Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([O:6][CH3:7])([CH3:5])[CH3:4].[OH2:8].[C:9]1([CH3:19])C=CC(S(O)(=O)=O)=C[CH:10]=1>CC(C)=O>[OH:8][CH2:10][CH2:9][CH:19]1[CH2:7][O:6][C:3]([CH3:5])([CH3:4])[O:2][CH2:1]1
Reactant: COC(C)(C)OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Solvent: CC(C)=O
Product: CC1(C)OCC(CCO)CO1
Reaction time: 1 h
Yield: 47 %

Procedure:
To a suspension of lithium aluminium hydride (2.87 g, 76 mmol) in tetrahydrofuran (125 ml), a solution of triethyl 1,1,2-ethanetricarboxylate (9.2 ml, 9.85 g, 40 mmol) in tetrahydrofuran (25 ml) was added dropwise with stirring over 2 hours. Excess reagent was then quenched with aqueous tetrahydrofuran (1:2). The inorganic salts were filtered off and washed with ethanol (100 ml). The filtrate and washings were combined and the solvent was evaporated under reduced pressure to afford a colourless oil (4.85 g). To a suspension of this oil in acetone (100 ml.), 2,2-dimethoxypropane (25 ml) and p-toluenesulphonic acid monohydrate (2.3 g, 12 mmol) were added and the mixture was stirred for 1 hour. The resulting solution was neutralised with Amberlite IR 45 (OH− form, methanol washed), filtered and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with chloroform-methanol mixtures (40:1 and 25:1) to afford 5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxan as a colourless liquid (3.01 g, 47%); νmax (film) 3420, 2940, 1375, 1200 and 1080 cm−1; δH (CDCl3) 1.34-1.70 (8H, m, C(CH3)2 and CH2CH2OH), 1.7-2.1 (1H, m, CH), 2.15 (1H, br, D2O exchangeable, OH), and 3.5-4.0 (6H, m, 3×CH2O); (Found: C, 58.33; H, 10.11%. C8H16O3 0.25H2O requires C, 58.34; H, 10.10%. [M−CH3]+ found 145.0864; C7H13O3 requires 145.0865).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H].[CH2:12]([C:16]1[N:17]([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18]2[C:23]([CH3:24])=[C:22]([CH3:25])[N:21]=[C:20](Cl)[C:19]=2[N:27]=1)[CH2:13][CH2:14][CH3:15]>COCCOCCOC>[CH2:12]([C:16]1[N:17]([CH2:28][CH2:29][O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:18]2[C:23]([CH3:24])=[C:22]([CH3:25])[N:21]=[C:20]([O:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:19]=2[N:27]=1)[CH2:13][CH2:14][CH3:15]
Reactant: [H][H]
Reactant: CCCCc1nc2c(Cl)nc(C)c(C)c2n1CCOc1ccccc1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: CCCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCOc1ccccc1
Temperature: 0 °C

Procedure:
2-Methoxyethyl ether (diglyme) (1.50 ml) and sodium hydride (60% in oil) (0.12 g) were combined and cooled to 0° C. Phenol (0.27 g) was added slowly in portions over 1 hour to allow for controlled release of hydrogen gas. 2-Butyl-4-chloro-6,7-dimethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]pyridine (0.96 g) from Part B was then added and the reaction mixture became dark brown. The reaction mixture was heated to reflux for 5 days, at which time HPLC analysis indicated the reaction was complete. The reaction mixture was cooled and washed with water. The mixture was filtered and the resulting solid was dried under vacuum at 60° C. overnight. NMR analysis of the product indicated sufficient purity for use of the product in the next step.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-:33])=[O:32])=[CH:13][N:14]2[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:10][CH:9]=1)(C)(C)C.CCCCCCC.C(OCC)(=O)C.C(OCC)(=O)C>C(N(CC)CC)C>[N+:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[S:24][C:12]1[C:11]2[C:15](=[CH:16][C:8]([NH2:7])=[CH:9][CH:10]=2)[N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:13]=1)([O-:33])=[O:32]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3ccccn3)c2c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: Nc1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3ccccn3)c2c1
