Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>[Pd].C(O)C>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=4)[NH:13][CH:12]=3)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: Fc1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Agent: [Pd]
Solvent: CCO
Product: Fc1ccc2[nH]cc(C3CCC4(CC3)OCCO4)c2c1
Reaction time: 5 h
Yield: 88.2 %

Procedure:
A mixture of of 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-5-fluoro-1H-indole (8.5 g) and 10% palladium on carbon (2.72 g) in ethanol (200 ml) was hydrogenated for 5 hours. The catalyst was filtered off and the solvent removed under vacuum. Chromatography (methanol-methylene chloride) afforded 7.55 g (82%) of product as a white solid: mp 183-185° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[I:5][C:6]1[C:7]([OH:16])=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([CH:13]=1)[CH:11]=[O:12].C(=O)([O-])[O-].[K+].[K+].CCCCCC.C(OCC)(=O)C>CN(C=O)C>[I:5][C:6]1[C:7]([O:16][CH2:1][CH2:2][CH3:3])=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([CH:13]=1)[CH:11]=[O:12]
Reactant: COc1cc(C=O)cc(I)c1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCCOc1c(I)cc(C=O)cc1OC

Procedure:
n-Propyl bromide (29.2 mL, 0.32 mol) was added to a solution of 5-iodovanillin (50.0 g, 0.18 mol) in DMF (200 mL) containing potassium carbonate (48 g, 0.35 mol) at 80° C. The mixture was stirred at 80° C. for 1-1.5 hours or until TLC (SiO2, 4:1 [v/v] hexane-ethyl acetate) showed the reaction to be complete. The mixture was cooled and the solvent was decanted into ice-water (1 L). The product was extracted with ether and the ethereal layer was washed with water, dried over sodium sulfate, and evaporated in vacuo to an oil, which was used without further purification. Anal. calc. for C11H15IO3 : C, 41.27; H, 4.09. Found: C, 41.59; H, 4.15.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([CH:12]([F:14])[F:13])=[C:7]([CH:11]=1)[C:8](O)=[O:9])#[N:2].C[N:16](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[N:5][C:6]([CH:12]([F:14])[F:13])=[C:7]([CH:11]=1)[C:8]([NH2:16])=[O:9])#[N:2]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: N#Cc1cnc(C(F)F)c(C(=O)O)c1
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cnc(C(F)F)c(C(N)=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution of 5-cyano-2-(difluoromethyl)nicotinic acid (0.600 g, 3.0 mmol) in dry DMF (20 mL), TBTU (10.0 g, 3.33 mmol) was added at 0° C. followed by slow addition of DIPEA (0.7 mL, 3.93 mmol). The reaction mass was stirred at 0° C. for 1 h and ammonium chloride (3.33 g, 60.7 mmol) was added. The reaction mass was stirred at RT for 30-48 h. After completion of reaction quenched the reaction mass with DCM, filtered off solid to afford 0.500 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 8.16 (m, 1H), 8.63 (s, 1H), 9.22 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:18])[CH2:12][C:13]([O:15]CC)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[Li+].[OH-].Cl>CO>[CH2:1]([O:8][C:9]([N:11]([CH3:18])[CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(C)C(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(CC(=O)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of ethyl 2-(((benzyloxy)carbonyl)(methyl)amino)acetate (2.66 mg, 10.6 mmol, prepared the previous step) in MeOH (24 mL) and THF (5 mL) and treated with a solution of LiOH (12 mL, 54 mmol, 4.52 M in water). After stirring at room temperature for 3 hours, the pH was adjusted to ˜5 by the addition of aqueous HCl. After extraction with ethyl acetate, the organic layer was dried over Na2SO4 and concentrated in vacuo to yield the product.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH:18][CH3:19])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][N:9]=1.C(N(CC)CC)C.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>ClCCl>[Cl:3][C:4]1[C:5]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:18]([CH3:19])[S:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:35])=[O:34])[CH2:14][CH2:15]2)=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: CNCCN1CCN(c2nccnc2Cl)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCN1CCN(c2nccnc2Cl)CC1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve [2-(3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-ethyl]-methyl-amine dihydrochloride salt (2.0 g, 6.09 mmol) in dichloromethane (50 mL). Add triethylamine (3.39 mL, 24.4 mmol), and benzenesulfonylchloride (854 μL, 6.69 mmol). Stir at ambient temperature for 18 hr. Add dichloromethane and aqueous 1 N HCl solution. Separate the organic layer and extract the aqueous layer twice with dichloromethane. Combine the organic layers and dry (magnesium sulfate), filter, and concentrate. Purify via SCX chromatography, followed by silica gel chromatography (100:0 to 0:100 hexanes:ethyl acetate) to give the title preparation (1.88 g, 78%). MS (ES): m/z=396 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O1CCCC1.[C:24]([C:26]1[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=4)[O:17][N:16]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cc2ccc(CC(Cl)=NO)cc2)o1
Reactant: C#Cc1ccc(N)nc1N
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(Cc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)cc2)o1
Temperature: 40 °C
Reaction time: 3 h
Yield: 75.1 %

