Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]([CH:26]2[CH2:28][CH2:27]2)=[O:25])[CH:11]=1)C.[Li+].[OH-].Cl>C1COCC1.CO>[CH2:29]([N:23]([CH2:22][C:13]1[CH:14]=[C:15]([C:18]([F:19])([F:20])[F:21])[CH:16]=[CH:17][C:12]=1[C:10]1[CH:11]=[C:6]([CH2:5][C:4]([OH:36])=[O:3])[CH:7]=[N:8][CH:9]=1)[C:24]([CH:26]1[CH2:28][CH2:27]1)=[O:25])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(Cc2ccccc2)C(=O)C2CC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(Cc2ccccc2)C(=O)C2CC2)c1
Temperature: 25 °C

Procedure:
To (5-{2-[(N-benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid ethyl ester (0.043 g, 0.09 mmol) in THF (3 mL) and MeOH (0.3 mL) was added 1N aqueous LiOH (3 mL), and the reaction was stirred at room temperature. The mixture was neutralized with 1N aqueous HCl to pH 4-5 and extracted three times with EtOAc. The combined organic layers were dried and concentrated, and the residue was purified by preparative HPLC to give Compound 17.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([I:8])=[CH:6][CH:7]=1.C([O:12][CH2:13][C:14](=O)[CH2:15]Cl)(=O)C.C(=O)([O-])O.[Na+]>C(O)C>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:15]=[C:14]([CH2:13][OH:12])[N:1]=2)[N:4]=1
Reactant: Nc1ccc(I)nn1
Reactant: CC(=O)OCC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: OCc1cn2nc(I)ccc2n1
Temperature: 25 °C
Yield: 20.1 %

Procedure:
To a solution of 3-amino-6-iodopyridazine (2.0 g, 9.0 mmol) in ethanol (40 mL) was added 3-chloro-2-oxopropyl acetate (2.73 g, 18.1 mmol), and the mixture was heated under reflux for 24 hr. After cooling the mixture to room temperature, saturated aqueous sodium hydrogencarbonate solution was added to the mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate/hexane to give the title compound (498 mg, 20%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH2:26][CH3:27])=[CH:4][CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH2:26]([N:13]1[CH:12]=[N:11][C:10]2[C:14]1=[N:15][C:16]([NH:18][C@H:19]1[CH2:20][CH2:21][C@H:22]([OH:25])[CH2:23][CH2:24]1)=[N:17][C:9]=2[NH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:3][CH:4]=1)[CH3:27]
Reactant: CCn1cnc2c(Nc3ccc(N)cc3)nc(N[C@H]3CC[C@H](O)CC3)nc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCn1cnc2c(Nc3ccc(NS(C)(=O)=O)cc3)nc(N[C@H]3CC[C@H](O)CC3)nc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
trans-4-[6-(4-amino-phenylamino)-9-ethyl-9H-purin-2-yl-amino]-cyclohexanol (100 mg, 0.272 mmol) is suspended in 1 ml dichloromethane and treated with 22 μl (0.272 mmol) methanesulfonyl chloride. The reaction mixture is stirred at RT for 48 h. The crude product is recovered by filtration and purified by chromatography on silica gel (CH2Cl2/MeOH 95:5). N-{4-[9-ethyl-2-(trans-4-hydroxy-cyclohexylamino)-9H-purin-6-yl-amino]-phenyl}-methane-sulfonamide is obtained as an amorphous material, 43 mg (36%); MS [M+H]+444; HPLC (System h) tR=4.63 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][NH2:13]>C1COCC1>[CH3:12][NH:13][S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:10])=[O:9]
Reactant: CN
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cccc(Br)c1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 mL) at 0° C. was added methylamine (2.0 M in THF; 28 mL, 56 mmol). The resulting solution was allowed to warm to room temp. and was stirred at room temp. overnight. The resulting mixture was separated between EtOAc (25 mL) and a 1 M HCl solution (25 mL). The aqueous phase was back-extracted with EtOAc (2×25 mL). The combined organic phases were sequentially washed with water (2×25 mL) and a saturated NaCl solution (25 mL), dried (MgSO4) and concentrated under reduced pressure to give N-methyl-3-bromobenzenesulfonamide as a white solid (2.8 g, 99%). Step 2. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)benzene
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C(OC([NH:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:28][CH:29]1[CH2:33][CH2:32][N:31]([C:11]2[CH:12]=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([CH3:16])[C:10]=2[F:15])[CH2:30]1
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(F)c(N2CCC(N)C2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110 %

