Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[C:9](OCC)(=[O:14])[CH2:10][C:11]([CH3:13])=O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:13][C:11]1[C:2]2[C:1](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=2[O:7][C:9](=[O:14])[CH:10]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C1CCCC(=O)C1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1cc(=O)oc2c1C(=O)CCC2
Reaction time: 3 h

Procedure:
231.2 g (2.0 mol) of cyclohexan-1,3-dione (97%) are refluxed under nitrogen for 2.5 hours in 670 ml of absolute pyridine with 325.3 q (1.25×2.0 mol) of ethyl acetoacetate and 4.88 (0.02×2 mol) of 4-dimethylaminopyridine. Then 65.1 g (0.25×2.0 mol) of ethyl acetoacetate are again added and the mixture is boiled for a further 3 hours. The pyridine is then distilled off in vacuo and the oily residue is stirred while still warm with 100 ml of a mixture of cyclohexane/ethyl acetate (1:1). The reaction product which crystallises out is suction filtered and dried. Yield: 136.9 g (39.2% of theory) The mother liquor is freed from solvent in vacuo using a rotary evaporator and the oily residue is distilled in vacuo. The distillate solidifies into a white crystalline substance.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH:4]([OH:7])[C:5]#[CH:6].[H-].[Na+].[CH2:11](Br)[CH:12]=[CH2:13]>CN(C=O)C.CCOCC>[CH2:13]([O:7][CH:4]([CH2:3][CH:2]([CH3:8])[CH3:1])[C:5]#[CH:6])[CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: C#CC(O)CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CC(CC(C)C)OCC=C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.1 %

Procedure:
A solution of 5-methylhex-1-yn-3-ol (2.11 g, 18.81 mmol) in DMF (30 ml) was cooled (0° C. ice bath) and treated with 60% NaH (0.903 g, 22.57 mmol). The reaction was stirred for 20 min, then warmed to room temperature and stirred for 1 hr. To this was added allyl bromide (4.9 ml, 56.6 mmol) over 5 min. The reaction was stirred overnight. The reaction was diluted with Et2O (100 mL), washed with water (4×25 mL), brine (25 mL), dried (MgSO4), filtered and concentrated to give the product, 3-(allyloxy)-5-methylhex-1-yne (2.83 g, 13.94 mmol, 74.1% yield) as a yellow mobile oil. 1H NMR consistent with expected product, contains ca. 4:1 product/SM. Used as-is without further purification. 1H NMR (CDCl3) δ: 5.89-6.00 (m, 1H), 5.34 (dq, J=17.2, 1.6 Hz, 1H), 5.22 (dq, J=10.3, 1.4 Hz, 1H), 4.29 (ddt, J=12.6, 5.1, 1.5 Hz, 1H), 4.14 (ddd, J=7.6, 6.7, 2.0 Hz, 1H), 3.99 (ddt, J=12.6, 6.3, 1.3 Hz, 1H), 2.44 (d, J=2.0 Hz, 1H), 1.90 (dsxt, J=13.5, 6.8 Hz, 1H), 1.64-1.80 (m, 2H), 1.56-1.64 (m, 2H), 0.95 (d, J=4.6 Hz, 3H), 0.94 (d, J=4.6 Hz, 3H).
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=[O:8])=[O:2].O>CO>[CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:2]
Reactant: COC(=O)CCCCC=O
Solvent: CO
Solvent: O
Product: O=CCCCCC(=O)O
Yield: 40.9 %

Procedure:
36 g of methyl 5-formylvalerate, 90 g of water and 1 g of p-toluenesclfonic acid were heated under reflux for 8 hours, the methanol formed being distilled off continuously. Fractional vacuum distillation gave 13.3 g of 5-formylvaleric acid (yield 41% of theory).
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.[H-].[Na+].[Cl:15][C:16]1[C:17]([N:27]=[C:28]=[O:29])=[C:18]([F:26])[S:19][C:20]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23]>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:15][C:16]1[C:17]([N:27]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:28]2=[O:29])=[C:18]([F:26])[S:19][C:20]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)Cc1sc(F)c(N=C=O)c1Cl
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1sc(F)c(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c1Cl
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 15 %

