4([CH3:57])[CH2:52][CH2:53][C@@H:54]([OH:56])[CH2:55][C@H:50]4[CH2:49][C@@H:48]([OH:58])[C@H:47]3[C@@H:42]2[CH2:41][CH2:40]1)[CH2:34][CH2:35][C:36]([O:38][CH3:1])=[O:37]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CO
Solvent: CC(=O)Cl
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
Preparation of the starting compounds of the formula III using the example of methyl cholanate (Fieset et al., J. Am. Chem. Soc. 74, 1952, 3309) ##STR6## 450 ml of acetyl chloride are slowly added dropwise to 4.5 l of methanol, while cooling with ice, such that the temperature does not exceed 10° to 15° C. After the addition, the mixture is subsequently stirred at about 10° C. for a further 15 minutes. 600 g (1.47 mol) of cholic acid are then introduced at about 5° C. The ice-bath is removed, and after a further hour, while stirring, the reaction is ended. The reaction mixture is slowly added to 12 l of water. The mixture is stirred for a further 2 hours and then filtered with suction, and the residue is rinsed with 3 l of water. The crystalline substance is dried in vacuo at 50° C. 610 g (98%) of methyl cholate (melting point 154° C.) are obtained.
Reaction SMILES: [OH-].[Na+].[OH:3][C@H:4]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C@@H:5]([NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH3:6].C(O)C.Cl>O1CCCC1>[OH:3][C@H:4]([C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=1)[C@@H:5]([NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)[CH3:6]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCN[C@@H](C)[C@H](O)c3ccc(O)cc3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@H](NCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1)[C@H](O)c1ccc(O)cc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (0.43 mL) was added to a solution of ethyl 4′-(2-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethylamino]ethoxy)biphenyl-4-carboxylate (0.15 g), ethanol (20 mL) and tetrahydrofuran (5 mL). The mixture was stirred at 60° C. for 16 hrs, and heated under reflux at 100° C. for 7.5 hrs. A 2 mol/L aqueous solution of sodium hydroxide (0.17 mL) was added, and heated under reflux for 16 hrs. After being cooled to room temperature, 2 mol/L hydrochloric acid (0.60 mL) was added, and the precipitate was collected by filtration to afford the title compound as a pale yellow amorphous (0.13 g). The structure and physical data were shown in table 3.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.Cl.[CH2:11]([O:13][C:14](=[O:24])[C@H:15]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH2:16])[CH3:12]>>[CH2:11]([O:13][C:14](=[O:24])[C@@H:15]([NH:16][C:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9])[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:12]
Reactant: O=C(O)c1ccc(Br)s1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: Cl
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(Br)s1)C(=O)OCC
Yield: 72 %

Procedure:
Target compounds AAG154353, AAG154360 and AAG154484 were synthesized as shown in Scheme 1. Commercially available pent-4-ynoic acid 1a or hex-5-ynoic acid 1b or hept-6-ynoic acid 1c (Scheme 1) was converted to the acid chlorides 2a-c and immediately reacted with diazomethane followed by 48% HBr to give the desired α-bromomethylketones 4a-c. Condensation of 2,4-diamino-6-hydroxypyrimidine with 4a-c at room temperature for 3 days afforded the 6-substituted pyrrolo[2,3-d]pyrimidines 5a-c (51-74% yield). Compounds 6a-c were obtained by a Sonogashira coupling of 5a-c with (S)-2-[(5-bromo-thiophene-2-carbonyl)-amino]-pentanedioic acid diethyl ester 9. Hydrogenation and saponification of 6a-c afforded AAG154353, AAG154360 and AAG154484, respectively. Compound 9 (Scheme 1) was synthesized by coupling the commercially available 5-bromo-2-thiophene-carboxylic acid 8 and L-glutamate diethyl ester hydrochloride in 72% yield.
Reaction SMILES: S(Cl)(Cl)(=O)=O.[C:6]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:10]=1[N:11]([CH3:14])[CH:12]=O)(=[O:8])[CH3:7].[OH2:20]>ClCCl>[C:6]([O:8][C:7]1[C:6](=[O:8])[C:9]2[C:10](=[C:15]([F:19])[CH:16]=[CH:17][CH:18]=2)[N:11]([CH3:14])[CH:12]=1)(=[O:20])[C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:10]=1
Reactant: O
Reactant: CC(=O)c1cccc(F)c1N(C)C=O
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: Cn1cc(OC(=O)c2ccccc2)c(=O)c2cccc(F)c21
Reaction time: 3.25 h