Yield: 64.9 %

Procedure:
[3-(2-Nitro-phenylsulfanyl)-1-pyridin-2-ylmethyl-1H-indol-6-yl]-carbamic acid tert-butyl ester (Example 2, step iv; 3.4 g, 6.3 mmol) was deprotected to give, after column chromatography (heptane/ethyl acetate 2:8→ethyl acetate, containing some triethylamine), the title compound (1.54 g). 1H-NMR (CDCl3) δ 8.62 (bd, 1H, J=5.0 Hz), 8.26 (dd, 1, J=8.0 and 1.5 Hz), 7.61 (dt, H, J=7.5 and 2.0 Hz), 7.34 (s, 1H), 7.25-7.30 (m, 2H), 7.22 (ddd, 1H, J=7.5, 5.0 and 1.0 Hz), 7.16 (ddd, 1H J=8.0, 7.0 and 1.0 Hz), 7.05 (dd, 1H, J=8.0 and 1.0 Hz), 6.86 (d, 1H, J=8.0 Hz), 6.63 (d, 1H, J=1.5 Hz), 6.60 (dd, 1H, J=8.0 and 1.5 Hz), 5.41 (s, 2H), 3.70 (bs, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[F-:11].[K+].C(#N)C>[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC>[F:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: [F-]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [Br-]
Agent: [K+]
Agent: c1ccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(F)nc1
Yield: 51.5 %

Procedure:
2-Chloro-5-nitropyridine (100 g, 0.656 mol, Aldrich), potassium fluoride (84.1 g, 1.45 mol, Aldrich), tetraphenylphosphonium bromide (95.3 g, 0.227 mol, Aldrich), and acetonitrile (1.5 L) were combined and heated at reflux until consumption of the 2-chloro-5-nitropyridine was complete. The volume of the mixture was reduced to 750 mL, diluted with 2 L of ether, filtered and concentrated. The resultant residue was triturated with hot hexane, and the combined hexane extracts were concentrated to give of the title compound (48 g, 54%): 1H NMR (CDCl3, 300 MHz) δ 7.15 (dd, J=3, 6 Hz, 1H), 8.64 (m, 1H), 9.15 (d, J=1.6 Hz, 1H).
Reaction SMILES: [Br:1][C:2](=[CH2:8])[CH2:3][Si](C)(C)C.[F:9][C:10]([F:19])([F:18])[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:15]([O:14][C:12](=[O:13])[C:11]([OH:17])([C:10]([F:9])([F:18])[F:19])[CH2:3][C:2]([Br:1])=[CH2:8])[CH3:16]
Reactant: C=C(Br)C[Si](C)(C)C
Reactant: CCOC(=O)C(=O)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: C=C(Br)CC(O)(C(=O)OCC)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
To a chilled (−78° C.) solution of 5.2 mL (30.18 mmol) of 2-bromoallyltrimethylsilane and 5.3 g (31.16 mmol) of ethyl trifluoropyruvate in 75 mL of dichloromethane was added 30 mL (30 mmol) of a 1 M solution of titanium tetrachloride in dichloromethane over a 10 minute period. The cold bath was then removed and the mixture was warmed to room temperature. After 3 hours, the mixture was cautiously added to 100 mL of saturated aqueous ammonium chloride and filtered through diatomaceous earth, washing with dichloromethane. The dichloromethane was separated and the aqueous layer was extracted with three 50 mL portions of dichloromethane. The combined organic layers were washed with two 50 mL portions of saturated aqueous sodium bicarbonate, 50 mL of brine, dried over magnesium sulfate, filtered, and concentrated to afford 6.7 g (76%) of 4-bromo-2-hydroxy-2-trifluoromethylpent-4-enoic acid ethyl ester as a yellow oil which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(O)(C(F)(F)F)=O.