Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[C:9]1([P:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:16]C)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>ClC1C=CC=CC=1Cl>[C:9]1([P:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:2]2[N:3]=[N:4][C:5]([P:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)([C:26]3[CH:25]=[CH:24][CH:29]=[CH:28][CH:27]=3)=[O:16])=[CH:6][CH:7]=2)=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: COP(c1ccccc1)c1ccccc1
Reactant: CCCCCC
Solvent: Clc1ccccc1Cl
Product: O=P(c1ccccc1)(c1ccccc1)c1ccc(P(=O)(c2ccccc2)c2ccccc2)nn1

Procedure:
To a stirred, refluxing solution of 3.00 g of 3,6-dichloropyridazine in 50 ml of o-dichlorobenzene under nitrogen was added dropwise 10.00 g of methyl diphenylphosphinite. After the addition was completed, the mixture was refluxed for 7 hours and then cooled. The cooled mixture was mixed with excess hexane; the oil which formed slowly crystallized. The resultant solid was separated by filtration, washed with hexane, and recrystallized twice from ethanol with decolorizing charcoal treatment to give 0.93 g of 3,6-bis(diphenylphosphinyl)pyridazine (shown by formula in claim 7) as slightly off-white crystals, mp 248°-251.5° C. Anal. Calcd for C28H22N2O2P2 : C, 70.00; H, 4.62; N, 5.83; P, 12.89. Found: C, 69.72; H, 4.92; N, 5.78; P, 12.82.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+]>O.CO.[Pd]>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1ccc2ccccc2n1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: c1ccc2nc(-c3ccc4ccccc4n3)ccc2c1
Temperature: 82.5 °C
Reaction time: 24 h
Yield: 43.4 %