Procedure:
To a mixture of (4-(5-methyl-furan-2-ylmethyl)-phenyl)-acetohydroximoyl chloride (11 mg, 0.043 mmol) described in Manufacturing Example 46-1-6 and tetrahydrofuran (1 mL) were added 3-ethynyl-pyridin-2,6-diamine (4.5 mg, 0.034 mmol) described in Manufacturing Example 13-1-3 and triethylamine (9.4 μL, 0.068 mmol), which was stirred for 3 hours at 40° C. Water was added thereto at the same temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane=3:2) to obtain the title compound (9.2 mg, 76%).
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][NH:13][CH2:14][C:15]1[N:16]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:17]=[CH:18][N:19]=1.[CH:30]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)=[O:31]>>[CH:30]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([N:13]([CH2:14][C:15]2[N:16]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:17]=[CH:18][N:19]=2)[CH2:12][C:8]2[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:29])([CH3:28])[CH3:1])[CH:11]=[CH:10][N:9]=2)=[O:37])=[CH:34][CH:33]=1)=[O:31]
Reactant: C[Si](C)(C)CCOCn1ccnc1CNCc1nccn1COCC[Si](C)(C)C
Reactant: O=Cc1ccc(C(=O)O)cc1
Product: C[Si](C)(C)CCOCn1ccnc1CN(Cc1nccn1COCC[Si](C)(C)C)C(=O)c1ccc(C=O)cc1

Procedure:
The same procedure as a series of reactions of Example 17 was carried out, except that the compound 2 was used in place of the compound 16 and 4-formylbenzoic acid was used in place of 1H-imidazole-2-carboxylic acid, to obtain the title compound having the following physical properties.
Reaction SMILES: [C:1]([C:5]1([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([C:23]3[O:24][C:25]4[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][C:26]=4[CH:27]=3)([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][C:13]=2[CH3:35])[O:9][CH2:8][CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.Cl.C[O:42][C:43](=[O:46])[CH2:44][NH2:45]>CN(C1C=CN=CC=1)C>[C:1]([C:5]1([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([C:23]3[O:24][C:25]4[CH:31]=[CH:30][C:29]([C:32]([NH:45][CH2:44][C:43]([OH:46])=[O:42])=[O:33])=[CH:28][C:26]=4[CH:27]=3)([CH2:19][CH3:20])[CH2:21][CH3:22])=[CH:14][C:13]=2[CH3:35])[O:9][CH2:8][CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CN
Reactant: CCC(CC)(c1ccc(OCC2(C(C)(C)C)OCCO2)c(C)c1)c1cc2cc(C(=O)O)ccc2o1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC2(C(C)(C)C)OCCO2)c(C)c1)c1cc2cc(C(=O)NCC(=O)O)ccc2o1
Yield: 89.4 %

Procedure:
2-{1-[4-(2-tert-butyl-[1,3]dioxolan-2-ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-5-carboxylic acid (125 mg, 0.260 mmol), EDC (75 mg, 0.391 mmol), DMAP (95 mg, 0.781 mmol), and glycine methyl ester hydrochloride (49 mg, 0.39 mmol) are reacted to produce the intermediate followed by hydrolysis analogous to Example 1, step K to give title compound (125 mg, 90%).
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O=C1[N:21](CCC(C)C)[C:20]2[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=2[N:18]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)C(=O)C1=NNC1C=CC=CC=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[C:1]12([C:11]([NH:21][C:20]3[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=3[NH:18][CH2:31][C:32]3[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COc1ccc(Cn2c(=O)c(=NNc3ccccc3)c(=O)n(CCC(C)C)c3ccccc32)cc1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2ccccc2NC(=O)C23CC4CC(CC(C4)C2)C3)cc1
Yield: 151.4 %

