Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:32]=[N:31][C:18]3[N:19]([CH2:28][CH2:29][CH3:30])[CH2:20][CH2:21][CH2:22][C:23]([C:25](O)=[O:26])=[CH:24][C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH2:44]([N:47]1[C:51]([CH2:52][S@@:53]([C:55]2[CH:61]=[CH:60][C:58]([NH2:59])=[CH:57][CH:56]=2)=[O:54])=[CH:50][N:49]=[CH:48]1)[CH2:45][CH3:46]>ClCCl.O1CCCC1.O.N1C=CC=CC=1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:32]=[N:31][C:18]3[N:19]([CH2:28][CH2:29][CH3:30])[CH2:20][CH2:21][CH2:22][C:23]([C:25]([NH:59][C:58]4[CH:60]=[CH:61][C:55]([S@:53]([CH2:52][C:51]5[N:47]([CH2:44][CH2:45][CH3:46])[CH:48]=[N:49][CH:50]=5)=[O:54])=[CH:56][CH:57]=4)=[O:26])=[CH:24][C:17]=3[CH:16]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCn1cncc1C[S@](=O)c1ccc(N)cc1
Reactant: CCCCOCCOc1ccc(-c2cnc3c(c2)C=C(C(=O)O)CCCN3CCC)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: CCCCOCCOc1ccc(-c2cnc3c(c2)C=C(C(=O)Nc2ccc([S@@](=O)Cc4cncn4CCC)cc2)CCCN3CCC)cc1
Reaction time: 0.5 h

Procedure:
(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline di-p-toluoyl-D-tartrate monohydrate (495 mg) was dissolved in ethyl acetate (5 ml) and 1 N hydrochloric acid (2.52 ml), followed by separation. To the aqueous layer was added an aqueous 25% potassium carbonate solution (2.52 ml), followed by extraction with 2-propanol-ethyl acetate (1:4) twice. The organic layers were combined, washed with saturated brine and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. To the resulting residue was added tetrahydrofuran, and then the solvent was again distilled off under reduced pressure to give (S)-(4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. Then, to a solution of 3-[4-(2-butoxyethoxy)phenyl]-10-propyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylic acid (250 mg) in dichloromethane (10 ml) were added a drop of DMF, and then oxalyl chloride (0.065 ml) at 0° C. The mixture was returned to room temperature and stirred for 30 minutes under a nitrogen atmosphere, and then the resulting solution was added dropwise to a solution of (S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and pyridine (1.2 ml) in tetrahydrofuran (10 ml) at 0° C. under a nitrogen atmosphere. The mixture was returned to room temperature and stirred overnight. Then, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water twice and saturated brine once, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the residue was separated and purified by basic silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=3:100) to give (S)-3-[4-(2-butoxyethoxy)phenyl]-10-propyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxamide (310 mg) (Compound 2) as a yellow amorphous material.
Reaction SMILES: [F-:1].[K+].[Cl-].[NH4+].[Cl:5][C:6]1[CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10][C:11]=1Cl>C1(C)C(C)=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10][C:11]=1[F:1]
Reactant: [F-]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc(F)c(Cl)c1
Yield: 71 %

Procedure:
In a 1-liter flange flask fitted with a distillation bridge and impeller stirrer, 240 g (4.1 mol) of potassium fluoride, 30 g (0.05 mol) of dimethyldi (ethoxypolyoxypropyl methyl ether)ammonium chloride and 30 g of xylene were introduced at 70° C. into the melt of 767 g (4.0 mol) of 3,4-dichloronitrobenzene, and the reaction suspension was azeotropically dried under reduced pressure up to 120° C. 498 g (2.84 mol) of 3-chloro-4-fluoronitrobenzene were isolated. Amount of 3-chloro-4-fluoronitrobenzene formed, according to GC analysis:
Reaction SMILES: [OH-].[K+].C(O)C.[F:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][C:8]=1[NH:20]C(=O)OC>O>[F:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][C:8]=1[NH2:20]
Reactant: COC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 25 °C
Yield: 97.1 %