Procedure:
A solution of 4.75 g of ethyl 3-amino-4,4,4-trifluorocrotonate in 50 ml of anhydrous toluene was added dropwise to a solution prepared by suspending 1.14 g of sodium hydride (purity: 55%) in 110 ml of dimethylformamide. Said dropwise addition was conducted at 0° C. under stirring over a period of 15 minutes. The resulting mixture was further stirred at 0° C. for 15 minutes. Then the reaction mixture was cooled to -30° C., and a solution of 6.9 g of 4-chloro-2-fluoro-5-methoxycarbonylmethylthiophenyl isocyanate in 50 ml of anhydrous toluene was added dropwise thereto. The resulting reaction mixture was returned to room temperature and stirred for 2 hours. After distilling off the solvent, the residual solution was added with ethyl acetate, washed twice with a solution of 20 ml of 2N hydrochloric acid and 500 ml of water, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off to obtain a crude product. This crude product was preliminarily purified by silica gel column chromatography using CHCl3 as developing solvent and then purified by silica gel column chromatography using ethyl acetate/hexane (3:1) as developing solvent to obtain 1.5 g of the objective compound as viscous oil.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.[CH3:22][O:23][C:24]1[N:29]=[C:28]([CH3:30])[C:27](B(O)O)=[CH:26][CH:25]=1.[CH2:34](N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:22][O:23][C:24]1[N:29]=[C:28]([CH3:30])[C:27]([CH2:34][C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=2)[CH:5]=[C:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)=[CH:26][CH:25]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(O)c2)CC1
Reactant: COc1ccc(B(O)O)c(C)n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: COc1ccc(Cc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)c(C)n1
Reaction time: 48 h
Yield: 34.3 %

Procedure:
A mixture of tert-Butyl 4-(3-hydroxybenzylidene)piperidine-1-carboxylate (1 g, 3 mmol; Example 57, Step 3), 6-methoxy-2-methylpyridin-3-ylboronic acid (1.15 g, 6 mmol), copper acetate (0.627 g, 3 mmol), 4 Å molecular sieves, and triethylamine (2.40 mL, 15 mmol) in dichloromethane (5 mL) was stirred at r.t for 48 hours. The reaction mixture was filtered through a celite bed, and the filtrate was concentrated under reduced pressure and purified by column chromatography (3.5% ethyl acetate/hexane) to give the title compound (0.42 g, 30% yield). 1HNMR (500 MHz, CDCl3): δ ppm 7.20 (m, 2H), 6.86 (d, J=7.45 Hz, 1H), 6.68 (m, 2H), 6.59 (d, J=8.6 Hz, 1H), 6.28 (s, 1H), 3.94 (s, 1H), 3.49 (s, 2H), 3.38 (s, 2H), 2.42 (s, 2H), 2.36 (s, 3H), 2.31 (d, J=5.45 Hz, 2H), 1.47 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28](C)[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][O:33][C@H]1CC[C@H](N)CC1.C1(CCC(O)=O)C=CC=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:32][O:33][C@H:28]1[CH2:29][CH2:30][C@H:25]([N:11]([CH2:10][CH2:9][CH2:8][C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH2:26][CH2:27]1
Reactant: CO[C@H]1CC[C@H](N)CC1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: O=C(O)CCc1ccccc1
Product: CO[C@H]1CC[C@H](N(CCCc2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using trans-4-methoxy-cyclohexylamine, 3-phenyl propionic acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:15])[N:4]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][C:2]1[C:3](=[O:15])[N:4]([CH:8]2[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Cc1cccn(C2CCC(=O)CC2)c1=O
Product: Cc1cccn(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1=O

Procedure:
The title compounds were prepared as white solids from the reductive amination of 3-methyl-1-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:5]=[C:4]([O:17][C:18]2[C:25]([CH3:26])=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=2[CH3:27])[CH:3]=1.O1CCOCC1.O.[NH3:35]>C1(C)C=CC=CC=1>[NH2:35][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:5]=[C:4]([O:17][C:18]2[C:25]([CH3:26])=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=2[CH3:27])[CH:3]=1
Reactant: Cc1cc(C#N)cc(C)c1Oc1cc(Cl)nc(Nc2ccc(C#N)cc2)n1
Reactant: N
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C#N)cc(C)c1Oc1cc(N)nc(Nc2ccc(C#N)cc2)n1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
4-[[6-chloro-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethyl-benzonitrile (24 gm) was dissolved in aqueous ammonia (240 ml) and 1,4-dioxane (274 ml) at room temperature. The contents were heated to 120° C. and maintained for 12 hours at 120° C. To the reaction mass was added water (360 ml) and the reaction mass was slowly cooled to 50 to 60° C. The reaction mass was further cooled to 0 to 5° C. and stirred for 1 hour at 0 to 5° C., filtered. The wet solid obtained was dissolved in toluene (150 ml) under stirring. The separated solid was filtered and dried at 50° C. to obtain 10 gm of 4-[[6-amino-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]([Si:16]([CH3:26])([CH3:25])[O:17][C:18]1[CH:19]=[C:20]([SH:24])[CH:21]=[CH:22][CH:23]=1)([CH3:15])([CH3:14])[CH3:13].CCOCC.OS([O-])(=O)=O.[K+].Br[CH2:39][Cl:40]>>[C:12]([Si:16]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([S:24][CH2:39][Cl:40])[CH:19]=1)([CH3:26])[CH3:25])([CH3:15])([CH3:14])[CH3:13]
Reactant: ClCBr
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(S)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(SCCl)c1
Reaction time: 2 h