Procedure:
1-Adamantanecarbonyl chloride (1.91 g )) was dropped into a solution of intermediate 2 (1.83 g ) and triethylamine (1.45 ml) in dry THF (100 ml at 23°, under a nitrogen atmosphere. The mixture was stirred at reflux for 3 h, allowed to cool to 20°, then diluted with ethyl acetate (120 ml) washed with brine (150 ml), dried, and concentrated in vacuo. This material (3.21 g) was crystallised from DCM/CH to give the title compound as a white solid (2.3 g). T.l.c. CH-EA (8:2), Rf 0.34 IR:3393, 3304 (NH) cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]12[CH2:15][O:14][C:13]2[CH:16]=[C:17]3[C:21](=[CH:22][C:12]1=2)[CH2:20][CH2:19][O:18]3.N1C2C(=CC=CC=2)[C:25]2([C:35]3=CC4OCOC=4[CH:42]=[C:34]3[O:33][CH2:32]2)C1=O.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:42][C@H:34]1[CH2:35][CH2:25][CH2:32][O:33]1)[C:8](=[O:11])[C:7]12[CH2:15][O:14][C:13]2[CH:16]=[C:17]3[C:21](=[CH:22][C:12]1=2)[CH2:20][CH2:19][O:18]3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: O=C1Nc2c(Cl)cccc2C12COc1cc3c(cc12)CCO3
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Product: O=C1N(C[C@H]2CCCO2)c2c(Cl)cccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 7′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 7′-chloro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (98%) as a colorless solid: mp 192-193° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 7.23-7.18 (m, 1H), 7.08-6.98 (m, 2H), 6.53 (d, J=17.6 Hz, 1H), 6.42 (d, J=2.0 Hz, 1H), 4.80-4.69 (m, 2H), 4.53-4.47 (m, 2H), 4.20-4.11 (m, 1H), 3.95-3.60 (m, 4H), 2.99-2.93 (m, 2H), 2.04-1.59 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ177.7, 177.6, 161.1 (2C), 160.5, 160.3, 138.3, 138.0, 135.8, 135.4, 130.7, 130.6, 124.1, 122.7, 122.6, 120.5, 120.2, 119.9, 119.8, 119.2, 118.8, 114.3, 114.2, 92.4, 92.2, 80.0, 76.3, 76.1, 72.0, 72.0, 67.2, 66.9, 56.7, 56.5, 45.0, 44.9, 28.3, 28.2, 24.9, 24.9; MS (ES+) m/z 397.7 (M+1), 399.7 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14].N1C=CN=C1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14]
Reactant: Oc1ccc2ccccc2c1Br
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)[Si](Oc1ccc2ccccc2c1Br)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 99.1 %

Procedure:
1-Bromo-2-naphthol (5.00 g, 22.4 mmol) was mixed with triisopropylsilyl chloride (7.2 mL, 33.6 mmol), DMAP (402 mg, 3.30 mmol), imidazole (3.81 g, 56.0 mmol), and pyridine (6 mL) in CH2Cl2 (50 mL). The reaction was refluxed for two hours. TLC analysis (silica, 15% EtOAc-hexanes) indicated the reaction was complete. The reaction was allowed to cool to room temperature and then was diluted with H2O. The dilution was extracted three times with CH2Cl2. The organic extracts were combined, washed with brine solution, dried over Na2SO4, filtered through celite, and concentrated. The crude product was purified by flash chromatography (SiO2, 100% hexanes) to give (1-bromo-naphthalen-2-yloxy)-triisopropyl-silane (8.4 g, 22.2 mmol) as a colorless oil in 99% yield. 1H NMR (300 MHz) CDCl3 8.21 (d, J=7.5 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.54 (m, 1H), 7.38 (m, 1H), 7.15 (d, J=8.8 Hz, 1H), 1.38 (m, 3H), 1.16 (d, J=7.1 Hz, 18H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]=[C:6]1[CH2:10][C@H:9]([CH3:11])[C@H:8]([CH3:12])[CH2:7]1)[CH3:2].[N+:14]([CH3:17])([O-:16])=[O:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1([CH2:17][N+:14]([O-:16])=[O:15])[CH2:7][C@@H:8]([CH3:12])[C@H:9]([CH3:11])[CH2:10]1)[CH3:2]
Reactant: CCOC(=O)C=C1C[C@@H](C)[C@@H](C)C1
Reactant: C[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(C[N+](=O)[O-])C[C@@H](C)[C@H](C)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.3 %