Procedure:
A mixture of 0.70 g (2.50 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.56 g (3.00 mmol) of 3-(t-butoxycarbonyl) aminopyrrolidine, 0.76 g (7.52 mmol) of triethylamine, and 25 mL of acetonitrile was refluxed for 4.5 hours, then stirred at room temperature overnight. The solids were collected by filtration and washed with acetonitrile and ether. The crude product was dissolved in 20 mL of 6N hydrochloric acid and 20 mL of acetic acid and was stirred at room temperature for 3 hours. The solution was concentrated to an oil which was triturated with 2:1 ether:isopropanol. The solids were removed by filtration, washed with ether, and dried to give 0.95 g of the title compound as the hydrochloride salt, mp>300° C.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:6][CH:5]([OH:7])[CH2:4]1.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15](=O)[O:16]C1C=CC=CN=1>C1COCC1.CCOC(C)=O>[C:15](=[O:16])([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=1)[O:7][CH:5]1[CH2:6][O:3][CH2:4]1
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Reactant: OC1COC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Oc1ccccn1)OC1COC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.2 %

Procedure:
To a suspension of sodium hydride, 60% in mineral oil (0.594 g, 14.85 mmol) in THF (50 mL) was added oxetan-3-ol (1 g, 13.50 mmol) at 0° C. After stirring 30 min, the solution was transferred to a solution of di(pyridin-2-yl)carbonate (2.92 g, 13.50 mmol) in THF (50 mL) through a cannula. The formed slurry was stirred at 0° C. for 30 min. The slurry was warmed to rt and stirred for 2 h. The reaction was diluted with EtOAc, washed with brine, dried over MgSO4, filtered, concentrated to give a residue that was purified by Biotage eluting with 20-50% EtOAc in hexanes to afford the desired product oxetan-3-yl pyridin-2-yl carbonate (452 mg, 17.16% yield) as an oil. 500 mg sm recovered. 1H NMR (400 MHz, CHLOROFORM-d) d 8.42 (dd, J=4.6, 1.6 Hz, 1H), 7.89-7.77 (m, 1H), 7.33-7.27 (m, 1H), 7.14 (d, J=8.3 Hz, 1H), 5.62-5.52 (m, 1H), 4.96-4.91 (m, 2H), 4.83-4.78 (m, 2H).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5]2=[CH:12][CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:4]2[NH:3]1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5]2=[CH:12][CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:4]2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cccc2c1[nH]c(=O)c1ccncc12
Product: COC(=O)c1cccc2c1nc(Cl)c1ccncc12
Yield: 92 %

Procedure:
Methyl 5-oxo-5,6-dihydrobenzo[c][2,6]naphthyridine-7-carboxylate (1.0 eq, 85 mg, 0.334 mmol) was stirred in phosphorus oxychloride (2 ml) at 120° C. for 2 hours. The solvent was removed in vacuo. Ice and water were added. The resulting solid was filtered and dried to afford methyl 5-chlorobenzo[c][2,6]naphthyridine-7-carboxylate as a solid (84 mg, 92% yield). LCMS (ES): >95% pure, m/z 273 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:26])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][CH:7]([C:13]1[CH:14]=[N:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:18]=1)[CH2:6][CH2:5]2.[F:27][C@@H:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:29]O>>[F:1][C:2]1[C:3]([O:26][CH2:29][CH:28]([F:27])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][CH:7]([C:13]1[CH:14]=[N:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:18]=1)[CH2:6][CH2:5]2
Reactant: CCCCCCOc1ccc(C2CCc3c(cc(F)c(F)c3O)C2)cn1
Reactant: CCCCCCCC[C@H](F)CO
Product: CCCCCCCCC(F)COc1c(F)c(F)cc2c1CCC(c1ccc(OCCCCCC)nc1)C2

