Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].C(N(CC)CC)C.C1(C)C=CC=CC=1.[C:30]([O:34][CH3:35])(=[O:33])[CH:31]=[CH2:32]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O>[C:5]([C:4]1[CH:3]=[C:2]([CH:15]=[CH:14][CH:13]=1)[CH:32]=[CH:31][C:30]([O:34][CH3:35])=[O:33])(=[O:6])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C=CC(=O)OC
Reactant: O=C(c1ccccc1)c1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C=Cc1cccc(C(=O)c2ccccc2)c1
Temperature: 100 °C
Yield: 90.9 %

Procedure:
To a mixture of 3-bromobenzophenone (5.0 g, 19 mmol), palladium acetate (215 mg, 0.958 mmol), and tri-o-tolylphosphine (290 mg, 0.953 mmol) was added triethylamine (3.3 mL, 45 mmol), toluene (4 mL), and methyl acrylate (2.2 mL, 27 mmol). The mixture was heated at 100° C. for 18 hours at which time—TLC analysis showed the reaction was still incomplete. Additional portions of palladium acetate (215 mg, 0.958 mmol), tri-o-tolylphosphine (290 mg, 0.953 mmol), triethylamine (3.3 mL, 45 mmol) and methyl acrylate (2.2 mL, 27 mmol) were added, and the mixture was heated at 110° for a further 18 hours. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed sequentially with water and brine, and then dried (MgSO4) and concentrated to a brown oil (5.3 g). The oil was chromatographed over silica gel. Elution with ethyl acetate/hexanes (1:9) afforded methyl 3-benzoylcinnamate (4.6 g, 91%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH:13]=O.[Br:15][C:16](Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Br:15][C:16]([Br:17])=[CH:13][C:3]1[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][O:6][C:2]=1[CH3:1]
Reactant: Cc1onc(-c2ccccc2)c1C=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1onc(-c2ccccc2)c1C=C(Br)Br
Yield: 82.8 %

Procedure:
To a stirred solution of 5-methyl-3-phenyl-isoxazole-4-carbaldehyde (5.20 g, 27.8 mmol) was added tetrabromomethane (12.9 g, 38.9 mmol) and then triphenylphosphine (14.57 g, 55.5 mmol) and the resulting mixture stirred under argon for 2 h at 0° C. The solution was concentrated to approximately 90 mL and the resulting precipitate filtered, washed with dichloromethane and discarded. This was repeated until the majority of the triphenylphospine oxide and bromide was removed. Purification by chromatography (silica, heptane:ethyl acetate 9:1 to 2:3) afforded the title compound (7.9 g, 83%) which was obtained as a colorless oil. MS: m/e=344.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]C2C=CC=C3C(NC(=O)C=23)=O)=[CH:4][CH:3]=1.O.[NH2:27]N.CCO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:27])=[CH:6][CH:7]=1
Reactant: NN
Reactant: O=C1NC(=O)c2c(CCCCCCSc3ccc(Cl)cc3)cccc21
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: NCCCCCCSc1ccc(Cl)cc1

Procedure:
2-[6-(4-Chloro-phenylsulfanyl)-hexylphthalimide (7.47 g, 20 mmol) and hydrazine hydrate (6.1 ml, 100 mmol) were dissolved in THF (50 mL) and EtOH (50 mL) and stirred under reflux for 17 h. The solvent was removed under reduced pressure, the residue was suspended in THF (100 mL) and the precipitate was filtered off, washed with THF (1×50 mL) and the filtrate was concentrated under reduced pressure. The residue was resuspended in THF (25 mL), the precipitate was filtered off and the filtrate was concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[CH:33]=[CH:32][C:15]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][N:21]3[CH:29]=[CH:30][CH:31]=[C:20]3[CH2:19]2)=[O:17])=[CH:14][CH:13]=1>C(Cl)Cl>[CH:31]1[CH:30]=[CH:29][N:21]2[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:18]([C:16]([C:15]3[CH:14]=[CH:13][C:12]([NH:11][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[Cl:1])=[CH:33][CH:32]=3)=[O:17])[CH2:19][C:20]=12
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1Cl
Reaction time: 0.05 h
Yield: 72.1 %