[CH2:19]([N:26]([CH2:30][Si](C)(C)C)[CH2:27]OC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH2:19]([N:26]1[CH2:30][C@@H:3]([C:2]([F:10])([F:11])[F:1])[C@H:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of (E)-ethyl 4,4,4-trifluorobut-2-enoate (100 g, 0.6 mol) in DCM (1.8 L) was added dropwise TFA (20.52 g, 0.18 mol) at 0° C. and then N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (170.64 g, 0.72 mol) was added and the resulting mixture was stirred at rt overnight. The reaction mixture was washed with sat. aqueous NaHCO3 (two×500 mL), dried over Na2SO4 and concentrated in vacuo and the residue was purified by silica column chromatography eluted with petroleum ether/EtOAc=100:1 to give the title compound (142 g, 79% yield) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=2)=[CH:5][CH:4]=1.[H][H]>C(O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: COc1ccc(C2=CC(=O)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C2CCC(=O)C2)cc1
Reaction time: 4 h
Yield: 52.1 %

Procedure:
3-(4-Methoxyphenyl)-2-cyclopenten-1-one (11.2 g) was dissolved in ethanol, and 10% palladium-carbon (1.1 g) was added thereto. After substituting the reaction vessel with hydrogen gas, hydrogen addition was carried out at normal pressure, 40° C. for 4 hours. After the reaction, the catalyst was filtered off and the solvent was distilled off under reduced pressure to produce a light yellow oily substance which was then purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to give 5.90 g of 3-(4-methoxyphenyl) cyclopentanone (52.2% yield).
Reaction SMILES: [C:1]1([C:7](=[N:14][C:15]2[CH:16]=[C:17]([C:21]([C:23]3[C:31]4[CH:30]=[N:29][CH:28]=[N:27][C:26]=4[NH:25][CH:24]=3)=[O:22])[CH:18]=[N:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].FC(F)(F)S(O[CH:44]([CH2:54][O:55][Si:56]([CH3:62])([CH3:61])[C:57]([CH3:60])([CH3:59])[CH3:58])[CH2:45][O:46][Si:47]([CH3:53])([CH3:52])[C:48]([CH3:51])([CH3:50])[CH3:49])(=O)=O>CN(C=O)C>[C:1]1([C:7](=[N:14][C:15]2[CH:16]=[C:17]([C:21]([C:23]3[C:31]4[CH:30]=[N:29][CH:28]=[N:27][C:26]=4[N:25]([CH:44]([CH2:45][O:46][Si:47]([CH3:53])([CH3:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:54][O:55][Si:56]([CH3:62])([CH3:61])[C:57]([CH3:60])([CH3:58])[CH3:59])[CH:24]=3)=[O:22])[CH:18]=[N:19][CH:20]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1cncc(N=C(c2ccccc2)c2ccccc2)c1)c1c[nH]c2ncncc12
Reactant: CC(C)(C)[Si](C)(C)OCC(CO[Si](C)(C)C(C)(C)C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (5-((Diphenylmethylene)amino)pyridin-3-yl)(7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Preparation 195, 1120 mg, 2.77 mmol) and Cs2CO3 (2710 mg, 8.31 mmol) in DMF (10 mL) was stirred at room temperature for 30 min. A solution of crude 2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-yl trifluoromethanesulfonate (Preparation 108) in DMF (3.8 mL) was then added to the reaction and the resulting mixture stirred at room temperature for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (100 mL) and the mixture extracted with EtOAc (100 mL×3). The combined organic layers were washed with water (200 mL), dried over sodium sulfate and concentrated in vacuo. The resulting material was purified by column chromatography on silica gel (gradient of heptane:EtOAc 100:0 to 50:50) to provide (5-((diphenylmethylene)amino)pyridin-3-yl)(7-(2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH2:36]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:36][CH2:35][C:34]1[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=1[O:32][CH3:31])=[O:29]
Reactant: COc1ccccc1CN
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3c(OC)ccc(OC)c32)cc1OC