Procedure:
4N potassium hydroxide aqueous solution (4.75 liters) was added to an ethanol solution (3 liters) of methyl N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)carbamate (2.25 kg, 7.85 mol) and the mixture was heated under reflux for 5 hours. After reaction, the reaction liquid was cooled to room temperature, water (5 liters) was added thereto, and this was extracted with toluene (5 liters×2). The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The drying agent was taken out by filtration, and the solvent was removed by distillation under reduced pressure to obtain an oily product of 2-fluoro-4-chloro-5-cyclopentyloxyaniline (1.75 kg, 7.62 mol). Yield: 98.3%. Spectral data and other data of the product are those as shown in Example 21.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][CH2:7][C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27](Cl)(=[O:29])=[O:28]>>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27]([NH:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:7][O:6][CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([F:1])[CH:3]=2)[N:13]=1)(=[O:29])=[O:28]
Reactant: Nc1cccc(COCc2cccc(F)c2)n1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1cccc(COCc2cccc(F)c2)n1

Procedure:
This material was prepared in analogy to example 1 from 6-(3-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.06 g) and 2,4-dichloro-6methyl-benzenesulfonyl chloride (0.074 g) as a yellow solid (0.12 g). MS (ESI−): 453.1 ([M−H]−).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH2:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)(C)(C)C.[NH:27]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([S:36](Cl)(=[O:38])=[O:37])[C:30]=2[CH:29]=[CH:28]1>>[CH3:25][CH:22]1[CH2:21][CH2:20][N:19]([C:17]([CH:8]([NH:7][S:36]([C:31]2[C:30]3[CH:29]=[CH:28][NH:27][C:35]=3[CH:34]=[CH:33][CH:32]=2)(=[O:37])=[O:38])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:18])[CH2:24][CH2:23]1
Reactant: O=S(=O)(Cl)c1cccc2[nH]ccc12
Reactant: CC1CCN(C(=O)C(CCc2cccnc2)NC(=O)OC(C)(C)C)CC1
Product: CC1CCN(C(=O)C(CCc2cccnc2)NS(=O)(=O)c2cccc3[nH]ccc23)CC1

Procedure:
Example 52 is prepared from 70 mg (0.19 mmol) of tert-butyl{1-[(4-methylpiperidin-1-yl)carbonyl]-3-pyridin-3-ylpropyl}carbamate and indole-4-sulfonyl chloride in the same manner as Example 49 (39 mg, 46% yield). ESI MS Calc. 440.2; Found: 441.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=1.O.[CH3:22][N:23](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([C:22]#[N:23])[CH:5]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(C#N)c(OS(=O)(=O)C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COC(=O)c1ccc(C#N)c(C#N)c1
Temperature: 100 °C

Procedure:
4-Cyano-3-(trifluoromethanesulfonyloxy)-benzoic acid methyl ester (from L-819,063 step 1, 4.92 g, 16 mmol) was dissolved in DMF (22.9 ml) and treated with Zn(CN)2 (1.3 g, 11.2 mmol). The reaction mixture was degassed by bubbling in argon for 1 hr. Pd(PPh3)4 (924 mg, 0.8 mmol) was then added and the reaction was heated to 100° C. for 15 hours. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (2×20 mL). The organic layer was washed with water (2×10 mL), 5% HCl (1×10 mL), brine (1×10 mL), dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (100% CH2Cl2) to yield the desired compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)=[CH:14][C:9]=2[O:8][C:7]=1[C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30])=[O:5])C.[OH-].[K+].Cl>CO.O.C1COCC1>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:22]([C:7]1[O:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:11][C:10]=2[C:6]=1[C:4]([OH:5])=[O:3])=[O:31]
Reactant: CCOC(=O)c1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(-c3cccc(C)c3)ccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(-c2ccc3c(C(=O)O)c(C(=O)c4ccc(Cl)cc4Cl)oc3c2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
To a solution of 2-(2,4-Dichloro-benzoyl)-6-m-tolyl-benzofuran-3-carboxylic acid ethyl ester from step 5 (91.3 mg, 0.20 mmol, 1 eq) in MeOH/H2O/THF (2 mL, ratio:1:1:1) solution was added potassium hydroxide (72.0 mg, 0.52 mmol, 2.6 eq). The reaction mixture was stirred at rt for 6 h. 2N HCl (500 uL) was added to the reaction mixture and the solvent was removed under reduced pressure. The residue was purified by pre-HPLC to afford an yellow solid (68 mg, 80%) as desired product. 1H-NMR (CDCl3): δ 8.58 (d, J=8.3 Hz, 1H), 7.75 (dd, J=1.5, 8.3 Hz, 1H), 7.69 (s, 1H), 7.57 (d, J=1.5 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.46 (dd, J=1.5, 8.3 Hz, 1H), 7.43 (m, 2H), 7.34 (t, 1H), 7.21 (d, J=8.3 Hz, 1H), 2.43 (s, 3H); LC-MS (MH+=425/427).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH2:23])=[O:22])[C:5]2[C:14]3[N:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:36].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>>[NH2:36][C:7]1[C:6]2[N:15]=[C:3]([CH2:1][CH3:2])[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH2:23])=[O:22])[C:5]=2[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: [NH4+]
Reactant: CCc1nc2cnc3cccnc3c2n1CCCCCC(N)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCc1nc2c(N)nc3cccnc3c2n1CCCCCC(N)=O
Reaction time: 0.25 h