Procedure:
To a solution of 347 mg of 2-chlorobenzoyl chloride in 5 ml of methylene chloride at 0° C. is added 346 μl of triethylamineo After stirring for 3 minutes, 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 18 hours. The volatiles are concentrated in vacuo to give a residue which is dissolved in methylene chloride, washed with water, 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried with Na2SO4, filtered and concentrated in vacuo to give a residue which is crystallized from methylene chloride to give 525 mg of the desired product as a white crystalline solid, m.p. 228°-230° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CS(C)=O.C(N(CC)CC)C>ClCCl>[F:23][C:2]([F:1])([F:24])[C:3]1[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[O:22])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: OCCCCCCCCOc1ncc(C(F)(F)F)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CCCCCCCCOc1ncc(C(F)(F)F)cc1C(F)(F)F

Procedure:
The above alcohol (0.6 g) was oxidised under Swern conditions (dimethyl sulphoxide (0.26 g) oxalyl chloride (160 μl), triethylamine (1.0 ml)) in dichloromethane (30 ml) to give 8-(3,5-bistrifluoromethyl-2-pyridyloxy)octan-1-al. This was used directly in the next stage.
Reaction SMILES: CC(O[C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)C.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.[C:27](O)(=O)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]C.C1CCC(N=C=NC2CCCCC2)CC1>>[CH2:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: CCCCCCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Nc1ccccn1
Product: CCCCCCCCCCN[C@@H](Cc1ccccc1)C(=O)O

Procedure:
The acylated phenylalanine anilide imprint molecule was synthesized in three steps. (1) N-α-t-BOC-L-phenylalanine was coupled with 2-aminopyridine using DCC to give N-α-t-BOC-L-phenylalanine-2-aminopyridine. (2) The a-amine was then deprotected with TFA to give N-α-L-phenylalanine-2-aminopyridine.(3) To create a compound having the properties of a surfactant, the free amine was then acylated with decanoic acid using DCC to give N-α-decyl-L-phenylalanine-2-aminopyridine.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:32].Br[C:34]1[CH:44]=[CH:43][CH:42]=[C:41]([N:45]2[CH:54]=[CH:53][C:52]3[C:47](=[CH:48][CH:49]=[C:50]([N:55]([CH3:57])[CH3:56])[CH:51]=3)[C:46]2=[O:58])[C:35]=1[CH2:36][O:37][C:38](=[O:40])[CH3:39].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:57][N:55]([CH3:56])[C:50]1[CH:51]=[C:52]2[C:47](=[CH:48][CH:49]=1)[C:46](=[O:58])[N:45]([C:41]1[CH:42]=[CH:43][CH:44]=[C:34]([C:6]3[CH:5]=[C:4]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)=[O:25])=[CH:20][N:19]=4)[C:3](=[O:32])[N:2]([CH3:1])[CH:7]=3)[C:35]=1[CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH:54]=[CH:53]2
Reactant: CC(=O)OCc1c(Br)cccc1-n1ccc2cc(N(C)C)ccc2c1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)c2)cccc1-n1ccc2cc(N(C)C)ccc2c1=O
Temperature: 100 °C
Yield: 52.6 %