Product: COc1ccccc1CNC(=O)CN1CCc2c(OC)ccc(OC)c2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-methoxybenzylamine
Reaction SMILES: O.NN.[F:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]#[C:13][CH2:14][CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)[CH:9]=[CH:8][CH:7]=1.C(Cl)Cl>CCO>[F:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]#[C:13][CH2:14][CH2:15][NH2:16])[CH:9]=[CH:8][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCC#Cc1cccc(CF)n1
Agent: NN
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: NCCC#Cc1cccc(CF)n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 63.5 %

Procedure:
Hydrazine hydrate (1.0 mL, 5.2 mmol) was added to a solution of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione (320 mg, 1.04 mmol) in EtOH (3 mL) and the reaction mixture was stirred for 4 hours at 50° C. The mixture was cooled down, DCM was added and the aqueous phase was extracted. The organic phase was washed with saturated solution of NaHCO3, dried over Na2SO4, filtered and concentrated to yield 117 mg (0.66 mmol, 63%) of 4-(6-(fluoromethyl)pyridin-2-yl)but-3-yn-1-amine as a white solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C@:3]([C:7]1[N:8]=[N:9][N:10]([CH2:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[CH:18][C:19]([CH:23]([OH:25])[CH3:24])=[N:20]3)=[CH:15][CH:14]=2)[CH:11]=1)([OH:6])[CH2:4][CH3:5].I[CH3:36].[H-].[Na+]>C1COCC1>[F:34][C:2]([F:1])([F:33])[C@:3]([C:7]1[N:8]=[N:9][N:10]([CH2:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17]([C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)=[CH:18][C:19]([CH:23]([O:25][CH3:36])[CH3:24])=[N:20]3)=[CH:15][CH:14]=2)[CH:11]=1)([OH:6])[CH2:4][CH3:5]
Reactant: CI
Reactant: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(C(C)O)nc3c2)nn1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(C(C)OC)nc3c2)nn1)C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of (S)-1,1,1-trifluoro-2-(1-{[4-(4-fluorophenyl)-2-(1-hydroxyethyl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)butan-2-ol (33 mg, 0.070 mmol) in THF (1 mL) was added iodomethane (5 μL, 0.077 mmol) and sodium hydride 60% in oil (6 mg, 0.15 mmol). After 2 h at rt, the reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with acetone/dichloromethane, 2:8) gave the title compound. MS (+ESI): 490 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[H-].[Na+].CS(O[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[S:21][C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24](=[O:26])[N:25]=2)[N:15]=1)(=O)=O.[C:31](OCC)(=O)C>CN(C=O)C.O>[O:26]=[C:24]1[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[S:21][C:20]([C:16]2[N:15]=[C:14]([CH2:31][S:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH:19]=[CH:18][CH:17]=2)=[N:25]1
Reactant: CCOC(C)=O
Reactant: CS(=O)(=O)Oc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CSCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
Methyl thioglycolate (0.35 g, 3.30 mmol) and sodium hydride (60% in oil, 0.15 g, 3.60 mmol) were dissolved in DMF (30 ml), and 6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl methanesulfonate (1.05 g, 3.00 mmol) was added thereto. The reaction mixture was stirred at room temperature for 18 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was recrystallized from ethanol to give the titled compound (0.55 g, 51%) as pale yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19]([O:26][C:27]([C:29]1[O:30][C:31]([CH:34]=O)=[CH:32][CH:33]=1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([O:26][C:27]([C:29]1[O:30][C:31]([CH:34]=[CH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:16])=[CH:32][CH:33]=1)=[O:28])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=Cc1ccc(C(=O)OCc2ccccc2)o1