Procedure:
A modification of the method described in Part F of Example 53 was used to treat 6-(2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)hexanamide (1.18 g, 3.8 mmol) with mCPBA (2.54 g of 70-77% purity) followed by ammonium hydroxide (4 mL), and p-toluenesulfonyl chloride (0.72 g). After the amination reaction was stirred for 15 minutes, a precipitate was present and was isolated by filtration. The precipitate was purified by chromatography using a HORIZON HFPC system (silica cartridge, eluting with 0-55% CMA in chloroform) and dried for three days at 90° C. to provide 0.34 g of 6-(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)hexanamide as a light yellow solid, mp 220-221° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])[C:5]([Cl:25])=[CH:4][N:3]=1.[CH3:26][S:27][CH2:28][CH2:29][NH2:30]>O1CCOCC1>[Cl:25][C:5]1[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])=[CH:7][C:2]([NH:30][CH2:29][CH2:28][S:27][CH3:26])=[N:3][CH:4]=1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Reactant: CSCCN
Solvent: C1COCCO1
Product: CSCCNc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Temperature: 25 °C
Yield: 13 %

Procedure:
A 1,4-dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (200 mg, 0.48 mmol) obtained in Example 54 and 2-methylthioethylamine (200 μl) was stirred at 120° C. for 2 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to give the title compound (29 mg, 13%) as an oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:32]I.O>CN(C=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([N:21]([CH3:32])[C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:2])[CH3:3]
Reactant: CI
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C)c(N(C)C(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
To a solution of N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (200 mg, 0.51 mmol) synthesized in Example 1 in DMF (3 mL) was added sodium hydride (a 60% dispersion in liquid paraffin, 24 mg, 0.6 mmol) at 0° C. and the resulting mixture was stirred at room temperature for 30 minutes. To the reaction solution was added methyl iodide (78 mg, 0.55 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution and the product was extracted with diisopropyl ether. The extracts were washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 25 mg (yield: 12%) of the desired product having low polarity, of two rotational isomers of the title compound. Melting point: 122-123° C. (petroleum ether).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH:22]1(O)[CH2:26][CH2:25][CH2:24][CH2:23]1.CO>ClCCl>[CH:22]1([O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: OC1CCCC1
Solvent: CO
Solvent: ClCCl
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OC1CCCC1
Yield: 77 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using cyclopentanol (31 μL, 0.34 mmol) as the coupling partner. Chromatography (1:1 methanol:dichloromethane) through SiO2 yielded 47 mg (77%) of the titled compound as fine white needles. ESI-MS m/z 360 (MH+), 358 (M−H−).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH3:8][C:9]1[C:16]([CH3:17])=[C:15]([O:18][CH3:19])[CH:14]=[CH:13][C:10]=1[CH:11]=O>CCO.Cl>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:10]([CH:11]=[C:3]2[C:4](=[O:7])[C:5](=[CH:11][C:10]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[C:16]([CH3:17])[C:9]=3[CH3:8])[CH2:6][O:1][CH2:2]2)=[C:9]([CH3:8])[C:16]=1[CH3:17]
Reactant: COc1ccc(C=O)c(C)c1C
Reactant: O=C1CCOCC1
Agent: Cl
Solvent: CCO
Product: COc1ccc(C=C2COCC(=Cc3ccc(OC)c(C)c3C)C2=O)c(C)c1C
Yield: 38.6 %