Procedure:
A solution of sulphuryl chloride (11.9 ml) in dichloromethane (200 ml) was added dropwise to the solution of 2'-acetyl-6'-fluoro-N-methylformanilide at 0° under a nitrogen atmosphere. The reaction mixture was stirred at 0° for 3.25 hours. Water (100 ml) was added dropwise and the mixture stirred for 30 minutes. The dichloromethane layer was separated, washed with water (160 ml) and dried over magnesium sulphate before removing the solvent under reduced pressure at ambient temperature. The residue was added to a mixture of benzoic acid (22.6 g), potassium carbonate (42.5 g), 25 molecular sieves (4A°, 50 g) and dry dimethylformamide (200 ml) and the resultant mixture stirred at ambient temperature for 3 hours and then at 60° for 2 hours. Further dimethylformamide (600 ml) and potassium carbonate (17 g) were added and the mixture was heated at 60° overnight. The mixture was cooled, filtered and the solvent removed from the filtrate under reduced pressure at 60°. The residue was triturated with water (400 ml) and then with diethyl ether (400 ml). The resultant solid was crystallised from industrial methylated spirit (200 ml) to give the novel compound 8-fluoro-1-methyl-4-oxo-1,4-dihydroquinol-3-yl benzoate, m.p. 179°-181°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=2)[N:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cn2nc(Cl)ccc2n1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.6 %

Procedure:
To a 250-mL, round-bottomed flask was added 6-chloroimidazo[1,2-b]pyridazin-2-amine from Step 3 (0.67 g, 4.0 mmol), CH2Cl2 (60 mL), acetic anhydride (0.45 mL, 4.8 mmol), pyridine (0.49 mL, 6.0 mmol), and 4-(dimethylamino)pyridine (4.9 mg, 0.040 mmol). The mixture was stirred at 25° C. for 24 h. The reaction mixture was concentrated and then diluted with aq. NaHCO3 and extracted with 25% iPrOH/CHCl3 (3×100 mL). The combined extracts were washed with brine (100 mL), dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (0 to 4% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as a yellow solid (0.62 g, 74%). MS (ESI positive ion) m/z: 211 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.10 (s, 3H), 7.33 (d, J=9.4 Hz, 1H), 8.06 (d, J=9.4 Hz, 1H), 8.26 (s, 1H), 10.95 (s, 1H).
Reaction SMILES: N[C:2]1([O:8]O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:10](=[O:14])[CH2:11][CH2:12][CH3:13].C(O)(=O)C.N>CO>[C:2]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:10](=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: NC1(OO)CCCCC1
Agent: N
Solvent: CC(=O)O
Solvent: CO
Solvent: CCCC=O
Product: O=C1CCCCC1
Reaction time: 8 h

Procedure:
1-Aminocyclohexyl hydroperoxide (13.1 g.), butyraldehyde (7.2 g.), methanol (25 cc.) and ammonia acetate (1.0 g.) were mixed and stored at 0°C overnight. Working up as in Example 39 gave cyclohexanone and butyraldehyde, and a product (8.4 g.), b.p. 89°/0.3 mm. (peroxide equivalent, 204; pechloric acid equivalent, 206; which was identified as ##SPC37##
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[I-].[K+].O.[PH2](=O)[O-].[Na+].[PH2](=O)O>C(O)(=O)C>[Br:1][C:2]1[C:15]2[C:6](=[C:7]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:8]3[C:13]([C:14]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: OC1(c2ccccc2)c2ccccc2C(O)(c2ccccc2)c2c(Br)cccc21
Agent: O=[PH2]O
Agent: O=[PH2][O-]
Agent: [I-]
Solvent: O
Solvent: CC(=O)O
Product: Brc1cccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c12
Temperature: 120 °C
Reaction time: 18 h
Yield: 3.8 %