Procedure:
From 6,7-difluoro-2-(6-hexyloxypyridin-3-yl)-5-hydroxy-1,2,3,4-tetrahydronaphthalene and 2-(S)-fluorodecan-1-ol by means of the Mitsunobu reaction.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:7][CH:6]=1)(=[NH:4])=[O:3].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:21][CH:22]=1)(=[N:4][S:31]([CH3:30])(=[O:33])=[O:32])=[O:3]
Reactant: CS(=N)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N=S(C)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reaction time: 1.5 h

Procedure:
A solution of 2-(4-(S-methylsulfonimidoyl)benzyl)isoindoline-1,3-dione (preparation 17b, 2.50 g, 7.95 mmol) and triethylamine (2.2 mL, 16 mmol) in dichloromethane (20 mL) is cooled at 0° C. and treated with methanesulfonyl chloride (620 μL, 8.0 mmol). The mixture is stirred at this temperature for 1.5 h and then washed with water. The organic layer is concentrated under reduced pressure, and the residue is suspended in a mixture of methanol and water. The precipitate is filtered, washed with water, and dried. Yield: 273 mg (8% of theory); ESI mass spectrum: [M+H]+=393, r.t. HPLC: 0.44 min (X012_S01).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].I[C:8]1[CH:9]=[CH:10][C:11]2[NH:15][C:14](=[O:16])[N:13]([CH3:17])[C:12]=2[CH:18]=1.[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O)#[N:20]>>[CH3:17][N:13]1[C:12]2[CH:18]=[C:8]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:19]#[N:20])[CH:9]=[CH:10][C:11]=2[NH:15][C:14]1=[O:16]
Reactant: Cn1c(=O)[nH]c2ccc(I)cc21
Reactant: N#Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cn1c(=O)[nH]c2ccc(-c3ccccc3C#N)cc21
Reaction time: 0.25 h

Procedure:
A solution of Cesium carbonate (1100 mg, 3.38 mmol, 5.0 eq) was treated with a solution of 6-iodo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (6-3, 185 mg, 0.68 mmol) and 2-Cyanophenylboronic acid (198 mg, 1.35 mmol, 2.0 eq). The 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (27.6 mg, 0.03 mmol, 0.05 eq) was introduced and the mixture was irradiated in a microwave at 140 deg C. for 15 min. The product was worked up by partitioning between EtOAc (2×85 ml) and saturated aqueous NaHCO3 (95 ml), and the combined organic layers were dried over Na2SO4 and concentrated. Afforded 2-(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)benzonitrile (6-4), as a maroon-orange solid.
Reaction SMILES: [F:1][CH:2]([O:7][C:8]([F:25])([F:24])[C:9]([F:23])([F:22])[O:10][C:11]([F:21])([F:20])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)[C:3]([F:6])([F:5])[F:4].[CH2:26]([O:33][C:34]1[CH:35]=[N:36][C:37]([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)=[N:38][CH:39]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:26]([O:33][C:34]1[CH:39]=[N:38][C:37]([C:40]2[CH:41]=[CH:42][C:43]([O:46][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][CH2:12][C:11]([O:10][C:9]([F:23])([F:22])[C:8]([F:25])([F:24])[O:7][CH:2]([F:1])[C:3]([F:6])([F:5])[F:4])([F:21])[F:20])=[CH:44][CH:45]=2)=[N:36][CH:35]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(OC(F)(F)C(F)(F)OC(F)(F)COCCCCCBr)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCOc1cnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)C(F)(F)F)cc2)nc1