Temperature: 0 °C
Yield: 87.8 %

Procedure:
A solution of diethylphosphonoacetic acid tert-butyl ester (1.54 g, 6.09 mmol) in tetrahydrofuran (3 mL) was added dropwise to a suspension of 60% sodium hydride (0.19 g, 4.87 mmol) in tetrahydrofuran (50 mL) with stirring at 0° C. After stirring at room temperature for 20 minutes, a solution of 5-formyl-2-furancarboxylic acid benzyl ester (1.0 g, 4.06 mmol) in tetrahydrofuran (3 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was worked up according to a conventional method, and the object product was extracted by column chromatography (10-30% ethyl acetate/hexane mixed solvent) to give the title compound (1.17 g)
Reaction SMILES: C(Br)C1C=CC=CC=1.[F:9][C:10]([F:21])([F:20])[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.[CH3:22][C:23]1[N:24]=[C:25]([N:33]2[CH2:37][CH2:36][NH:35][C:34]2=[O:38])[S:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH3:22][C:23]1[N:24]=[C:25]([N:33]2[CH2:37][CH2:36][N:35]([CH2:16][C:15]3[CH:18]=[CH:19][C:12]([O:11][C:10]([F:21])([F:20])[F:9])=[CH:13][CH:14]=3)[C:34]2=[O:38])[S:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: BrCc1ccccc1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)nc1C
Yield: 90 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with 4-(trifluoromethoxy)benzyl bromide to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 90% yield: 1H NMR (300 MHz, DMSO-d6) δ 7.32 (d, J=8.7 Hz, 2H), 7.18 (d, J=8.7 Hz, 2H), 4.48 (s, 2H), 4.27 (q, J=7.2 Hz, 2H), 4.08 (t, J=7.8 Hz, 2H), 3.46 (t, J=7.8 Hz, 2H), 2.60 (s, 3H), 1.32 (t, J=7.2 Hz, 3H); MS (ES+) m/z 430.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].I[C:13]1[CH:14]=[C:15]([CH:37]=[CH:38][CH:39]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[C:21]([C:33]([F:36])([F:35])[F:34])[CH:20]=1)=[O:17]>>[N:5]1[CH:4]=[C:3]([C:1]#[C:2][C:13]2[CH:14]=[C:15]([CH:37]=[CH:38][CH:39]=2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[C:21]([C:33]([F:35])([F:34])[F:36])[CH:20]=2)=[O:17])[N:7]2[C:6]=1[CH:11]=[CH:10][CH:9]=[N:8]2
Reactant: C#Cc1cnc2cccnn12
Reactant: CN1CCN(Cc2ccc(NC(=O)c3cccc(I)c3)cc2C(F)(F)F)CC1
Product: CN1CCN(Cc2ccc(NC(=O)c3cccc(C#Cc4cnc5cccnn45)c3)cc2C(F)(F)F)CC1

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine and 3-iodo-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for Example 14, The product was obtained as a solid: 519 m/z (M+H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11]([N+]([O-])=O)=[N:10][C:9]=3[N:8]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:6]2=[O:7])[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:25])=O.O>CN(C)C=O>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11]([Cl:25])=[N:10][C:9]=3[N:8]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:6]2=[O:7])[CH2:3][CH2:2]1