Procedure:
A solution of 6.0 g (0.06 mole) of tetrahydro-4H-pyran-4-one, 21.6 g (0.13 mole) of 2,3-dimethyl-p-anisaldehyde in 75 ml of EtOH and 10 ml of concentrated HCl is stirred and heated at reflux for 3 hours. The product gradually precipitates during this period. After cooling, this material is filtered and treated with ether to give 9.1 g (39%) of yellow crystals, m.p. 225°-227°.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10]C)=[O:9])=[O:5].[OH-].[K+].C(O)C.Cl>O>[F:1][C:2]1[CH:15]=[C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)CCC(=O)OC)c(F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)CCC(=O)O)c(F)c1
Temperature: 25 °C

Procedure:
A solution of 5.4 g. of methyl 3-[2-fluoro-4-(hexadecylamino)benzoyl]propionate is stirred with 5.4 g. of potassium hydroxide in 100 ml. of 95% ethanol for 3 hours at reflux. The reaction mixture is cooled, diluted with 50 ml. of ethanol and 100 ml. of water, and neutralized with hydrochloric acid. The solution is cooled to room temperature and filtered. The white solid is washed with 50% aqueous ethanol and dried. The product is recrystallized from ethanol to yield 3-[2-fluoro-4-(hexadecylamino)benzoyl]propionic acid as a white crystalline solid.
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][C:17]#[C:18][CH2:19][CH3:20])(C1C=CC(C)=CC=1)(=O)=O.[Br-:21].[Na+]>CN(C)C=O>[Br:21][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][C:17]#[C:18][CH2:19][CH3:20]
Reactant: CCC#CC=CCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC#CC=CCCCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 42.7 g. of 1-tosyloxynon-4-en-6-yne (0.14 moles) in 150 ml. of anhydrous dimethylformamide is added 18.7 g. of sodium bromide (0.16 moles) and the mixture is heated at 75° for 2 hours and then allowed to stir overnight at room temperature. The reaction mixture is then diluted with 200 ml. of ice water and extracted with pentane. The pentane extract is washed with water and dried over sodium sulfate. Evaporation of solvent in vacuo and distillation of the residual oil gave 24.3 g. of 1-bromonon-4-en-6-yne (84% yield) b.p. 52°-55° at 0.15 mm.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[C:23]([CH:27]=1)[C:24](O)=[O:25])(=[O:18])=[O:17]>>[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[C:23]([C:24]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=3)[CH2:9]2)=[O:25])[CH:27]=1)(=[O:17])=[O:18]
Reactant: CS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Reactant: FC(F)(F)c1ccc2c(c1)CCNC2
Product: CS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)N2CCc3cc(C(F)(F)F)ccc3C2)c1

Procedure:
Prepared in analogy to example 1.1 from 6-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline and 5-methanesulfonyl-2-morpholin-4-yl-benzoic acid (Example 2.4).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([NH:15][CH2:16][CH2:17][C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:19]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>[Pt].C(#N)C>[Cl:1][C:2]1[C:11]([NH2:12])=[C:10]([NH:15][CH2:16][CH2:17][C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH:19]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCCc1cc(-c2ccc(F)cc2)no1
Agent: [Pt]
Solvent: CC#N
Product: Nc1c(Cl)nc2ccccc2c1NCCc1cc(-c2ccc(F)cc2)no1
Yield: 52.5 %

Procedure:
Under a nitrogen atmosphere, acetonitrile (1.5 L) was added to a Parr vessel containing 5% platinum on carbon (1.5 g), which had been wet with a small amount of acetonitrile, and 2-chloro-N-{2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}-3-nitroquinolin-4-amine (23.20 g, 56.20 mmol). The vessel was sealed, purged three times with hydrogen, and placed under hydrogen pressure (30 psi, 2.1×105 Pa) for 18 hours at room temperature. The catalyst was removed by filtration, and the majority of the filtrate was concentrated under reduced pressure. A solid was present in the remaining filtrate and was isolated by filtration to provide 11.3 g of 2-chloro-N4-{2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}quinoline-3,4-diamine as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[C:14]([C:15](OCC)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]3[CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].[Br-]>>[OH:16][CH2:15][C:14]1[C:9]2[N:10]([CH:20]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1cccn2cc(-c3ccccc3)nc12
Agent: [Br-]
Agent: [K+]
Product: OCc1cccn2cc(-c3ccccc3)nc12

