Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[NH2:17][C:18]1[N:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][CH3:32])[CH:25]=2)=[CH:20][C:19]=1[C:33]1[O:34][C:35]2[C:36]([N:41]=1)=[N:37][CH:38]=[CH:39][CH:40]=2.[O:42]1[CH2:47][CH2:46][N:45]([CH2:48][CH2:49]O)[CH2:44][CH2:43]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:32][O:31][C:26]1[CH:25]=[C:24]([C:21]2[CH:20]=[C:19]([C:33]3[O:34][C:35]4[C:36]([N:41]=3)=[N:37][CH:38]=[CH:39][CH:40]=4)[C:18]([NH2:17])=[N:23][CH:22]=2)[CH:29]=[CH:28][C:27]=1[O:30][CH2:49][CH2:48][N:45]1[CH2:46][CH2:47][O:42][CH2:43][CH2:44]1
Reactant: COc1cc(-c2cnc(N)c(-c3nc4ncccc4o3)c2)ccc1O
Reactant: OCCN1CCOCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(-c2cnc(N)c(-c3nc4ncccc4o3)c2)ccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[C2] A solution of di-tert-butyl azodicarboxylate (241 mg) in dichloromethane (1 ml), was added dropwise to a stirred suspension of 4-(6-amino-5-(oxazolo[4,5-b]pyridin-2-yl)pyridin-3-yl)-2-methoxyphenol (130 mg), 2-morpholinoethanol (0.054 ml) and triphenylphosphine polymer bound (350 mg, 1.05 mmol) dissolved in dichloromethane (3 ml). The resulting suspension was stirred at room temperature for 2 hours. The mixture was filtered, washed with dichloromethane (1 ml) and methanol (1 ml). The solvent was evaporated. The resulting residue was diluted with 1 ml of dichloromethane and 1 ml of TFA; the mixture was stirred overnight and concentrated. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 5-[3-methoxy-4-(2-morpholinoethoxy)phenyl]-3-oxazolo[4,5-b]pyridin-2-yl-pyridin-2-amine (70 mg) as a solid. The 4-(6-amino-5-oxazolo[4,5-b]pyridin-2-yl-3-pyridyl)-2-methoxy-phenol used as starting material was made as follows:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:6]=[C:7]([C:19]2[NH:20][CH:21]=[CH:22][CH:23]=2)[C:8]2[C:9](=[O:18])[NH:10][C:11]3[C:16]=2[C:15]=1[C:14]([F:17])=[CH:13][CH:12]=3.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>ClCCCl>[F:17][C:14]1[C:15]2[C:16]3[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:18])[C:8]=3[C:7]([C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1)=[CH:6][C:5]=2[N:4]1[CH2:3][CH2:2][NH:1][C:24]1=[O:25]
Reactant: NCCNc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: O=C1Nc2ccc(F)c3c(N4CCNC4=O)cc(-c4ccc[nH]4)c1c23

Procedure:
To a suspension of 5-(2-amino-ethylamino)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one (from Example 9 above) (31.1 mg, 0.1 mmol) in 1,2-dichloroethane (3 mL) was added 1,1′-carbonyidiimidazole (Aldrich, 162 mg, 1.0 mmol) at room temperature. The reaction mixture was heated under reflux overnight. The reaction was then quenched with saturated aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were successively washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was triturated with ethyl acetate and hexanes, filtered, and dried to give 6-fluoro-5-(2-oxo-imidazolidin-1-yl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 19.5 mg, 58.0%).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][O:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>ClCCl.C(O)C>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]2[CH2:16][CH2:17][CH:12]([O:11][CH3:10])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: COC1CCNCC1
Reactant: BrCc1ccc(I)cc1
Solvent: CCO
Solvent: ClCCl
Product: COC1CCN(Cc2ccc(I)cc2)CC1

Procedure:
Prepared analogously to Example 1.1.c. from 4-iodobenzyl bromide and 4-methoxypiperidine. Yield: 0.93 g (66.7% of theory); C13H18INO (M=331.19); calc.: molecular ion peak (M+H)+: 332; found: molecular ion peak (M+H)+: 332; Rf value: 0.55 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[C:10]([C:20]1[O:24][CH:23]=[N:22][CH:21]=1)=[CH:9]2.[N:30]([Si](C)(C)C)=[N+:31]=[N-:32].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:2]([Cl:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][C:18]1[NH:32][N:31]=[N:30][N:19]=1)[C:10]([C:20]1[O:24][CH:23]=[N:22][CH:21]=1)=[CH:9]2
Reactant: N#CCCCn1c(-c2cnco2)cc2cc(OCc3c(Cl)cccc3Cl)ccc21
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Clc1cccc(Cl)c1COc1ccc2c(c1)cc(-c1cnco1)n2CCCc1nnn[nH]1
Yield: 78.3 %