Procedure:
5.00 g of 2-chloroquinoline and 1.80 g of sodium hydroxide are dissolved in a mixture of 20 ml of water and 16 ml of methanol. Following the addition of 1.5 g of palladium (10% by weight on activated carbon) as catalyst, the mixture is stirred for 24 h at 80-85° C. at 0.1 MPa. Then, following cooling, the catalyst and the precipitated product are filtered off. Extraction of the catalyst gives 1.7 g of 2,2′-biquinoline (43% yield). According to 1H NMR, the crude product has a purity of about 98%. CAS Registry Number: 119-91-5.
Reaction SMILES: CN(C(O[N:9]1N=N[C:11]2C=CC=[CH:15][C:10]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CC[O:27]CC1.[CH:30]1([CH2:36][O:37][C:38]2[C:39]3[N:40]([C:44]([C:49]([OH:51])=O)=[C:45]([CH2:47][CH3:48])[N:46]=3)[CH:41]=[CH:42][CH:43]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>CS(C)=O>[CH:30]1([CH2:36][O:37][C:38]2[C:39]3[N:40]([C:44]([C:49]([NH:9][C@H:10]([CH3:11])[CH2:15][OH:27])=[O:51])=[C:45]([CH2:47][CH3:48])[N:46]=3)[CH:41]=[CH:42][CH:43]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CCc1nc2c(OCC3CCCCC3)cccn2c1C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CN1CCOCC1
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Product: CCc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@H](C)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
3.3 mg (0.044 mmol) of L-alaminol, 14 mg (0.044 mmol) of TBTU and 20 mg (0.198 mmol) of N-methylmorpholine were added to a solution of 12 mg (0.040 mmol) of 8-(cyclohexylmethoxy)-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid in 750 μl of DMSO, and the mixture was then shaken at room temperature overnight. The mixture was then purified by preparative HPLC (Method 6), giving 12 mg (84% of theory) of 8-(cyclohexylmethoxy)-2-ethyl-N-[(2R)-1-hydroxypropan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide as formic acid salt.
Reaction SMILES: [C:1]1([OH:12])([C:6]2(O)[CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.COC(OC)OC.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:7]1[C:6]2([CH2:2][CH2:3][CH2:4][CH2:5][C:1]2=[O:12])[CH2:10][CH2:9][CH2:8]1
Reactant: OC1(C2(O)CCCC2)CCCC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: COC(OC)OC
Product: O=C1CCCCC12CCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of bi(cyclopentane)-1,1′-diol (5.16 g, 29.4 mmol) in methylene chloride (80 mL), cooled to −20° C., was added trimethoxymethane (3.22 mL, 29.4 mmol), followed by boron trifluoride etherate (2.98 mL, 23.52 mmol). The cold bath was removed, and the reaction was stirred at ambient temperature for 2 hours. The mixture was then diluted with methylene chloride (100 mL), washed with saturated sodium bicarbonate, dried with magnesium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel (100% hexane to 15:85 ethyl acetate/hexane, eluant) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 2.40 (t, 2H), 2.00-2.11 (m, 2H), 1.78-1.87 (m, 2H), 1.71 (t, 4H), 1.59 (t, 4H), 1.39 (t, 2H); MS (DCI+) m/z 153 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][C@@:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23]([C:25]4[CH:30]=[N:29][C:28]([O:31][CH3:32])=[CH:27][N:26]=4)=[O:24])[CH:20]=3)[O:15][C:14]([CH3:34])([CH3:33])[C:13]32[CH2:36][CH2:35]3)[N:12]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:7][C:8]1[O:9][CH2:10][C@@:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23]([C:25]4[CH:30]=[N:29][C:28]([O:31][CH3:32])=[CH:27][N:26]=4)=[O:24])[CH:20]=3)[O:15][C:14]([CH3:33])([CH3:34])[C:13]32[CH2:35][CH2:36]3)[N:12]=1
Reactant: COc1cnc(C(=O)Nc2ccc3c(c2)[C@@]2(COC(NC(=O)OC(C)(C)C)=N2)C2(CC2)C(C)(C)O3)cn1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc(C(=O)Nc2ccc3c(c2)[C@@]2(COC(N)=N2)C2(CC2)C(C)(C)O3)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a solution of tert-butyl[(4′R)-6′-{[(5-methoxypyrazin-2-yl)carbonyl]amino}-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl]carbamate (392 mg, 0.769 mmol) in chloroform (3 ml) was added trifluoroacetic acid (1.8 ml), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (precolumn: NH-silica gel, main column: neutral silica gel, chloroform/methanol=10:0-10:1). To the purified product was added a mixture of hexane/ethyl acetate (4:1) and the mixture was stirred at room temperature over night. The precipitate was collected, washed with mixture of hexane/ethyl acetate (4:1), and dried in vacuo to afford N-[(4′R)-2″-amino-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-6′-yl]-5-me thoxypyrazine-2-carboxamide (246 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[N:10]=2)[N:7]=1.[F:15][C:16]1[CH:21]=[C:20]([C:22]([OH:25])([CH3:24])[CH3:23])[CH:19]=[C:18]([F:26])[C:17]=1[C:27]1[S:31][C:30]([NH2:32])=[C:29]([C:33]([NH2:35])=[O:34])[CH:28]=1>>[F:15][C:16]1[CH:21]=[C:20]([C:22]([OH:25])([CH3:24])[CH3:23])[CH:19]=[C:18]([F:26])[C:17]=1[C:27]1[S:31][C:30]([NH:32][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[N:10]=3)[N:7]=2)=[C:29]([C:33]([NH2:35])=[O:34])[CH:28]=1
Reactant: CC(C)(O)c1cn2nc(Cl)ccc2n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc4nc(C(C)(C)O)cn4n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1, Step 5 using 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)propan-2-ol (258 mg, 1.22 mmol) and 5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-amino-thiophene-3-carboxamide (90 mg, 0.31 mmol) as starting materials.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(N(CC)C(C)C)(C)C.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([C:42](Cl)=[O:43])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>C1COCC1.C(OCC)(=O)C>[C:29]([O:33][C:34]([N:36]1[CH2:37][CH2:38][N:39]([C:42]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:13]2[C:11](=[O:12])[NH:10][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[O:9][N:8]=2)=[O:43])[CH2:40][CH2:41]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2)no1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCCC[C@H]2C(=O)Nc2cc(C(C)(C)C)on2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-Piperidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl) amide; hydrochloride (675 mg; 2.345 mmol) in THF (18 mL) is added N,N-diisopropylethylamine (0.81 mL; 4.65 mmol) and 4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butyl ester (609 mg; 2.45 mmol). The reaction mixture is left stirring at room temperature for 18 hours. After this time, the reaction mixture is diluted with ethyl acetate and washed with water then brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using ethyl acetate/Hexanes provides the title compound, m/z 464 [M+H+].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH3:16]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COc1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccccc3OC)c2cc1OC
Temperature: 150 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (102 mg) and commercially available 2-methoxyphenol (0.5 ml) were mixed and stirred at 150° C. for 8 hours. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and then partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with brine and then dried with sodium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting first with hexane/ethyl acetate and then with chloroform/methanol to obtain 76 mg of the title compound (yield: 54%).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[O:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:19][C:18](=O)[C:17](=[O:28])[CH:16]=2)[CH2:11][CH2:10]1>C(O)(=O)C>[O:24]1[CH2:25][CH2:26][N:21]([C:20]2[C:15]([N:12]3[CH2:11][CH2:10][O:9][CH2:14][CH2:13]3)=[CH:16][C:17]([OH:28])=[C:18]([N:2]=[N:1][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[CH:19]=2)[CH2:22][CH2:23]1
Reactant: NNc1ccccn1
Reactant: O=C1C=C(N2CCOCC2)C(N2CCOCC2)=CC1=O
Solvent: CC(=O)O
Product: Oc1cc(N2CCOCC2)c(N2CCOCC2)cc1N=Nc1ccccn1
Reaction time: 8 h