Procedure:
14.4 g (32.4 mmol) of 1-bromo-9,10-diphenyl-9,10-dihydroanthracene-9,10-diol, 9.68 g (58.3 mmol) of potassium iodide, 18.6 g (175 mmol) of sodium phosphinate monohydrate, and 100 mL of glacial acetic acid were put into a 500 mL three-neck flask, and the mixture was refluxed for 5 hours at 120° C. After the reaction was completed, 40 mL of a 50% phosphinic acid was added to the mixture, and stirring was kept for 18 hours at room temperature. After the reaction was completed, the reaction solution was washed with water, and the aqueous layer was extracted with ethyl acetate. The extracted part was combined with the organic layer, and then dried with magnesium sulfate. After drying, a mixture was subjected to suction filtration, and the filtrate was concentrated. The obtained residue was dissolved in toluene, and filtered through Florisil, celite, and then alumina, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent; toluene:hexane=1:5). The resulting solid was washed with ethanol, providing 0.50 g of 1-bromo-9,10-diphenylanthracene as light yellow powder in 3.8% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:10])[CH:7]=[N:8][CH:9]=1)=[O:4].[CH2:11]=[O:12].ClCCl>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:10])[C:7]([CH2:11][OH:12])=[N:8][CH:9]=1)=[O:4]
Reactant: C=O
Reactant: COC(=O)c1cncn1C
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cnc(CO)n1C
Temperature: 135 °C
Yield: 56 %

Procedure:
A suspension of 3-methyl-3H-imidazole-4-carboxylic acid methyl ester (4.0 g, 29 mmol) and paraformaldehyde (18 g, corresponding to 570 mmol) in methanol (40 ml) was heated in a sealed vessel to 135° C. for 60 h. After cooling to ambient temperature, the solution was evaporated to dryness. Flash chromatography (silica, eluent dichloromethane containing 5% methanol) afforded the title compound as white crystals (56% yield). MS: m/e=171(M+H+), mp 145-147° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N:12]2[CH:16]=[N:15][N:14]=[CH:13]2)=[CH:4][C:3]=1/[CH:17]=[CH:18]/[C:19]([O:21]CC)=O.Cl>>[F:9][C:8]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([N:12]2[CH:16]=[N:15][N:14]=[CH:13]2)[CH:4]=[C:3]2[C:2]=1[NH:1][C:19](=[O:21])[CH:18]=[CH:17]2
Reactant: CCOC(=O)/C=C/c1cc(-n2cnnc2)cc(C(F)(F)F)c1N
Agent: Cl
Product: O=c1ccc2cc(-n3cnnc3)cc(C(F)(F)F)c2[nH]1

Procedure:
The following compound, m.p.>320°, was prepared similarly to the previous Example, starting from trans-ethyl 3-(2-amino-3-trifluoromethyl-5-[1,2,4-triazol-4-yl]phenyl)prop-2-enoate and 5M HCl. ##STR62##
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH2:22][CH2:23][C:24](=[O:27])[NH:25][N:26]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C(O)(=O)C.[C:32]1(=O)[CH2:35][CH2:34][CH2:33]1.C([BH3-])#N.[Na+]>CN(C=O)C.CO>[CH:32]1([N:8]2[CH2:9][CH2:10][CH:11]([O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4[CH2:22][CH2:23][C:24](=[O:27])[NH:25][N:26]=4)=[CH:19][CH:20]=3)[CH2:12][CH2:13]2)[CH2:35][CH2:34][CH2:33]1
Reactant: O=C1CCC(c2ccc(OC3CCNCC3)cc2)=NN1
Reactant: O=C1CCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1CCC(c2ccc(OC3CCN(C4CCC4)CC3)cc2)=NN1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To 6-[4-(piperidin-4-yloxy)-phenyl]-4,5-dihydro-2H-pyridazin-3-one trifluoroacetate (6.50 g, 23.8 mmol) in DMF (10 mL), methanol (50 mL), and acetic acid (2 mL) was added cyclobutanone (5.33 mL, 71.3 mmol) and sodium cyanoborohydride (7.47 g, 119 mmol) in portions. After stirring at 60° C. for 4 h, the reaction was concentrated, diluted with dichloromethane, washed with water/brine, dried over sodium sulfate, and concentrated. The product was purified using a Single Step column (9:1 dichloromethane:methanol) and recrystallized from chloroform/ether to obtain 2.2 g (40%); Mp=196-198° C.; MS m/z 328 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.S(=O)=O.COC1C=CC(C2C=CC(S(O)=O)=CC=2)=CC=1.[Li].[S:42](Cl)([Cl:45])(=[O:44])=[O:43]>O1CCCC1>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([S:42]([Cl:45])(=[O:44])=[O:43])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2ccc(Br)cc2)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: COc1ccc(-c2ccc(S(=O)O)cc2)cc1
Agent: O=S=O
Agent: [Li]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.7 %