Procedure:
The unsaturated ester (2) (1.384 g, 7.60 mmol) was dissolved in tetrahydrofuran (10 mL) and stirred at 70° C. with nitromethane (0.82 mL, 15.2 mmol) and tetrabutylammonium fluoride (1.0M in tetrahydrofuran, 11.4 mL, 11.4 mmol). After 6 hours, the mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and washed with 2N HCl (30 mL) followed by brine (50 mL). The organic phase was collected, dried (MgSO4), and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate:heptane 5:95) to give 0.837 g (45%) of a clear oil.
Reaction SMILES: C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[NH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([NH:23][C:24]2[CH:25]=[C:26]([N:43]([CH:53]3[CH2:55][CH2:54]3)CC3C=CC(OC)=CC=3)[C:27]3[N:28]([C:30]([C:33]([NH:35][C:36]4[CH:41]=[CH:40][N:39]=[CH:38][C:37]=4[F:42])=[O:34])=[CH:31][N:32]=3)[N:29]=2)[CH2:19][CH2:18]1.[N:56]1([C:62](OC(C)(C)C)=[O:63])[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1.C(O)(C(F)(F)F)=O>ClCCl.CN(C1C=CN=CC=1)C>[CH:53]1([NH:43][C:26]2[C:27]3[N:28]([C:30]([C:33]([NH:35][C:36]4[CH:41]=[CH:40][N:39]=[CH:38][C:37]=4[F:42])=[O:34])=[CH:31][N:32]=3)[N:29]=[C:24]([NH:23][C@H:20]3[CH2:21][CH2:22][C@H:17]([NH:16][C:62]([N:56]4[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]4)=[O:63])[CH2:18][CH2:19]3)[CH:25]=2)[CH2:54][CH2:55]1
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)C2CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccncc1F)c1cnc2c(NC3CC3)cc(N[C@H]3CC[C@H](NC(=O)N4CCNCC4)CC3)nn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To di-tert-butyl dicarbonate (10.66 μL, 0.046 mmol) in dichloromethane (1 mL) was added DMAP (2.80 mg, 0.023 mmol) followed by 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (25 mg, 0.046 mmol, 83A). The clear yellow solution was stirred at room temperature for 10 minutes then tert-butyl piperazine-1-carboxylate (8.55 mg, 0.046 mmol) was added, and stirred at room temperature for 1 hr. TFA (0.5 mL) was added, and after 10 minutes, the reaction mixture was concentrated to dryness, taken up in DMSO and methanol and purified using reverse phase HPLC to isolate 8-(cyclopropylamino)-N-(3-fluoropyridin-4-yl)-6-((trans)-4-(piperazine-1-carboxamido)cyclohexylamino)imidazo[1,2-b]pyridazine-3-carboxamide (22 mg, 0.027 mmol, 59.5% yield) as a white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.39 minutes [M+H]=537.37. 1H NMR (500 MHz, METHANOL-d3) δ ppm 8.90 (1H, t, J=6.64 Hz), 8.76 (1H, d, J=3.67 Hz), 8.50 (1H, d, J=5.96 Hz), 8.05-8.22 (1H, m), 6.11 (1H, s), 3.84-4.03 (1H, m), 3.61-3.72 (4H, m), 3.58 (1H, t, J=10.77 Hz), 3.14-3.27 (4H, m), 2.51-2.62 (1H, m, J=6.76, 6.76, 3.67, 3.44 Hz), 2.19 (2H, d, J=12.37 Hz), 1.98 (2H, d, J=13.29 Hz), 1.21-1.69 (4H, m), 0.84-1.05 (2H, m), 0.51-0.71 (2H, m)
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17]Br.Cl>CS(C)=O.CS(C)=O.CCOCC.O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]#[N:12])[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: BrCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: N#CC1(c2ccc(Br)cc2)CCCC1
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a suspension of NaH (2.55 g, 63.75 mmol, 60%) in dimethyl sulfoxide (50 mL) were added dropwise a mixture of 4-bromophenyl-acetonitrile (223) (5 g, 25.51 mmol) and 1,4-dibromobutane (3.04 mL, 25.51 mmol) dissolved in dimethyl sulfoxide:ether (1:1) (50 mL) at 0° C. and the reaction mixture was stirred at this temperature for 2 h. After completion of the reaction, water (20 mL) and 10% HCl solution (50 mL) were added to the mixture and the mixture was extracted with ethyl acetate (2×200 ml). The organic layer was dried over Na2SO4, concentrated and purified by 100-200 silica column chromatography using hexane as the eluent to give 1-(4-bromophenyl)-cyclopentanecarbonitrile (224) (5.7 g, 89%) as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH:5]=[C:4]([Cl:16])[N:3]=1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=1)([O-:19])=[O:18].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[Cl:16][C:4]1[N:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH:5]=1.[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH:5]=[C:4]([C:23]2[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)[N:3]=1
Reactant: Clc1cc(N2CC3CCC(C2)O3)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-c2cc(N3CC4CCC(C3)O4)nc(Cl)n2)cc1
Product: O=[N+]([O-])c1ccc(-c2nc(Cl)cc(N3CC4CCC(C3)O4)n2)cc1
Yield: 10 %
Yield: 8 %