Procedure:
DBU (914 mg, 6.0 mmol) was added to a solution of 3-(tert-Butyl-dimethyl-silanyloxy)-benzenethiol (1.00 g, 4.16 mmol) in bromo-chloro methane (5 ml) at room temperature. Stirring was continued for 2 hours and Et2O (50 ml) and 2M KHSO4 (30 ml) were added. The organic layer was separated, washed with 2M KHSO4 (30 ml) and brine (30 ml), dried (Na2SO4) and concentrated under reduced pressure. The resulting oil was analysed by 1H-NMR spectroscopy and was used without further purification. Yield: 1.01 g (84%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[N:19][N:20]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:21]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].CC(O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:8][C:6]1[CH:7]=[C:2]([C:17]2[CH:18]=[N:19][N:20]([C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:21]=2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC1(C)OB(c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Clc1cc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)ncn1
Temperature: 108 °C

Procedure:
In a microwave reaction tube were combined 4,6-dichloropyrimidine (480 mg, 3.22 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazole (1.28 g, 2.93 mmol; JP 2005232071), bis(triphenylphosphine)-palladium(II) chloride (82 mg, 0.117 mmol), sodium carbonate (776 mg, 7.32 mmol), followed by the solvents 2-propanol (9.0 mL) and water (3.0 mL). The tube was sealed, and the reaction was heated to 108° C. for 30 minutes in the microwave reactor. After cooling to room temperature, the mixture was partitioned between ethyl acetate (2×100 mL) and water (200 mL). The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated under reduced pressure, and the resulting material was purified by silica gel flash column chromatography to afford the titled compound: 1H NMR (300 MHz, methanol-D4) δ ppm 7.11-7.22 (m, 6H), 7.28-7.41 (m, 9H), 7.81-7.83 (m, 1H), 8.23-8.26 (m, 1H), 8.30 (s, 1H), 8.75-8.78 (m, 1H). MS (DCI/NH3) m/z=423 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][CH2:18][CH2:19][C:20]#N)[CH2:13]1)[CH:6]=[CH:5]2.[OH-:32].[K+].[OH2:34]>CO>[Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][CH2:18][CH2:19][C:20]([OH:34])=[O:32])[CH2:13]1)[CH:6]=[CH:5]2
Reactant: N#CCCN[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Reactant: [OH-]
Reactant: O
Agent: [K+]
Solvent: CO
Product: O=C(O)CCN[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1

Procedure:
N-[6-Chloro-2-[(3S)-3-[(2-cyanoethyl)amino]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide (0.1 g), potassium hydroxide (0.051 g), water (1 mL) and methanol (2 mL) were heated within a single mode microwave in a sealed 10 mL vial for 100 minutes at 90° C. The resulting mixture was dissolved in methanol (20 mL) and purified on a Varian® SCX cartridge, washed with methanol (50 mL) and eluted with ammonia in methanol (0.7M, 50 mL). The residue was further purified on a Varian® NH2 cartridge washed with methanol (50 mL) and eluted with acetic acid:methanol (10:90). The solvent was removed under vacuum and the residue triturated with hot methanol, cooled and filtered to afford the title compound (7 mg).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29](O)=[O:30])[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[CH3:32][CH:28]([N:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:34])([F:33])[F:1])=[O:6])[CH:13]=[CH:12][CH:11]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)[CH:24]=[N:25]1)[C:29]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)=[O:30]
Reactant: C1COCCN1
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Product: CC(C(=O)N1CCOCC1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and morpholine. LCMS (M+H)+: m/z=543.2.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][N:13]([CH3:24])[C:14](/[CH:16]=[C:17]1\[CH2:18][NH:19][CH2:20][CH2:21][CH:22]\1[OH:23])=[O:15].[Cl:25][C:26]1[CH:37]=[CH:36][CH:35]=[CH:34][C:27]=1[CH:28](Br)[C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:25][C:26]1[CH:37]=[CH:36][CH:35]=[CH:34][C:27]=1[CH:28]([N:19]1[CH2:20][CH2:21][CH:22]([OH:23])/[C:17](=[CH:16]/[C:14](=[O:15])[N:13]([CH3:12])[CH3:24])/[CH2:18]1)[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)C(Br)c1ccccc1Cl
Reactant: CN(C)C(=O)/C=C1\CNCCC1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(c1ccccc1Cl)N1CCC(O)/C(=C/C(=O)N(C)C)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78 %