Procedure:
Part B: 5.2 grams (20 mmol) of 4-(4′-bromophenyl)-anisole was dissolved in 100 mL of anhydrous tetrahydrofuran and placed under nitrogen to cool to −78 C. To this flask was added 8.0 mL of 2.5 molar butyl lithium over 10 minutes. In an adjacent flask was added 100 mL of anhydrous tetrahydrofuran which was cooled to −60 C and a stream of sulfur dioxide was added through a dispersion tube while the system is under nitrogen atmosphere. After the addition of approximately 10 mL of liquid sulfur dioxide the dispersion tube was removed and the cold sulfur dioxide solution was transferred by a cannula to the stirred aryl lithium solution over five minutes. After one hour at −70 C the contents were warmed to room temperature and the solution was concentrated to dryness to yield a crude lithium sulfinate. The crude lithium 4-(4′-methoxyphenyl)phenylsulfinic acid was slurried in 100 mL of dry hexanes under nitrogen atmosphere and cooled to 0 C. To this cooled suspension was added 2.45 grams (18.1 mmol) of sulfuryl chloride and the suspension was allowed to warm to room temperature. The contents were concentrated by rotory evaporation to yield 5.1 grams of crude 4-(4′-methoxyphenyl)phenyl-sulfonyl chloride which was purified by recrystallization from chloroform.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:18][C:19](I)=[CH:20][C:21]=3[O:22][CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[Br-].[S:26]1[CH:30]=[CH:29][N:28]=[C:27]1[Zn+]>CCOC(C)=O.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]>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:18][C:19]([C:27]4[S:26][CH:30]=[CH:29][N:28]=4)=[CH:20][C:21]=3[O:22][CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(I)cc3OC)c(C)nc12
Reactant: [Zn+]c1nccs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4nccs4)cc3OC)c(C)nc12
Temperature: 65 °C
Yield: 70.7 %

Procedure:
To a flask containing 8-(1-ethyl-propyl)-3-(5-iodo-3-methoxy-thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.45 g, 0.99 mmol) and PdCl2(dppf) (0.057 g, 0.078 mmol) is added a 0.5 M solution of 2-thiazolylzinc bromide (9.9 mL, 4.94 mmol). The solution is heated at 65° C. overnight, diluted with EtOAc (50 mL), washed with sat. NH4Cl (50 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15%-20% EtOAc/hexane gradient) furnish the title compound (0.29 g, 0.70 mmol, 71%). 1H NMR (CDCl3) δ0.86 (t, J=7.5 Hz, 6H), 1.72-1.90 (m, 4H), 2.51 (s, 3H), 2.53 (s, 3H), 3.28-3.37 (m, 1H), 3.93 (s, 3H), 6.67 (s, 1H), 7.28 (d, J=3.3 Hz, 1H), 7.41 (s, 1H), 7.80 (d, J=3.3 Hz, 1H). LC/MS (m/z): calcd. for C21H24N4OS2 (M+H)+: 413.6; found: 414.3.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15](O)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][OH:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccccc1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1ccccc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a solution of 2-benzylphenylacetic acid (5.5 g, 24 mmol, J. Am. Chem. Soc. 1955, 77, 5078) in THF (100 ml) a solution of lithium aluminiumhydride in THF (24 ml, 24 mmol, 1M) was added dropwise on an ice-bath. When addition was complete the mixture was stirred for 1 h at ambient temperature. Water (1 ml), 4N sodium hydroxide (2 ml) and water (4 ml) were added successively. The mixture was filtered and the filtrate was diluted with diethylether (250 ml). The phases were separated and the organic phase was washed with saturated ammonium chloride solution (3×100 ml) and dried (MgSO4). The solvent was evaporated in vacuo to give 4.8 g of crude 2-(2-benzylphenyl)ethanol as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9])=[O:2].[CH3:13]O>>[CH3:13][O:9][C:8](=[O:10])[C:7]1[CH:11]=[C:3]([CH:1]=[O:2])[CH:4]=[CH:5][C:6]=1[OH:12]
Reactant: CO
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Product: COC(=O)c1cc(C=O)ccc1O
Temperature: 25 °C
Yield: 79 %