Procedure:
Using essentially the procedure of Comparative Example A, the title compound was prepared by combining 5-(2-(2-(tetrafluoroethoxy)tetrafluoroethoxy)-2,2 -difluoroethoxy)-1-bromopentane (7.2 g, 15.0 mmol), 5 -heptyloxy-2-(4-hydroxyphenyl)pyrimidine (3 g, 11.0 mmol), potassium carbonate (1.6 g, 12.7 mmol), and acetonitrile (50 mL). The resulting crude product was isolated and purified essentially as in Comparative Example A to yield 4.95 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:25])([F:24])[F:23])[CH:16]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[NH2:10][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:25])([F:23])[F:24])[CH:16]=1)[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[OH:12]
Reactant: O=C1NC(Cc2cccc(OC(F)(F)F)c2)C(c2ccc(F)cc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(Cc1cccc(OC(F)(F)F)c1)C(O)c1ccc(F)cc1

Procedure:
(4RS,5SR)-5-(4-Fluorophenyl)-4-[3-(trifluoromethoxy)benzyl]-1,3-oxazolidin-2-one (4.071 g, 11.46 mmol) and sodium hydroxide (1.83 g, 45.8 mmol) were heated under reflux in ethanol (30 ml)—water (2 ml) for 6 hrs. The reaction solution was diluted with water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel (APS type) column chromatography (hexane/ethyl acetate=3/1-ethyl acetate) to give the objective substance.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C:3](=[N:8][C@H](C1C=CC=CC=1)C)[C:4]([NH:6][CH3:7])=[O:5]>CO.[Pd]>[CH3:7][NH:6][C:4](=[O:5])[C@H:3]([C:2]([CH3:18])([CH3:17])[CH3:1])[NH2:8]
Reactant: CNC(=O)C(=N[C@@H](C)c1ccccc1)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CNC(=O)[C@@H](N)C(C)(C)C
Reaction time: 6 h

Procedure:
A solution of 100.0 g (406 mmol) of (S)-3,3,N-trimethyl-2-(1-phenylethylimino)-butyramide in 775 ml of methanol was hydrogenated in a 21 autoclave in the presence of 5 g of 5 percent Pd/C at 40° C. and at a pressure of 1 bar for 7 hours. Re-hydrogenation was carried out for 6 hours at 70° C. and under a pressure of 2 bar in order to complete the hydrogenolysis. After cooling the catalyst was filtered off and the filtrate was evaporated to dryness: 58.3 g (99.6%) of white crystals with 99.6% N-methyl-tert-leucinamide content, e.e. 97.2%. Recrystallization from 425 ml of cyclohexane yields (S)-N-methyl-tert-leucinamide as white crystals, m.p. 90°-93° C., [α]=-40.8 (c=1, CHCl3), 99.3% e.e. In order to determine the e.e value, the product was derivatized with (-)-camphanoyl chloride and the diastereomer mixture was analyzed by gas chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:28]([O:30][CH3:31])=[O:29]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][N:9]2[C:28]([O:30][CH3:31])=[O:29])=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCNC(c2ccc(F)cc2)C1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Methyl 2-(4-fluorophenyl)piperidine-4-carboxylate (7.4 g, 31.19 mmol) was dissolved in DCM (100 mL) and DIPEA (6.52 mL, 37.43 mmol) added followed by methyl chloroformate (2.95 mL, 37.43 mmol) at 0° C. The solution was stirred at room temperature for 1 h. The reaction mixture washed with 0.1 M HCl and satd NaHCO3. The organic phase was passed through a phase separator and evaporated to yield dimethyl 2-(4-fluorophenyl)piperidine-1,4-dicarboxylate (8.07 g, 97%) as a brown oil. MS m/z 296 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].Cl[C:14](=[CH2:17])[C:15]#[N:16]>C(O)C>[C:15]([C:14]1[N:7]=[N:6][N:5]([CH2:4][C:3]2[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:8]=2[F:12])[CH:17]=1)#[N:16]
Reactant: C=C(Cl)C#N
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Solvent: CCO
Product: N#Cc1cn(Cc2c(F)cccc2F)nn1
Temperature: 77 °C
Reaction time: 24 h