Procedure:
From 2c (yield: 92%); mp 85-87° C.; IR (KBr) 2926, 1731, 1605, 1481, 1371 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.95 (s, 2H), 6.71 (t, 1H, J=7 Hz), 7.05 (d, 1H, J=7 Hz), 7.32 (t, 1H, J=7.5 Hz), 7.42 (t, 2H, J=7.5 Hz), 7.81 (s, 1H), 7.92 (d, 2H, J=7.5 Hz), 8.00 (d, 1H, J=7 Hz); 13C NMR (100 MHz, CDCl3) δ 62.4, 108.2, 112.5, 121.5, 124.6, 126.1, 128.1, 128.6, 129.6, 133.3, 144.6, 145.0; MS m/z 224 (M+, 52), 223 (100), 195 (50), 91 (26), 78 (30), 51 (28).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[CH:9]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]1.C1(C)C=CC=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>CCOC(C)=O.O>[F:8][C:4]1[N:3]=[C:2]([C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cccc(F)n1
Reactant: N#CC1CCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#CC1(c2cccc(F)n2)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
To a 0° C. solution of 2,6-difluoropyridine (5.0 g, 43 mmol), cyclobutanecarbonitrile (3.5 g, 43 mmol), and toluene (100 mL) was added sodium hexamethyldisilazide (NaHMDS, 2.0 M in THF, 24 mL, 47 mmol). The resulting mixture was warmed to rt and stirred for 2 h. The mixture was then diluted with EtOAc (200 mL) and water (100 mL). The aqueous layer was extracted with EtOAc and the combined organic phases were washed with brine, dried over Na2SO4, concentrated, and purified using silica gel chromatography to provide the desired product (4.9 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([NH2:9])=[O:8])[N:5]=[CH:4][CH:3]=1.CO[C:12](OC)(OC)[CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:13]([C:12]1[NH:1][C:2]2[N:6]([N:5]=[CH:4][CH:3]=2)[C:7](=[O:8])[N:9]=1)[CH2:14][CH2:15][CH3:16]
Reactant: NC(=O)n1nccc1N
Reactant: CCCCC(OC)(OC)OC
Product: CCCCc1nc(=O)n2nccc2[nH]1
Temperature: 25 °C

Procedure:
A solution of 3.0 g of the product of Example 14 in 10 ml of trimethylorthovalerate is heated at 130° C. for 1 hour. The reaction mixture is cooled to room temperature and diluted with hexanes. The resulting solid is collected, washed with hexanes and dried to give 2.0 g of the desired product as a solid. M+H=193.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH2:10][O:11][CH3:12].[Br:13]N1C(=O)CCC1=O>ClCCl>[Br:13][C:6]1[CH:7]=[C:2]([F:1])[C:3]([O:9][CH2:10][O:11][CH3:12])=[CH:4][C:5]=1[OH:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCOc1cc(O)ccc1F
Solvent: ClCCl
Product: COCOc1cc(O)c(Br)cc1F
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
4-Fluoro-3-methoxymethoxy-phenol from example A1 (6.89 g; 40.0 mmol) is dissolved in dry di-chloromethane (160.0 mL). The stirred solution is cooled to −15° C. N-bromosuccinimide (7.12 g; 40.0 mmol) is added in small portions over one hour. After complete addition the reaction mixture is stirred for another 30 min at −15° C.
Reaction SMILES: [Br:1]Br.[N:3]1[CH:4]=[CH:5][N:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[N:7]2.[OH-].[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:5]1[N:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:11]2=[N:3][CH:4]=1
Reactant: c1cnn2ccnc2c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Brc1cnc2cccnn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (0.649 mL, 12.6 mmol) was added dropwise to a stirred mixture of Imidazo[1,2-b]pyridazine (1.0 g, 8.39 mmol) in acetic acid (42 ml) and the mixture was stirred at room temperature for 1 h. The mixture was neutralized with 1 N sodium hydroxide (100 mL) and solid sodium hydroxide, poured into ethyl acetate and sodium bicarbonate solution, and extracted with ethyl acetate (3×200 mL). The combined organics were washed with brine, dried (MgSO4), and concentrated to afford the title compound. 1H NMR (600 MHz, CD3SOCD3) δ 8.66 (d, 1H); 8.17 (d, 1H); 7.93 (s, 1H); 7.31 (dd, 1H). LRMS (APCI) calc'd for (C6H5BrN3) [M+H]+, 198.0. found 198.0.