Procedure:
To a solution of 4-[5-(2,6-dichlorobenzyloxy)-2-(oxazol-5-yl)indol-1-yl]butyronitrile (0.21 g, 0.49 mmol) in toluene (10 mL) was added azidotrimethylsilane (0.20 mL, 1.48 mmol) and dibutyltin oxide (0.037 g, 0.148 mmol). The reaction was refluxed for 16 h. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (silica gel, MeOH/CH2Cl2) to yield a yellow solid (0.18 g, 78%). MS(ES) m/e 469.0 [M+H]+.
Reaction SMILES: B([O-])([O-])[O-:2].C1C(=O)N(OC(CCCCCN[C:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH:27]2[S:31][CH2:30][CH:29]3[NH:32][C:33]([NH:35][CH:28]23)=[O:34])=[O:22])=O)C(=O)C1>[Na+].[Cl-]>[OH:2][C:21]([CH2:23][CH2:24][CH2:25][CH2:26][C@H:27]1[C@@H:28]2[C@@H:29]([NH:32][C:33]([NH:35]2)=[O:34])[CH2:30][S:31]1)=[O:22]
Reactant: [O-]B([O-])[O-]
Reactant: O=C(CCCCC1SCC2NC(=O)NC21)NCCCCCC(=O)ON1C(=O)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21

Procedure:
50 mg bovine serum albumin (BSA) (Fraction V, Fluka) were dissolved in pH 8.5 50 mM NaCl, 20 mM borate buffer. A solution of biotin X NHS (20 mg/200 μl anhydrous dimethylformamide) was then added, and the following steps were identical to those described for the preparation of biotinylated XO.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.[C:13](OC(C)=C)(=[O:15])[CH3:14]>>[C:13]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[C:11]([Cl:12])[C:2]([NH2:1])=[CH:3][CH:4]=2)[CH2:9]1)(=[O:15])[CH3:14]
Reactant: C=C(C)OC(C)=O
Reactant: Nc1ccc2c(c1Cl)CNCC2
Product: CC(=O)N1CCc2ccc(N)c(Cl)c2C1

Procedure:
7-Amino-8-chloro-1,2,3,4-tetrahydroisoquinoline is treated with one molar equivalent of isopropenyl acetate by the procedure of Example 15 to give 2-acetyl-7-amino-8-chloro-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13](=[O:15])[NH:12][N:11]=2)=[CH:6][CH:5]=1.[Cl:18][C:19]1[N:20]([CH2:27][C@:28]2([CH3:31])[CH2:30][O:29]2)[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[N:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:18][C:19]1[N:20]([CH2:27][C@:28]([OH:29])([CH3:30])[CH2:31][N:12]2[N:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:16])[F:17])=[CH:9][CH:8]=3)[O:14][C:13]2=[O:15])[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[N:23]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: O=c1[nH]nc(-c2ccc(OC(F)(F)F)cc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@](O)(Cn1cc([N+](=O)[O-])nc1Cl)Cn1nc(-c2ccc(OC(F)(F)F)cc2)oc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
To a solution of 5-(4-trifluoromethoxy-phenyl)-3H-[1,3,4]oxadiazol-2-one (0.68 g, 2.76 mmol) and (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (0.50 g, 2.30 mmol) in DMF (5 ml), potassium carbonate (0.38 g, 2.76 mmol) was added followed by stirring at room temperature for 16 hours, and then water was added. The solution was extracted with ethyl acetate, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=4/1) to afford (R)-3-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]-5-(4-trifluoromethoxyphenyl)-3H-[1,3,4]oxadiazol-2-one (1.06 g, quantitative yield) as a white amorphous form.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]2[N:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[CH:24][CH:23]=3)=[CH:18][N:17]=2)[CH:10]=1)(=O)=O.[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:34][CH2:33]1>CN(C=O)C>[F:31][CH:29]([F:30])[O:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]2[CH:20]=[N:21][C:16]([NH:15][C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][CH2:7][CH2:6][N:32]3[CH2:37][CH2:36][CH:35]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:34][CH2:33]3)=[N:17][CH:18]=2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: CS(=O)(=O)OCCOc1cccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)c1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(CCOc2cccc(Nc3ncc(-c4ccc(OC(F)F)cc4)cn3)c2)CC1
Temperature: 95 °C