Procedure:
3-(2,6-Dichloropyrimidin-4-yl)-8-oxa-3-aza-bicyclo[3.2.1]octane (9) was dissolved in toluene (24 mL) and EtOH (16 mL). To this solution was added 4-nitrophenylboronic acid pinacol ester (1.25 g, 5 mmol) and 8 mL of a 2M solution of Na2CO3. The mixture was degassed by bubbling nitrogen through the solution. Pd(PPh3)4 (231 mg, 0.2 mmol) was added and the mixture was heated under reflux overnight. The mixture was filtered. The solids, consisting of 3-[2,6-bis-(4-nitro-phenyl)-pyrimidin-4-yl]-8-oxa-3-aza-bicyclo[3.2.1]octane (15), were collected and washed with water and dichloromethane. The combined filtrates were concentrated, dissolved in dichloromethane and washed with saturated NaHCO3. The organic phase was dried (MgSO4), filtered and concentrated. The crude product was added to a silica gel column and was eluted with 10-50% ethyl acetate in hexanes. Collected fractions were concentrated to give 3-[6-chloro-2-(4-nitro-phenyl)-pyrimidin-4-yl]-8-oxa-3-aza-bicyclo[3.2.1]octane (13, 135 mg, 10%) along with 3-[2-chloro-6-(4-nitro-phenyl)-pyrimidin-4-yl]-8-oxa-3-aza-bicyclo[3.2.1]octane (14, 110 mg, 8%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](CC3C=C(C=CC=3)C(O)=O)[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[C:4](OCC2CCCC2)[CH:3]=1.FC1C=C(N)C(N)=CC=1F.[CH3:46][O:47][C:48](=[O:58])C1C(=CC=CC=1)C(O)=O>>[CH3:46][O:47][C:48](=[O:58])[C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=1[C:8]1[NH:9][C:10]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:11]=2[N:12]=1
Reactant: COC(=O)c1ccccc1C(=O)O
Reactant: O=C(O)c1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1
Agent: Nc1cc(F)c(F)cc1N
Product: COC(=O)c1ccccc1-c1nc2cc(F)c(F)cc2[nH]1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate c, from 4,5-difluoro-benzene-1,2-diamine (CAS Reg. No. 76179-40-3) and phthalic acid monomethyl ester (CAS Reg. No. 4376-18-5). Off-white powder (12%). MS (Turbo Spray): m/z=289.0 (M+H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:23]1[N:28]([CH3:29])[C:27](=[O:30])[CH:26]=[C:25]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[N:24]=1>O1CCCC1>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([C:23]3[N:28]([CH3:29])[C:27](=[O:30])[CH:26]=[C:25]([C:31]4[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=4)[N:24]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: Brc1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCC(c3ccc(Br)cc3)CC2)nc(-c2ccncc2)cc1=O
Yield: 93.1 %

Procedure:
A solution of (4-(4-bromophenyl)-piperidine hydrochloride (279 mg, 1.01 mmol) and triethylamine (554 mg, 5.47 mmol), 2-chloro-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (206 mg, 0.929 mmol) in tetrahydrofuran (20 mL) was stirred for 3 hr. The resulting solution was diluted with tetrahydrofuran and filtrated. After removal of the solvents under reduced pressure and the purification of the resulting residue by CHEM ELUT CE1010 (manufactured by VARIAN) eluting dichloromethane/ethanol (15/1, v/v) and wash with ethyl acetate afforded 2-(4-(4-Bromophenyl)-piperidin-1-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (368 mg, 93%) as a solid.