Procedure:
7.95 g (23.3 mmol) of the (E)-3-(N,N-dimethylcarbamoyl)methylidene-4-hydroxypiperidine p-toluenesulfonate were dissolved in 50 ml of N,N-dimethylformamide (DMF), followed by the addition of 7.35 g (purity: 80.0%, 22.3 mmol) of 2-chloro-α-methoxycarbonylbenzyl bromide and 7.40 g (53.5 mmol) of potassium carbonate. The resulting mixture was stirred at room temperature for 15 hours. After completion of the reaction, 150 ml water were added. The resulting mixture was extracted with toluene and ethyl acetate. The extract was distilled under reduced pressure. The residue was then purified by chromatography on a silica gel column (eluting solvent: chloroform/methanol=9/1 to 4/1), whereby 6.38 g (77.9%) of the title compound were obtained as a yellowish brown oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](OC)=[N:4][CH2:3]1.[Cl-:11].[NH4+:12]>C(O)C>[ClH:11].[CH3:1][C:2]1([CH3:10])[CH2:3][NH:4][C:5](=[NH:12])[CH2:6][CH2:7]1
Reactant: [NH4+]
Reactant: COC1=NCC(C)(C)CC1
Reactant: [Cl-]
Solvent: CCO
Product: CC1(C)CCC(=N)NC1
Product: Cl

Procedure:
The mixture of 3,3-dimethyl-6-methoxy-2,3,4,5-tetrahydropyridine (9.0 g, 64 mmol) and ammonium chloride (3.4 g, 64 mmol) in dry ethanol (160 mL) was heated to reflux for 2 h. The reaction mixture was then concentrated under reduced pressure and the titled compound was obtained as a white solid (9.9 g, 94.6%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=O)[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:24][NH2:25]>C(O)C>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][C:14]1[C:19]([CH2:20][CH3:21])=[N:24][NH:25][C:15]=1[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCC(=O)C(Cc1nccn1Cc1ccccc1)C(=O)CC
Solvent: O
Solvent: CCO
Product: CCc1n[nH]c(CC)c1Cc1nccn1Cc1ccccc1

Procedure:
To a solution of 140 mg (0.47 mmol) 4-(1-benzyl-1H-imidazol-2-ylmethyl)-heptane-3,5-dione in 1.5 ml ethanol was added a solution of 24 mg (0.48 mmol) hydrazine monohydrate in 0.5 ml ethanol and the mixture heated to reflux for 10 min. The reaction mixture was evaporated under reduced pressure, the residue dissolved in 1N aqueous HCl solution and extracted three times with t-butyl methyl ether. The aqueous phase was adjusted to pH 12 and extracted three times with t-butyl methyl ether, the combined extracts washed with brine, dried over sodium sulfate, filtered and evaporated. Purification of the residue by flash-chromatography on silica gel with ethyl acetate as eluent provided 4-(1-benzyl-1H-imidazol-2-ylmethyl)-3,5-diethyl-1H-pyrazole as colourless viscous oil: MS (ISP): 295.3 ((M+H)+.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[C:4]([CH3:10])[CH:3]=1.[CH:11](O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]2[N:6]([CH:11]=[N:9][N:8]=2)[N:7]=1
Reactant: Cc1cc(Cl)nnc1NN
Reactant: O=CO
Product: Cc1cc(Cl)nn2cnnc12
Reaction time: 0.5 h