Procedure:
2-(3-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenoxy)ethyl methanesulfonate 40b (0.4 mmol), ethyl piperidine-4-carboxylate (0.9 mmol) are dissolved in DMF (3 mL) and heated to 95° C. for 6 h then cooled to rt. The reaction mixture is partitioned with EtOAC and water. The organic layer is washed with water, brine, dried over magnesium sulfate, filtered, and reduced to dryness. The crude product is triturated with MeOH and filtered to yield ethyl 1-(2-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylate 41 as white solid. MS (m/z) (M+1)+: 513.2.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])=[CH:4][CH:3]=1.[C:15]1([CH3:27])[CH:20]=[CH:19][C:18]([S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(#N)C>[C:15]1([CH3:27])[CH:16]=[CH:17][C:18]([S:21]([NH:24][C:25]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])=[CH:13][CH:14]=2)=[O:26])(=[O:22])=[O:23])=[CH:19][CH:20]=1
Reactant: CCCCOC(=O)c1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: CC#N
Product: CCCCOC(=O)c1ccc(NC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
A three necked flask equipped with a dropping funnel, a thermometer and a reflux condenser was charged with 15.4 g of n-butyl 4-aminobenzoate and then with 150 ml of acetonitrile. The mixture in the flask was agitated to dissolve the n-butyl 4-aminobenzoate in acetonitrile. To the solution, 17.3 g of p-toluenesulfonylisocyanate were added dropwise through the dropping funnel at room temperature, while the resultant mixture was agitated by a magnetic stirrer.
Reaction SMILES: [CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][NH:11][CH2:10][C@@H:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[N:24]2)=[CH:19][C:18]=1[O:27][CH3:28]>>[CH2:1]([N:8]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[CH:22][CH:23]=[N:24]3)=[CH:19][C:18]=2[O:27][CH3:28])[CH2:10][C@H:9]1[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2cccnc2cc1Br
Reactant: C[C@@H]1CNC[C@H](C)N1Cc1ccccc1
Product: COc1cc2cccnc2cc1N1C[C@@H](C)N(Cc2ccccc2)[C@@H](C)C1

Procedure:
The title compound was prepared from cis-1-benzyl-2,6-dimethylpiperazine (Org. Prep. Proc. 1976, 8, 19) and 7-bromo-6-methoxyquinoline (J. Org. Chem. 1990, 55, 2019) using a similar procedure to Description 2 (75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([CH3:17])([CH2:14][CH:15]=C)[CH:12]=[O:13].[BH4-].[Na+].ClCCl.C[OH:24]>[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([CH3:17])([CH2:14][CH2:15][OH:24])[CH2:12][OH:13]
Reactant: C=CCC(C)(C=O)c1cc([N+](=O)[O-])ccc1F
Reactant: CO
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(CO)(CCO)c1cc([N+](=O)[O-])ccc1F
Temperature: -78 °C

Procedure:
2-(2-fluoro-5-nitrophenyl)-2-methylpent-4-enal(1 eq) was dissolved in dichloromethane:methanol (3:1) and cooled to −78° C. Ozone was then bubbled through the solution until a blue color was noticed. Air was then passed through the solution followed by the addition of sodium borohydride(5 eq). Resulting solution was allowed to warm to room temperature and diluted with brine, extracted with dichloromethane. Organics were dried with sodium sulfate and concentrated to afford 2-(2-fluoro-5-nitrophenyl)-2-methylbutane-1,4-diol. The product was used in the next step with no further characterization.
Reaction SMILES: [Cl-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[OH:9][C:10]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]>C1COCC1>[CH3:18][C:17]1[C:10]2[O:9][CH2:2][CH:12]([OH:13])[C:11]=2[CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cccc(C=O)c1O
Reactant: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc2c1OCC2O

Procedure:
Under a nitrogen atmosphere 0.945 g (7.35 mmol) trimethylsulphoxonium chloride were placed in 20 mL THF and combined batchwise with 0.300 g (7.50 mmol) sodium hydride (55%, suspension in mineral oil). The reaction mixture was refluxed for 2 h. Then 1.00 g (7.35 mmol) 2-hydroxy-3-methylbenzaldehyde in 20 ml. THF were added dropwise to the reaction mixture and refluxed overnight. Then PE was added and the suspension obtained was filtered. The filtrate was evaporated down i.vac. and purified by flash chromatography. The fractions containing the product were combined and evaporated down.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[CH:19]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[OH-].[Na+]>ClCCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: c1ccc(CN2CCC(Nc3ccc4[nH]ncc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
To a solution of 1-benzyl-4-piperidone (7.11 g, 37.6 mmol) in 1,2-dichloroethane (125 ml) were added 5-aminoindazole (5.00 g, 37.6 mmol), sodium triacetoxyborohydride (11.5 g, 52.6 mmol) and acetic acid (2.15 ml, 37.6 mmol) at room temperature, and stirred overnight at room temperature. Then, the reaction solution was poured into a 1N-aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/methanol=100/1) to obtain N-(1-benzyl-4-piperidinyl)-1H-indazol-5-amine (8.56 g, 74%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[NH:8][C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][N:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:33]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[N:8]([CH2:31][C:32](=[O:33])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][N:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cnccc2[nH]c1=O
Reactant: O=C(CBr)c1ccccc1
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cnccc2n(CC(=O)c2ccccc2)c1=O