Procedure:
To 60 ml acetic acid were added in order 1.48 g (14 mmol) 2-hydrazinopyridine and 3.8 g (14 mmol) freshly prepared 4,5-di-morpholino-1,2-benzoquinone [Brackman and Havinga, Rec. trav. chim Pays-bas 74, 937 (1955)] at room temperature. The mixture was stirred overnight and the solvent taken off on a rotary evaporator. After dilution with water, the solid residue was filtered off, washed with water and air dried. The product was extracted twice with hot acetonitrile leaving 1.97 g product. The extract yielded another 1.02 g on cooling. Yield 3.0 g (59%).
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:26]=2)=[O:22])[CH2:17][CH2:16]1)=O)(C)(C)C>CO.CCOCC>[ClH:1].[C:34]1([CH2:33][CH2:32][O:31][C:27]2[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=2)[CH2:24][O:23][C:21]([N:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[O:22])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2cccc(OCCc3ccccc3)c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: C1COCCO1
Product: O=C(OCc1cccc(OCCc2ccccc2)c1)N1CCNCC1
Reaction time: 3 h
Yield: 93 %

Procedure:
4M HCl in 1,4-dioxane (2.3 mL, 9.2 mmol) was added to a solution of piperazine-1,4-dicarboxylic acid 3-(2-phenylethoxy)benzyl ester tert-butyl ester (0.10 g, 0.23 mmol) in methanol (2 mL) and ether (2 mL) and the solution was left to stand with occasional swirling at room temperature for 3 h. The solution was concentrated in vacuo and the residue was triturated with ether to yield the title compound (0.08 g, 93%) as a white solid. 1H-NMR (400 MHz, d6-DMSO): 3.03 (2H, t, J=6.8 Hz), 3.08 (4H, m), 3.61 (4H, m), 4.19 (2H, t, J=7.0 Hz), 5.06 (2H, s), 6.88–6.94 (3H, m), 7.20–7.33 (6H, m) and 9.19 (2H, br s).
Reaction SMILES: [O:1]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])S(C(F)(F)F)(=O)=O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][C:25]3[CH:35]=[C:34]([N:36]([C:41]4[CH:46]=[CH:45][C:44](O)=[C:43]([F:48])[CH:42]=4)[S:37]([CH3:40])(=[O:39])=[O:38])[C:33]([CH:49]4[CH2:51][CH2:50]4)=[CH:32][C:26]=3[C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[CH:19][CH:18]=1.N1C=CC=CC=1.O>C(Cl)Cl>[F:15][C:12]([F:13])([F:14])[S:9]([O:1][C:44]1[CH:45]=[CH:46][C:41]([N:36]([C:34]2[C:33]([CH:49]3[CH2:51][CH2:50]3)=[CH:32][C:26]3[C:27]([C:28](=[O:29])[NH:30][CH3:31])=[C:23]([C:20]4[CH:19]=[CH:18][C:17]([Cl:16])=[CH:22][CH:21]=4)[O:24][C:25]=3[CH:35]=2)[S:37]([CH3:40])(=[O:38])=[O:39])=[CH:42][C:43]=1[F:48])(=[O:10])=[O:11]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(O)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(OS(=O)(=O)C(F)(F)F)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Tf2O (0.157 mL, 0.930 mmol) in CH2Cl2 (1 mL) was added dropwise to a suspension of 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(3-fluoro-4-hydroxyphenyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide (328 mg, 0.620 mmol) and pyridine (0.251 mL, 3.10 mmol) in CH2Cl2 (5 mL) under N2 at room temperature. The mixture was stirred at room temperature for 3 h then water was added. The mixture was extracted with CH2Cl2 and the combined organic phases were dried over Na2SO4, filtered, concentrated at reduced pressure, and purified by flash chromatography on silica gel eluted (0-40% EtOAc/hexane) to give the desired compound as a white solid (410 mg, 83% yield). LCMS (m/z, ES+)=661 (M+H+).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:15][CH2:16][C:17](=O)[CH2:18][CH3:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:18]([C:17]1[CH2:16][CH2:15][C@@H:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1)[CH3:19]
Reactant: CCOC(=O)[C@H](CCC(=O)CC)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CCC(CC)=N1