Procedure:
A mixture of 2,6-difluorobenzyl azide (34.2 g), 2-chloroacrylonitrile (26.6 g) and absolute ethanol (125 ml) is stirred at about 77° C. for 24 hours. Unreacted 2-chloroacrylonitrile and 2,6-difluorobenzyl azide as well as ethanol are distilled off (distillate 100 ml) by raising the external temperature to about 130° C. After cooling to 70° C., water (100 ml) is allowed to run in dropwise at 70-60° C. The mixture is seeded, cooled to about 20° C. and the suspension is stirred at about 20° C. for about 1 hour. The product is isolated by filtration and washed with cyclohexane (100 ml) and then with water (100 ml). The product is dried in vacuo at about 60° C. Yield: 17.73 g=40.3% (pale beige powder).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([N:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]4)[CH2:13]3)=[CH:7][N:8]=2)[N:3]=1.[NH2:25][C:26]1[O:27][C:28]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:29]=2[N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH:22]([N:19]1[CH2:20][CH2:21][N:16]([CH:14]2[CH2:15][N:12]([C:6]3[CH:5]=[C:4]4[C:9]([CH:10]=[CH:11][C:2]([C:32]5[CH:33]=[CH:34][C:28]6[O:27][C:26]([NH2:25])=[N:30][C:29]=6[CH:31]=5)=[N:3]4)=[N:8][CH:7]=3)[CH2:13]2)[CH2:17][CH2:18]1)([CH3:24])[CH3:23]
Reactant: Nc1nc2cc(B(O)O)ccc2o1
Reactant: CC(C)N1CCN(C2CN(c3cnc4ccc(Cl)nc4c3)C2)CC1
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: C1COCCO1
Solvent: O
Product: CC(C)N1CCN(C2CN(c3cnc4ccc(-c5ccc6oc(N)nc6c5)nc4c3)C2)CC1
Yield: 42.5 %

Procedure:
A mixture of 2-chloro-7-(3-(4-isopropylpiperazin-1-yl)azetidin-1-yl)-1,5-naphthyridine (C-10) (220 mg, 0.636 mmol, 1.0 eq), 2-aminobenzo[d]oxazol-5-ylboronic acid (135 mg, 0.763 mmol, 1.2 eq), Pd(PPh3)4 (73 mg, 0.06 mmol, 0.1 eq), and Na2CO3 (202 mg, 1.908 mmol, 3.0 eq) were dissolved in a mixture of 1,4-dioxane (30 mL) and water (9 mL). The resulting mixture was degassed and back-filled with argon three times and heated at reflux under an argon atmosphere for 2 h. The reaction was complete based on TLC analysis. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (1:5 MeOH-DCM) to afford the desired product 5-(7-(3-(4-isopropylpiperazin-1-yl)azetidin-1-yl)-1,5-naphthyridin-2-yl)benzo[d]oxazol-2-amine (72) (120 mg, 42.5% yield). 1H NMR (300 MHz, DMSO-d6) δ: 8.35 (s, 1H), 8.20 (d, J=8.7 Hz, 1H), 8.02 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.87 (d, J=6.3 Hz, 1H), 7.48 (s, 2H), 7.42 (d, J=8.1 Hz, 1H), 7.08 (s, 1H), 4.12 (m, 2H), 3.85 (m, 2H), 3.36 (m, 1H), 3.23 (m, 4H), 2.47 (m, 1H), 2.37 (m, 4H), 0.95 (d, J=6.9 Hz, 6H); ESI-MS m/z: 444.21 [M+H]+.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][CH:13]([CH3:33])[CH2:14][N:15]1[C:27]2[C:26]3[N:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:17]=[C:16]1[NH:28][C:29](=[O:32])[O:30][CH3:31]>ClCCl>[CH3:12][CH:13]([CH3:33])[CH2:14][N:15]1[C:27]2[C:26]3[N:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:20]([O-:6])=[CH:19][C:18]=2[N:17]=[C:16]1[NH:28][C:29](=[O:32])[O:30][CH3:31]
Reactant: COC(=O)Nc1nc2cnc3cccnc3c2n1CC(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)Nc1nc2c[n+]([O-])c3cccnc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 76 h
Yield: 57 %