Procedure:
This compound was prepared from 2-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1,2-dihydro-[1,6]-naphthyridin-3-carboxylic acid ethyl ester (121) and 2-bromoacetophenone according to General Procedure B. Yield 127 mg (24%), MP 157° C.; 1H-NMR (DMSO-d6): δ 1.27 (t, J=6.8 Hz, 3H), 3.24 (m, 4H), 3.93 (m, 4H), 4.26 (q, J=7.2 Hz, 2H), 5.85 (s, 2H), 7.15 (dd, J=3.6, 5.2 Hz, 1H), 7.47 (m, 2H), 7.62 (m, 2H), 7.74 (m, 1H), 7.80 (d, J=5.2 Hz, 1H), 8.13 (d, J=5.2 Hz, 1H), 8.32 (d, J=7.2 Hz, 2H), 8.56 (d, J=6.0 Hz, 1H), 9.12 (s, 1H); EIMS: 531 (M+1). Anal. (C28H26N4O5S) C, H, N.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]#[CH:11].CCCCCC.C([Li])CCC.Br[CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH3:33]>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]#[C:11][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH3:33]
Reactant: CC/C=C\C/C=C\CCCBr
Reactant: C#CCCOC1CCCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC/C=C\C/C=C\CCCC#CCCOC1CCCCO1
Reaction time: 0.25 h
Yield: 55 %

Procedure:
A solution of 1-(tetrahydropyran-2-yloxy)-3-butyne (2.25 g, 14 mmol) in dry THF (15 ml) was treated at -50° C. with n-butyllithium hexane solution (11 ml, 17.5 mmol). After 15 min at -30° C., the mixture was kept at room temperature for 30 min. The mixture was then treated at 0° C. with 5 (3.0 g, 13.8 mmol) dissolved in 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H)-pyrimidine (DMPU) (15 mL) during 30 min. The reaction mixture was stirred 12 hr. at room temperature and quenched with saturated NH4Cl solution (30 ml). The product (6) was removed with ether (3×50 ml) and purified by silica-gel flash chromatography (2.2 g, 55% yield). 1H NMR (200 MHz) δ5.36 (m, 4H, CH=CH), 4.64 (m, 1H, CH-2'), 3.81 (m, 2H, CH2 -6' and 1), 3.54 (m, 2H, CH2 -6' and 1), 2.78 (dd, J=6.0, 6.0 Hz, 2H, =CH--CH2 --CH=), 2.47 (m, 4H, CH2 -2, and -5), 2.15 (m, 4H, CH2 -7, and -13), 1.8-1.4 (m, 8H, CH2 -6, -3', -4', and -5'), 0.96 (t, J=7.5, 7.6 Hz, 3H, CH3). 13C NMR (100.6 MHz) δ: 131.8 (12), 128.9 (9, 11), 127.2 (8), 98.7 (2'), 81.0 (3), 76.6 (4), 66.2 (1), 62.2 (6'), 33.4 (2), 30.6 (3'), 28.9 (7), 26.2 (6), 25.5 (14), 25.4 (4'), 20.5 (5), 20.2 (13), 18.3 (5'), 14.3 (10). MS [EI, m/z (%)] 159 (7), 131 (9), 119 (8), 117 (9), 105 (8), 93 (11), 91 (16), 86 (12), 85 (100), 79 (18), 77 (11), 67 (36), 57 (16), 55 (15), 43 (29), 42 (16), 41 (51), 40 (24).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][OH:8].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>CCOCC>[S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)([O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1)(=[O:22])=[O:21]
Reactant: OCCc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
A solution of 10.0 g (52.6 mmol) of 3-(trifluoromethyl)phenethyl alcohol in 75 mL of ether under nitrogen was treated with 10.53 g (55.2 mmol, 1.05 eq) p-toluenesulfonyl chloride. The solution was cooled to 0° and treated with 7.67 mL (5.57 g, 55.0 mmol, 1.05 eq) of triethylamine. The mixture was stirred at 0° for 30 minutes then warmed to room temperature and stirred for 16 hours. The precipitate was removed by filtration and washed with ether. The combined filtrate and ether was were evaporated under vacuum. The residue was redissolved in ethyl acetate and washed with 0.5N HCl and brine; the organic layer was removed, dried over sodium sulfate, filtered and concentrated under vacuum. Purification by flash chromatography on silica, eluting with 30% ethyl acetate/hexane, afforded 15.14 g (44.0 mmol, 84%) of the product. 1H NMR (200MHz, CDCl3): 2.44 (s,3H), 3.03 (t,7Hz,2H), 4.26 (t,7Hz,2H), 7.2-7.5 (m,6H), 7.66 (d,8Hz,2H). FAB-MS: calculated for C16H15F3SO3 344; found 345 (M+H,8%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C@@H:11]([N:13]1[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1)[CH3:12].C(N(C(C)C)CC)(C)C.[Cl:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[O:36][C:35](=[O:40])[CH:34]=[C:33]2OS(C(F)(F)F)(=O)=O>C1COCC1>[Cl:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[O:36][C:35](=[O:40])[CH:34]=[C:33]2[NH:19][CH:16]1[CH2:17][CH2:18][N:13]([C@H:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH3:12])[CH2:14][CH2:15]1
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2o1
Reactant: C[C@@H](c1ccc2ccccc2c1)N1CCC(N)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1ccc2ccccc2c1)N1CCC(Nc2cc(=O)oc3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.8 %