Procedure:
Ethyl(2S)-2-((tert-butoxycarbonyl)amino)-5-oxoheptanoate and trifluoroacetic acid (3 mL) were stirred in dichloromethane (3 mL) at room temperature for 3 hours. The mixture was concentrated under reduced pressure to provide the titled compound. MS (ESI) m/z 170 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][C:47]=1[F:48])[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([CH:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[N:35]=1>CN(C)C=O.CN(C)C(=O)C>[CH:42]1([C:40]([NH:39][C:37]2[N:38]=[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:45]=[CH:46][C:47]([F:48])=[C:26]([NH:25][C:7]([C:6]5[N:2]([CH3:1])[N:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=5)=[O:9])[CH:27]=4)=[N:35][N:34]3[CH:36]=2)=[O:41])[CH2:43][CH2:44]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: Cn1nc(C(F)(F)F)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cn1nc(C(F)(F)F)cc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 78.2 %

Procedure:
In the same manner as in Example 259 and using 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (150 mg, 0.79 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (140 μL, 1.6 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.61 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (240 mg, 77%) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.Br[CH2:13][CH2:14][O:15][CH3:16].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:13][CH2:14][O:15][CH3:16])[C:6]=2[CH:11]=1
Reactant: COCCBr
Reactant: O=c1[nH]c2cc(Br)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COCCn1c(=O)oc2ccc(Br)cc21
Temperature: 60 °C

Procedure:
A mixture of 5-bromobenzo[d]oxazol-2(3H)-one (2.06 g), 1-bromo-2-methoxyethane (1.085 mL) and potassium carbonate (3.99 g) in acetonitrile (15 mL) was heated at 60° C. for 16 h. Water was added and the mixture was extracted with ethyl acetate (3 times). The organic layers were dried over magnesium sulfate, evaporated and purified by flash silica chromatography eluting with 5:1 isohexane/acetone to give the subtitled compound (1.359 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1.O>CN(C=O)C.C(NCC)C.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:18]([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=3)=[CH:19][C:4]=2[CH:3]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: Oc1ccc(F)cc1I
Agent: [Cu]I
Solvent: O
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3cc(F)ccc3o2)cc1
Reaction time: 1 h

Procedure:
A solution of 4-Fluoro-2-Iodophenol [2713-29-3] (0.9 g, 3.8 mmol), 4-Methoxyphenylacetylene (0.53 g, 4.0 mmol), PdCl2P(PH3)2 (70 mg), and CuI (50 mg) in DMF/Diethylamine (10 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give a solid which was triturated with MeOH, and filtered to give 83 as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH2:4][C:3]1=[O:15].O1CCCC1.[N:21](OCCC(C)C)=[O:22].CC(C)([O-])C.[K+]>Cl.C(OC)(C)(C)C.C1CCCCC1>[CH3:1][N:2]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:4](=[N:21][OH:22])[C:3]1=[O:15]
Reactant: CN1C=CC(c2ccccc2)=CCC1=O
Reactant: CC(C)CCON=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: C1CCCCC1
Product: Cn1ccc(-c2ccccc2)cc(=NO)c1=O
Temperature: -10 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
The 1-methyl-5-phenyl-1,3-dihydro-azepin-2-one (183 g, 918.4 mmol) is combined with tetrahydrofuran (1500 mL) and the solution cooled to −25° C. to −30° C. Isoamyl nitrite (148.1 mL, 1.102 mol) is added followed by potassium tertiary-butoxide (108.2 g, 964.4 mmol) providing an exotherm to about −5° C. The solution is re-cooled to −10° C., then allowed to slowly warm to room temperature. The reaction contents are allowed to stir overnight. The reaction contents are diluted with 3N aqueous HCl (300 mL) providing a pH of about 2. It is then diluted with methyl tertiary-butyl ether (4 L) and washed the contents with 0.5-1.0 N HCl (2×600 mL) and saturated aqueous sodium chloride. The dark organic layer is dried over MgSO4, filtered, and concentrated to provide a residue wet with tetrahydrofuran. The residue is diluted with cyclohexane (300 mL) and concentrated to provide about 275 g of a crude residue that is slurried in methyl tertiary-butyl ether (450 mL) and cyclohexane (1000 mL). Heat the slurry to about 40° C., cool to room temperature, filter, and rinse with cyclohexane. Vacuum dry at 40° C. to provide the title compound (169 g, 81%) as a brown powder.
Reaction SMILES: [CH2:1]([N:5]1[CH2:22][C:21]([F:24])([F:23])[O:20][C:7]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH2:6]1)[C:2]#[C:3][CH3:4].Cl.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>ClCCl.C(Cl)Cl.C(#N)C>[CH2:1]([N:5]1[CH2:22][C:21]([F:23])([F:24])[O:20][C:7]2([CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)[CH2:6]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCN1CC(F)(F)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: C1COCCO1
Product: CC#CCN1CC(F)(F)OC2(CCNCC2)C1
Reaction time: 1 h
Yield: 96 %