Procedure:
To 1-Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (43 mg, 0.097 mmol), Acetic acid 2-bromo-6-(6-dimethylamino-1-oxo-1H-isoquinolin-2-yl)-benzyl ester (40 mg, 0.097 mmol), potassium phosphate (41 mg, 0.19 mmol), 2-(dicyclohexylphoshphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (2.7 mg, 0.0057 mmol), and bis(dibenzylidineacetone)palladium(0) (1.6 mg, 0.0028 mmol) was added 4 mL of degassed 1:3 water/n-butanol. The headspace of the vessel was evacuated and backfilled with argon 4 times. This was heated at 100° C. for 110 minutes. This was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 2 to 5% methanol/dichloromethane) to yield Acetic acid 2-(6-dimethylamino-1-oxo-1H-isoquinolin-2-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-benzyl ester (33 mg, 0.051 mmol). MS (ESI) 649.2 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCN(C)C.C([Li])(CC)C.[CH:29]([CH:31]=[CH2:32])=[O:30]>CCCCCC.O.O1CCCC1>[C:2]1([CH:1]([NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])[CH:29]([OH:30])[CH:31]=[CH2:32])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC=O
Reactant: CC(C)(C)OC(=O)NCc1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: C=CC(O)C(NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 78 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
4.2 g (20.3 mmol) of t-butyl benzylcarbamate, 40 cm3 of anhydrous tetrahydrofuran and 6.5 cm3 (5.0 g, 43 mmol) of tetramethylethylenediamine (TMEDA) are introduced successively into a 250 cm3 single-necked flask placed under argon and equipped with a magnetic stirring system. The solution obtained is cooled to 78° C. and 60 cm3 (60 mmol) of a 1M solution of secondary butyllithium in hexane are then added dropwise. The reaction is left to proceed for 3 hours at this temperature and the mixture is then cooled to -100° C. 3 cm3 (2.5 g, 44.9 mmol) of freshly distilled acrolein are then added and the reaction is left to proceed for 3 to 4 minutes at this temperature and then for 1 hour at -78° C. The resulting reaction mixture is hydrolyzed at -78° C. with 20 cm3 of water and then extracted with 2 times 30 cm3 of ether. The organic phases are combined and then washed twice with 20 cm3 of water and once with 10 cm3 of a saturated aqueous solution of sodium chloride. They are then dried over anhydrous sodium sulphate. After filtration, the solvents are driven off under reduced pressure. The residue obtained (11.6 g) is purified on a column of silica gel using a methylene chloride/ether mixture (95/5 by volume) as the eluent. 2.606 g (9.91 mmol) of 1-phenyl-1-t-butoxycarbonylamino-2-hydroxybut-3-ene are obtained with a yield of 49% in the form of a mixture of the syn and anti diastereoisomers in a ratio of 6/1.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[Na].C(O[CH:11]=[C:12]([C:15]#[N:16])[C:13]#[N:14])C.[CH2:17]([OH:19])[CH3:18]>>[CH2:5]([O:4][C:1](=[O:3])[C:2]1[CH:11]=[C:12]([C:13]#[N:14])[C:15]([NH2:16])=[CH:18][C:17]=1[OH:19])[CH3:6]
Reactant: CCO
Reactant: CCOC=C(C#N)C#N
Reactant: CCOC(C)=O
Agent: [Na]
Product: CCOC(=O)c1cc(C#N)c(N)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
According to H.-W-. Schmidt et al. (Liebigs Ann. Chem. 1979, 2005-10), ethyl acetate (42 g, 323 mmol) is added to a solution of sodium (15 g, 23 mmol) in ethanol (4.0 l) and the mixture is stirred at room temperature for 30 minutes. Ethoxymethylene-malononitrile (40.6 g, 332 mmol) is added. After 30 minutes at 80° C., the reaction mixture is allowed to cool to room temperature and the resulting precipitate is filtered off with suction. The precipitate is dissolved using water, and the aqueous phase is acidified with concentrated hydrochloric acid and the resulting precipitate is filtered off with suction again. After recrystallization from acetic acid, the crystals are filtered off with suction, washed with water and subsequently dried. The desired product is obtained in 29% yield (21.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][S@@](C(C)(C)C)=O)[CH3:9])=[CH:4][C:3]=1[CH3:17].C1(C2(CC(O)(C)C)OC(=O)N([C@H](C3C=CC(C4C=CN(C)C(=O)C=4)=CC=3)C)CC2)CC1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1cc([C@H](C)N[S@](=O)C(C)(C)C)ccc1Br
Agent: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CCC(CC(C)(C)O)(C2CC2)OC1=O
Product: Cc1cc([C@H](C)N)ccc1Br

Procedure:
The title compound was prepared from (R)-2-methyl-propane-2-sulfinic acid [(S)-1-(4-bromo-3-methyl-phenyl)-ethyl]amide following a procedure analogous to that described in Step 3 of Intermediate 1. LC-MS (Method 4): tR=3.56 min; Mass spectrum (ESI+): m/z=214/216 (Br) [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:5]=[N:6][N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12)[CH3:2].C([Li])CCC.[I:20]CCI.C(OCC)(=O)C.CCCCCC>C1COCC1>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[N:6][N:7]2[C:12]([I:20])=[CH:11][CH:10]=[CH:9][C:8]=12)[CH3:14]
Reactant: ICCI
Reactant: CCN(CC)c1cnn2ccccc12
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCN(CC)c1cnn2c(I)cccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-diethylaminopyrazolo[1,5-a]pyridine (0.57 g, 3.00 mmol) in THF (5.00 mL) was cooled to −78° C. and treated with a solution of n-butyl lithium (1.20 M in hexanes, 3.25 mL, 3.90 mmol). The reaction was stirred for 30 minutes then treated with a solution of 1,2-diiodoethane (1.01 g, 3.60 mmol) in THF (10 mL). The reaction was stirred at −78° C. for 3 hours then quenched with saturated NaHCO3 at −78° C. and warmed to room temperature. The reaction was diluted with water and extracted twice with methylene chloride, dried over MgSO4 and concentrated in vacuo to give a dark green oil which was subjected to column chromatography (5% ethyl acetate/hexane) to give 0.59 g (63%) of a yellow oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.58 (dd, J=8.8, 1.2 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 6.81–6.76 (m, 1H), 3.13 (q, J=7.1 Hz, 4H), 1.06 (t, J=7.1 Hz, 6H); MS (EI) m/z 316.14 (M++H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH2:18][CH2:19]O.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>C(Cl)Cl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH2:18][CH2:19][O:9][C:8]([C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10]
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: OCCOC1CCCCO1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCCOC1CCCCO1)c1cnc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
A solution of 5-chloro-pyrazine-2-carboxylic acid (prepared as in Example 29, 3.15 g, 19.94 mmol) in methylene chloride (50 mL) was treated with 2-(tetrahydropyran-2-yloxy)ethanol (2.91 g, 19.94 mmol). The solution was cooled to 0° C. and then was treated with triethylamine (5.60 mL, 39.88 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (5.07 g, 19.94 mmol). The mixture was stirred at 0° C. for 15 min and then at 25° C. for 24 h. The mixture was extracted with methylene chloride and water. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 2/1 hexanes/ethyl acetate) afforded 5-chloro-pyrazine-2-carboxylic acid 2-(tetrahydro-pyran-2-yloxy)-ethyl ester as a colorless oil (3.41 g, 60%).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[CH2:12](I)[CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+].C(OC1C=C(C=CC=1C)C=O)C>CN(C=O)C>[CH3:9][O:8][C:7]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH2:12][CH2:13][CH3:14]
Reactant: COc1ccc(C=O)cc1O
Reactant: CCCI
Agent: CCOc1cc(C=O)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1cc(C=O)ccc1OC