Procedure:
A mixture of 37.6 g of 6-chloro-3-hydrazino-4-methylpyridazine and 50 ml of formic acid was heated, with stirring, on a boiling water bath for 30 minutes. The mixture was cooled and excess acid was removed by distillation under reduced pressure. The residual damp solid was dissolved in 300 ml of methylene chloride and washed with aqueous saturated sodium bicarbonate solution. The organic solution was then dried over anhydrous sodium sulfate and filtered through Celite and the solvent was evaporated to leave a residual tan solid. This was recrystallized from ethyl acetate to give 6-chloro-8-methyl-1,2,4-triazolo[4,3-b]pyridazine melting at about 134-136° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11][CH:12]=O)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].Cl[CH:15](Cl)C.[Cl:18][C:19]1[N:24]=[CH:23][C:22]([NH2:25])=[CH:21][N:20]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:4])[C:5]([CH2:6][CH2:15][NH:25][C:22]1[CH:21]=[N:20][C:19]([Cl:18])=[N:24][CH:23]=1)([CH2:11][CH3:12])[CH2:10][CH2:9][O:8][CH3:7]
Reactant: Nc1cnc(Cl)nc1
Reactant: COC(=O)C1(CC=O)CCOCC1
Reactant: CC(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC(CCNc1cnc(Cl)nc1)(CCOC)C(=O)OC
Temperature: 25 °C
Yield: 46 %

Procedure:
To a solution of 4-(2-oxo-ethyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (0.12 g, 0.644 mmol) in 1-2 dichloroethane (DCE, 6 mL) was added 2-chloropyrimidin-5-amine (0.084 g, 0.644 mmol), acetic acid (3.1 eq) and allowed to stir at room temperature for an hour. NaBH(OAc)3 (3 eq) was then added in one portion and reaction mixture allowed to stir at room temperature for 16 hours. The reaction was diluted with DCM (10 mL), quenched with 2 M of NH4OH in water (1 mL). The layers were separated, and the aqueous layer was extracted with DCM (10 mL, 2×). The combined organic layers were washed with aqueous NaHCO3 (10 mL), brine (20 mL), dried over Na2SO4, and concentrated under vacuum. Purification over silica gel eluting with ethyl acetate in heptanes (0-75%) afforded 0.088 g (46%) of title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9]/[CH:10]=[C:11]2\[C:12](=[O:23])[NH:13][C:14](=[O:22])[C:15]3[C:20]\2=[CH:19][C:18]([I:21])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]=1[NH:24][C:25](=[O:30])/[C:26](/[CH3:29])=[CH:27]/C.NC1C=CC([CH2:36][NH:37]/[CH:38]=C2\C(=O)NC(=O)C3C\2=CC(I)=CC=3)=CC=1O[Si](C(C)C)(C(C)C)C(C)C.CN(CC(=C)C(O)=O)C>>[CH3:36][N:37]([CH2:29][C:26](=[CH2:27])[C:25]([NH:24][C:3]1[CH:4]=[CH:5][C:6]([CH2:8][NH:9]/[CH:10]=[C:11]2\[C:12](=[O:23])[NH:13][C:14](=[O:22])[C:15]3[C:20]\2=[CH:19][C:18]([I:21])=[CH:17][CH:16]=3)=[CH:7][C:2]=1[OH:1])=[O:30])[CH3:38]
Reactant: CC(C)[Si](Oc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)ccc1N)(C(C)C)C(C)C
Reactant: C/C=C(\C)C(=O)Nc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O
Agent: C=C(CN(C)C)C(=O)O
Product: C=C(CN(C)C)C(=O)Nc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O

Procedure:
Following the acetylation and desilylation procedure employed for the preparation of (2E)-N-[2-hydroxy-4-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)phenyl]-2-methylbut-2-enamide, (4Z)-4-[({4-amino-3-[(triisopropylsilyl)oxy]benzyl}amino)methylene]-6-iodoisoquinoline-1,3(2H,4H)-dione (65 mg, 0.11 mmol) is reacted with acid chloride derived from 2-dimethylaminomethyl acrylic acid (Wissner, A.; Overbeek, E.; Reich, M. F.; Floyd, M. B.; Johnson, B. D.; Mamuya, N.; Rosfjord, E. C.; Discafani, C.; Davis, R.; Shi, X.; Rabindran, S. K.; et al. J. Med. Chem. 46; 1; 2003; 49-63, 0.18 g, 1.1 mmol). Following desilylation and precipitation, 2-[(dimethylamino)methyl]-N-[2-hydroxy-4-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)phenyl]acrylamide is obtained as a solid (19 mg, 32%).