Procedure:
Tert-butyl 8-but-2-ynyl-10,10-difluoro-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (50.0 mg, 0.145 mmol) was dissolved in dichloromethane (1 mL) and treated with HCl in dioxane (1.3 mL of 4 M, 5.1 mmol). The reaction mixture was stirred for 1 h then concentrated in vacuo several times with acetonitrile to yield a white solid. The solid was dissolved in 1:1 DCM/acetonitrile and stirred with solid K2CO3 for 1 h. The mixture was filtered and concentrated to provide 8-but-2-ynyl-10,10-difluoro-11-oxa-3,8-diazaspiro[5.5]undecane (34 mg, 96%). ESI-MS m/z calc. 244.1. found 245.3 (M+1)+; Retention time: 0.79 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5](Cl)[C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][N:8]=2)[N:3]=1.Cl.Cl.[CH3:19][N:20]([CH3:28])[C@H:21]1[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]1>>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([N:20]([CH3:28])[CH3:19])[CH2:22][CH2:23]1
Reactant: CS(=O)(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CN(C)[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CN(C)[C@H]1CC[C@H](Nc2c(S(C)(=O)=O)cnc3ccc(Cl)nc23)CC1

Procedure:
Following general procedure I, 2,8-dichloro-7-(methylsulfonyl)-1,5-naphthyridine (140 mg, 0.52 mmol) was reacted with trans-N1,N1-dimethylcyclohexane-1,4-diamine dihydrochloride (140 mg, 0.65 mmol) to afford the desired product (68 mg, 34%) as an off-white solid: ESI MS m/z 383 [M+H]+
Reaction SMILES: CC1(C)[N:6](C([O-])=O)CCO1.[N+](C1C=C([N+]([O-])=O)C=CC=1[N:23]1[C:27]([CH2:28][C@@H:29]([C:31]([OH:33])=O)N)=[CH:26][N:25]=[CH:24]1)([O-])=O>>[NH:25]1[CH:26]=[C:27]([CH2:28][CH2:29][C:31]([NH2:6])=[O:33])[N:23]=[CH:24]1
Reactant: N[C@@H](Cc1cncn1-c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O
Reactant: CC1(C)OCCN1C(=O)[O-]
Product: NC(=O)CCc1c[nH]cn1

Procedure:
In an analogous manner to that described in Example 16, by reacting t-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(R or S)-hydroxy-[(R or S)-tetrahydro-2-furyl]-methyl]-2,2-dimethyl-3-oxazolidinecarboxylate with N-](S)-α-[(t-butylsulphonyl)methyl]hydrocinnamoyl]-3-(2,4-dinitrophenyl)-L-histidine there is obtained (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3R or S)-1-(cyclohexylmethyl)-2,3-dihydroxy-3-[(R or S)-tetrahydro-2-furyl]propyl]imidazole-4-propionamide in the form of a yellow amorphous powder, MS: 827 (M+H)+. The cleavage of the dinitropheyl group with thiolactic acid is effected in an analogous manner to Example 13 and yields (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hudrocinnamamido]-N-[(1S,2R,3R or S)-1-(cyclohexylmethyl)-2,3-dihydroxy-3-[(R or S)-tetrahydro-2-furyl]propyl]imidazole-4-propionamide as a pale yellow amorphous solid, MS: 661 (M+H)+.