Procedure:
The title compound was prepared by reaction of isovanillin with propyl iodide in DMF using K2CO3 as base in analogy to the preparation of 3-ethoxy-4-methyl-benzaldehyde (intermediate E10).
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([CH:16]=[CH:17][N:18]=2)[N:12]=[C:13]([Cl:15])[CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[ClH:15].[N:18]1[CH:17]=[CH:16][N:11]2[C:10]=1[C:9]([OH:8])=[CH:14][CH:13]=[N:12]2
Reactant: Clc1cc(OCc2ccccc2)c2nccn2n1
Agent: [Pd]
Solvent: CO
Product: Cl
Product: Oc1ccnn2ccnc12
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 8-(benzyloxy)-6-chloroimidazo[1,2-b]pyridazine (D-4) (6.2 g, 23.8 mmol, 1.0 eq) in MeOH (100 mL), Pd/C (10%, 620 mg) is added. The resulting mixture is degassed and back-filled with hydrogen three times and then stirred at 50° C. under hydrogen for 24 h. The resulting mixture is filtered and concentrated in vacuo to afford the product, imidazo[1,2-b]pyridazin-8-ol hydrochloride (D-5).
Reaction SMILES: Cl.C([O:5][CH2:6][CH2:7][N:8]([CH2:12][CH2:13][N:14]1[C:22]2[CH:21]=[CH:20][C:19]([NH2:23])=[C:18]3[S:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:16]([C:17]=23)=[N:15]1)C(=O)C)(=O)C.[Cl:31][CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][O:36]C1=O>C(Cl)Cl.CO>[ClH:31].[OH:36][CH2:37][CH2:38][NH:34][CH2:33][CH2:32][NH:23][C:19]1[CH:20]=[CH:21][C:22]2[N:14]([CH2:13][CH2:12][NH:8][CH2:7][CH2:6][OH:5])[N:15]=[C:16]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[S:24][C:18]=1[C:17]=23
Reactant: O=C1OCCN1CCCl
Reactant: CC(=O)OCCN(CCn1nc2c3c(c(N)ccc31)Sc1ccccc1-2)C(C)=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: OCCNCCNc1ccc2c3c(nn2CCNCCO)-c2ccccc2Sc13
Temperature: 150 °C
Reaction time: 2 h
Yield: 111.1 %