Procedure:
3-Chloroperoxybenzoic acid (1.73 g of approximately 75% pure material) was added to a stirred solution of methyl [1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]carbamate (1.5 g, 5.01 mmol) in dichloromethane (40 mL), and the reaction was stirred for 76 hours at room temperature. A precipitate formed and was collected by filtration, washed with a minimal amount of dichloromethane, and dried to provide 0.9 g of methyl [1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]carbamate as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[CH:6]=[O:7].[C:20]([Mg]Cl)#[CH:21]>C1COCC1>[OH:7][CH:6]([C:5]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:3]([O:2][CH3:1])[CH:4]=1)[C:20]#[CH:21]
Reactant: C#C[Mg]Cl
Reactant: COc1cc(C=O)ccc1OCCN1CCOCC1
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(OCCN2CCOCC2)c(OC)c1

Procedure:
3-Hydroxy-3-[3-methoxy-4-[2-(4-morpholinyl)-ethoxy]-phenyl]-1-propyne was prepared according to Method A above from 3-methoxy-4-(2-morpholin-4-yl-ethoxy)-benzaldehyde (0.60 g, 2.26 mmol) (see below) in THF (25 mL) and ethynylmagnesium chloride (5 mmol, 10 mL, 0.5M solution in tetrahydrofuran) (Aldrich). (Yield 502 mg, 76%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:4]([S:15](=[O:18])(=[O:17])N)=[CH:5][C:6]2[S:11](=[O:13])(=[O:12])[NH:10][CH:9]=[N:8][C:7]=2[CH:14]=1.[Cl:21]S(O)(=O)=O>O>[F:1][C:2]([F:20])([F:19])[C:3]1[C:4]([S:15]([Cl:21])(=[O:18])=[O:17])=[CH:5][C:6]2[S:11](=[O:13])(=[O:12])[NH:10][CH:9]=[N:8][C:7]=2[CH:14]=1
Reactant: NS(=O)(=O)c1cc2c(cc1C(F)(F)F)N=CNS2(=O)=O
Reactant: O=S(=O)(O)Cl
Solvent: O
Product: O=S(=O)(Cl)c1cc2c(cc1C(F)(F)F)N=CNS2(=O)=O

Procedure:
6-Trifluoromethyl-7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide (0.2 mole) is added portionwise with stirring to chlorosulfonic acid (300 ml.) cooled in an ice-bath over 30 minutes. The mixture is then heated for 2 hours on the steam bath, cooled and poured onto a mixture of ice and water. The solid is collected on the filter, washed with cold water and air-dried at room temperature and recrystallized from acetone-hexane.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CN1C(=O)CCC1.CCOC(C)=O>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: C1CNCCN1
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCNCC3)nn12
Temperature: 170 °C
Reaction time: 1 h

Procedure:
(rac)-6-[1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C, 200 mg, 0.569 mmol), KF (371 mg, 6.26 mmol) and piperazine (490 mg, 5.69 mmol) were suspended in NMP (2.85 mL). The RM was stirred at 170° C. for 1 h. The mixture was diluted with EtOAc and washed with 1M Na2CO3 (1×) and water (2×). The aqueous was further extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and afford the title compound as a yellow foam (tR 2.78 min (conditions 1), MH+=395).