Reactant: O=c1c2[nH]c([N+](=O)[O-])nc2n(CC2CC2)c(=O)n1CC1CC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2[nH]c(Cl)nc2n(CC2CC2)c(=O)n1CC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,3-Di-cyclopropylmethyl-8-nitro xanthine (6 g, 0.023 mol) was dissolved in dimethylformamide (20 ml) and reacted with phosphorus oxychloride (14 g), for 1 hour at 120° C. The mixture was then treated with water and stirred for 1 hour at room temperature. The precipitate was filtered off, dissolved in ethyl acetate, dried over anhydrous sodium sulphate and the solvent was removed in vacuo, yield 2.5 g (40%), m.pt. 220° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:8]([O:28][CH3:29])=[C:9]([NH:11][C:12](=[O:27])[NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24](O)=[O:25])=[CH:16][CH:15]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[CH3:64][O:65][C:66](=[O:74])[CH2:67][CH:68]1[O:73][CH2:72][CH2:71][NH:70][CH2:69]1>CN(C=O)C>[CH3:64][O:65][C:66](=[O:74])[CH2:67][CH:68]1[O:73][CH2:72][CH2:71][N:70]([C:24]([C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]([NH:13][C:12]([NH:11][C:9]3[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=[C:7]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:8]=3[O:28][CH3:29])=[O:27])=[CH:15][CH:16]=2)=[O:25])[CH2:69]1
Reactant: COc1c(NC(=O)Nc2ccc(C(=O)O)c3ccccc23)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: COC(=O)CC1CNCCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CC1CN(C(=O)c2ccc(NC(=O)Nc3cc(C(C)(C)C)cc(NS(C)(=O)=O)c3OC)c3ccccc23)CCO1
Reaction time: 0.08 h
Yield: 61.8 %

Procedure:
95 mg (0.24 mmol) of 4-[3-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-ureido]-naphthalene-1-carboxylic acid (Example 17) was dissolved in 1 mL of DMF. To this clear solution was added sequentially, 139 mg (0.44 mmol) of TBTU, and 102 microL (0.73 mmol) of triethylamine. The clear yellow solution was stirred for 5 min, then 50 mg (0.31 mmol) of morpholin-2-yl-acetic acid methyl ester (Loftus, F. Syn. Commun. 1980, 10, 59) was added. The reaction was stirred overnight, then concentrated in vacuo. The resulting amber oil was extracted with EtOAc and water, brine, and then dried over magnesium sulfate. Concentration in vacuo provide an amber oil which was purified on silica gel, eluting with 5% MeOH-methylene chloride to provide 93 mg (72%) of the title compound as a viscous oil.
Reaction SMILES: Cl.C(OC(=O)NC1(C(=O)NC2(C(=N)N)CC2)CC1)(C)(C)C.[C:22]([O:26][C:27](=[O:34])[NH:28][C:29]1([C:32]#[N:33])[CH2:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23].C(OC(=O)NC1(C(=O)NC2(C(=N)N)CC2)CC1)(C)(C)C.[Br:55][C:56](=[CH:59][N:60](C)C)[CH:57]=O>CCO.CO>[C:22]([O:26][C:27](=[O:34])[NH:28][C:29]1([C:32]2[N:60]=[CH:59][C:56]([Br:55])=[CH:57][N:33]=2)[CH2:31][CH2:30]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1(C#N)CC1
Reactant: CN(C)C=C(Br)C=O
Agent: CC(C)(C)OC(=O)NC1(C(=O)NC2(C(=N)N)CC2)CC1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2ncc(Br)cn2)CC1
Temperature: 80 °C

Procedure:
[1-(1-Carbamimidoyl-cyclopropylcarbamoyl)-cyclopropyl]-carbamic acid tert-butyl ester hydrochloride (1.0 g, 4.2 mmol) (made from (1-cyano-cyclopropyl)-carbamic acid tert-butyl ester using a procedure similar to that of [1-(1-carbamimidoyl-cyclopropyl-carbamoyl)-cyclopropyl]-carbamic acid tert-butyl ester) and 2-bromo-3-dimethylamino-acrolein (1.1 g, 6.36 mmol) were combined in EtOH (2 mL) in a sealed tube. The reaction was capped and the mixture heated at 80° C. for 24 hours. The resulting black mixture was allowed to cool to room temperature. Methanol (20 mL) was then added to the reaction solution. The solids were filtered and the resulting solution was dried under reduced pressure. The residue was diluted with 50 mL CH2Cl2 and the solids were removed. The solution was concentrated and purified by normal phase flash chromatography on silica gel (0→50% EtOAc in hexanes) to give 800 mg of [1-(5-bromo-pyrimidin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester as an off-white solid.