Procedure:
Heat a mixture of 5-formyl-2-hydroxy-benzoic acid (5.0 g, 30.09 mmol) concentrated sulfuric acid (5 mL) in methanol (100 mL) at reflux for 24 h. Cool the mixture to room temperature and concentrate under reduced pressure. Purify the resulting residue by chromatography over silica gel, eluting with hexanes/ethyl acetate (80:20), to provide the title compound as a colorless oil (4.28 g, 79%). 1H NMR (CDCl3, 300 MHz) δ 3.88 (s, 3H), 4.52 (bs, 1H), 7.05 (d, J=8.56 Hz, 1H), 7.84 (d, J=8.56 Hz, 1H), 8.40 (s, 1H), 9.85 (s, 1H); TLC Rf=0.34 (3:1 Hexanes/Ethyl Acetate).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24].[H-].[Na+].O>C1COCC1>[N:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=3[N+:23]([O-:25])=[O:24])[CH:7]=[CH:6][CH:5]=2)=[N:9][CH:10]=1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1cccc(-c2ccncn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(Nc2cccc(-c3ccncn3)c2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.6 %

Procedure:
To a mixture of (37) (5.5 g, 30 mmol) and 4-chloro-3-nitro-benzonitril (5.1 g, 30 mmol) in THF (120 ml) was added sodium hydride (2.3 g, 50% suspension in mineral oil). After stirring at room temperature for 2 days, the mixture was poured into water and extracted with CH2Cl2. The extract was concentrated under reduced pressure and the residue was triturated with diethyl ether to yield crystalline (38) (9.2 g, 96%).
Reaction SMILES: [C:1]1([C:7]2[C:12](I)=[CH:11][CH:10]=[C:9]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([C:22]1([OH:30])[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1)#[CH:21].C(N(CC)CC)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.CN(C)C=O>[C:1]1([C:7]2[C:12]([C:21]#[C:20][C:22]3([OH:30])[CH:27]4[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]4)[CH2:23]3)=[CH:11][CH:10]=[C:9]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: Ic1ccc(N2CCOCC2)nc1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC1(C#Cc2ccc(N3CCOCC3)nc2-c2ccccc2)CN2CCC1CC2
Reaction time: 4 h
Yield: 55.7 %

Procedure:
A mixture of 500 mg of 2-phenyl-6-morpholino-3-iodopyridine, 230 mg of 3-ethynyl-3-quinuclidinol, 79 mg of tetrakis(triphenylphosphine)palladium(0), 1.3 mg of cuprous iodide, 0.57 ml of triethylamine and 1 ml of N,N-dimethylformamide was heated under stirring for 4 hours in an oil bath kept at 75° C. in a nitrogen atmosphere. The mixture was extracted by adding aqueous dilute ammonia and ethyl acetate thereto, and the organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to NH-silica gel column chromatography, and eluted with 50% ethyl acetate/hexane, ethyl acetate and then 2.5% methanol/ethyl acetate, and crystallized from ethyl acetate, to give 296 mg of the target compound.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[S:8][CH:7]=[N:6][C:5]=1[C:9]([O:11]C)=[O:10])[CH3:3].[OH-].[Na+]>CO>[CH3:3][CH:2]([C:4]1[S:8][CH:7]=[N:6][C:5]=1[C:9]([OH:11])=[O:10])[CH3:1]
Reactant: COC(=O)c1ncsc1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1scnc1C(=O)O
Temperature: 20 °C
Reaction time: 18 h
Yield: 96.8 %

Procedure:
To a solution of methyl 5-(1-methylethyl)-1,3-thiazole-4-carboxylate (1.9 g) in methanol (20 ml) was added 2M sodium hydroxide (20 ml) and the mixture stirred at 20° C. for 18 h. The solvent was removed in vacuo and the residue taken up in water (20 ml) and acidified to pH=2 using 2M hydrochloric acid. The mixture was extracted with ethyl acetate (100 ml), dried over sodium sulphate and evaporated in vacuo to give the title compound (1.7 g) as a white solid.