Procedure:
A mixture of 5.1 g (0.012 mol) of N-[2-(acetyloxy)ethyl]-N-[2-(5-amino-2H[1]benzothiopyrano[4,3,2-cd]indazol-2-yl)ethyl]acetamide, hydrochloride salt and 11.6 g (0.077 mol) of 3-(β-chloroethyl)-2-oxazolidinone was stirred at 150° C. for 2 hours, dissolved in 20 ml of a CH2Cl2 /MeOH (20/1) mixture, and flash chromatographed over silica gel, eluting with a CH2Cl2 /MeOH (20/1) mixture. The appropriate fractions were combined and concentrated to dryness in vacuo. The residue was treated with 20 ml of 2N KOH in MeOH, 10 ml of H2O, and 10 ml of THF, and the mixture was heated under reflux under a N2 atmosphere for 16 hours. The mixture was treated with 100 ml of H2O and 100 ml of CH2Cl2 and the layers were separated. The aqueous phase was extracted twice with CH2Cl2 and the Ch2Cl2 extracts were combined, dried (MgSO4), and concentrated to dryness in vacuo. The residue was dissolved in 50 ml of EtOH and treated with an excess of i-PrOH saturated with gaseous HCl. The precipitate was collected and recrystallized from MeOH to give 6.0 g of product, mp 222°-225° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cu][C:22]#[N:23]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([C:22]#[N:23])=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2(c3ccc(I)cc3)CCNCC2)cc1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C2(c3ccc(Cl)cc3)CCNCC2)cc1
Temperature: 140 °C
Yield: 16 %

Procedure:
A mixture of 4-(4-chloro-phenyl)-4-(4-iodo-phenyl)-piperidine and copper (I) cyanide in DMF was heated at 140° C. under nitrogen for 6 hours then allowed to cool. The mixture was diluted with ethyl acetate, washed with a mixture of conc. ammonia and brine (×5), dried (MgSO4), filtered and concentrated to give a residue which was partially purified by column chromatography (SiO2), eluting with a gradient of 2M ammonia in methanol (5% to 10%) and dichloromethane to afford the title compound (46 mg, <16%). This was taken on to the next reaction without further purification. LCMS (PS-A2) Rt 2.39 min [M+H]+ 297.
Reaction SMILES: CO.O.S(=O)(=O)(O)[NH2:5].[Cl:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[N:20][C:21]1[CH:37]=[CH:36][C:24]([N:25]([CH2:34][CH3:35])[CH2:26][C:27](=[C:32]=[O:33])OCC#N)=[CH:23][C:22]=1[NH:38][C:39](=[O:41])[CH3:40].[CH3:42][C:43](C)=[O:44]>>[Cl:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[N:20][C:21]1[CH:37]=[CH:36][C:24]([N:25]([CH2:34][CH3:35])[CH2:26][CH2:27][C:32]([O:44][CH2:43][C:42]#[N:5])=[O:33])=[CH:23][C:22]=1[NH:38][C:39](=[O:41])[CH3:40]
Reactant: CCN(CC(=C=O)OCC#N)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2Cl)c(NC(C)=O)c1
Reactant: CC(C)=O
Reactant: NS(=O)(=O)O
Solvent: O
Solvent: CO
Product: CCN(CCC(=O)OCC#N)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2Cl)c(NC(C)=O)c1

Procedure:
The diazo solution was added gradually to a stirred coupling mixture of 3(N-ethyl, N-cyanomethoxycarbonylethyl)-amino-acetanilide (6.3 parts), methanol (40 parts), water (200 parts) and sulphamic acid (1 part). After two hours the product was isolated by filtration, washed with cold water and dried to yield, 4-(2-chloro-4-nitrophenylazo)-3-acetylamino-N-ethyl-N-(2-cyanomethoxy-carbonylethyl)-aniline (4.1 parts) λmax=525 nm (acetone).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:17]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)ccc1Br
Temperature: 100 °C

Procedure:
2-Bromo-5-methylbenzoic acid (9.3 g, 43.4 mmol) was dissolved in MeOH (100 mL) and then cat. conc. H2SO4 was added. The mixture was refluxed at 100° C. overnight. The mixture was cooled to rt and the solvent was removed at reduced pressure. The crude residue was dissolved with EtOAc, and washed with water twice, followed by saturated NaHCO3 and brine, dried over anhydrous Na2SO4. The solvent was removed in vacuo to obtain the title compound with no further purification.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(=O)[CH3:9].Cl.[NH2:21][OH:22]>C(O)C>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([C:8](=[N:21][OH:22])[CH3:9])=[CH:12]1
Reactant: CC(=O)c1c[nH]c2ccccc12
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=NO)c1c[nH]c2ccccc12
Temperature: 90 °C
Yield: 96.9 %

Procedure:
Triethylamine (3.93 mL) was added to a solution of 3-acetylindole (500 mg) and hydroxylamine hydrochloride (981 mg) in ethanol (20 mL), and the reaction solution was heated to reflux at 90° C. for 14 hours. The reaction solution was allowed to be cooled to room temperature, the solvent was concentrated under reduced pressure, and ethyl acetate and water were added to the resulting residue and the organic layer was partitioned. The resulting organic layer was washed with brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate) to obtain 0.53 g of the title compound. The physical properties of the compound are as follows.