Procedure:
To a mixture of (S)-1-(1-naphthalen-2-yl-ethyl)-piperidin-4-ylamine (0.24 g, 0.94 mmol) and diisopropylethylamine (0.34 mL, 2 mmol) in 5 mL THF was added trifluoromethanesulfonic acid 6-chloro-2-oxo-2H-chromen-4-yl ester (0.30 g, 0.93 mmol). The reaction was stirred at room temperature for about 3 hours. The reaction mixture was then washed with water, dried with MgSO4 and evaporated. The residue was purified by chromatography on silica gel with methanol/dichloromethane (2:98) to give the title compound (0.1 g, 25%). The final product was converted to the mono-HCl salt by addition of 1.0N HCl in ether to a suspension of the compound in dichloromethane. The solvent was removed by evaporation. 1H NMR of the mono-HCl salt (300 MHz, DMSO-d6) δ 1.20-1.28 (2H, m), 1.81 (3H, d, J=6.97 Hz), 1.74-2.18 (4H, m), 2.83-3.05 (2H, m), 3.30-3.80 (2H, m), 4.65-4.78 (1H, br), 5.37 (1H, s), 7.30-7.79 (5H, m), 7.92-8.16 (4H, m), 8.32 (1H, d, J=2.64 Hz), 10.09 (1H, br, s).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN(C(C)C)C(C)C.C[Al](C)C.[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH:38]=[C:37]([O:39][CH3:40])[C:36](=[O:41])[C:35]([C:42](OC)=[O:43])=[N:34]2)=[C:29]([F:46])[CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH:38]=[C:37]([O:39][CH3:40])[C:36](=[O:41])[C:35]([C:42]([N:3]([O:4][CH3:5])[CH3:2])=[O:43])=[N:34]2)=[C:29]([F:46])[CH:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CNOC
Reactant: COC(=O)c1nn(-c2ccc(OCc3ccccc3)cc2F)cc(OC)c1=O
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cn(-c2ccc(OCc3ccccc3)cc2F)nc(C(=O)N(C)OC)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (5.27 g, 54 mmol) and iPr2NEt (9.41 mL, 54 mmol) in CH2Cl2 (50 mL) was added AlMe3 (1.8 M solution in toluene, 30 mL, 54 mmol) slowly at 0° C. under Ar atmosphere. After stirring for 1 h, a solution of methyl 1-[4-(benzyloxy)-2-fluorophenyl]-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (8.07 g, 21 mmol) in CH2Cl2 (50 mL) was added slowly, and the mixture was stirred for 1 h at 0° C. The reaction mixture was poured into ice-water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt to give the title compound (7.79 g, 90% yield) as a pale yellow amorphous solid: 1H NMR (300 MHz, CDCl3): δ ppm 3.38 (3H, s), 3.70 (3H, s), 3.89 (3H, s), 5.11 (2H, s), 6.82-6.91 (2H, m), 7.33-7.45 (5H, m), 7.48-7.55 (1H, m), 7.73 (1H, d, J=1.9 Hz).