Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([NH:12]C(=O)OC)[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[C:3]([C:8]2([NH2:12])[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)NC1(c2ncccc2F)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC1(c2ncccc2F)CCC1
Temperature: 150 °C
Yield: 92.6 %

Procedure:
To a 20 mL microwave reaction vial was added methyl 1-(3-fluoropyridin-2-yl)cyclobutylcarbamate (1.47 g, 6.56 mmol, 1.0 equiv), ethanol (12 mL) and 3N aqueous sodium hydroxide (7 mL). The reaction mixture was heated in the microwave reactor at 150° C. for 30 min. The ethanol was evaporated under reduced pressure and the mixture was extracted with ethyl acetate (30 mL). The aqueous layer was then extracted with ethyl acetate (2×30 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to give 1-(3-fluoropyridin-2-yl)cyclobutanamine (1.01 g, 93%) as a crude yellow oil that was used in the next reaction step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:26]2[N:30]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)[N:29]=[CH:28][CH:27]=2)O1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[N:6]3[CH:7]=[C:2]([C:26]4[N:30]([C:31]5[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=5)[N:29]=[CH:28][CH:27]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[CH:12][CH:13]=1
Reactant: Fc1ccc(-c2cnc3ccc(Br)cn23)cc1
Reactant: Cc1ccc(-n2nccc2B2OC(C)(C)C(C)(C)O2)cc1
Product: Cc1ccc(-n2nccc2-c2ccc3ncc(-c4ccc(F)cc4)n3c2)cc1

Procedure:
The title compound, white solid (14 mg, 11%), MS (ISP) m/z=369.5 [(M+H)+], mp 141° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(4-fluoro-phenyl)-imidazo[1,2-a]pyridine (intermediate E) (0.1 mg, 0.34 mmol) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-p-tolyl-1H-pyrazole (intermediate C) (0.083 g, 0.41 mmol).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][Mg]Br.[O:11]=[C:12]1[CH2:18][CH:17]2[N:19]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]([C:30]#[N:31])=[CH:22][CH:21]=3)[CH:14]([CH2:15][CH2:16]2)[CH2:13]1>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][C:12]1([OH:11])[CH2:13][CH:14]2[N:19]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]([C:30]#[N:31])=[CH:22][CH:21]=3)[CH:17]([CH2:16][CH2:15]2)[CH2:18]1
Reactant: N#Cc1ccc(N2C3CCC2CC(=O)C3)c2ccccc12
Reactant: Br[Mg]CCC1OCCCO1
Solvent: C1CCOC1
Product: N#Cc1ccc(N2C3CCC2CC(O)(CCC2OCCCO2)C3)c2ccccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1,3-Dioxane-2-ylethyl magnesium bromide reagent (0.5 M solution in anhydrous THF: 860 μL, 0.43 mmol) was added dropwise to a solution of 156AF03-217 (80 mg, 0.29 mmol) in anhydrous THF (2 mL) at rt. After 48 h stirring at rt the reaction was quenched with saturated ammonium chloride. The mixture was partitioned between ammonium chloride and ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. Purification of the residue by silica gel column chromatography, eluting with a stepwise gradient of 40-100% ethyl acetate in n-heptane, afforded the desired compound as a diastereomeric mixture, ratio 85:15 (37 mg, 45%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[CH:4][CH:3]=1.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[NH:1]1[C:2]2=[C:11]3[C:6](=[CH:5][CH:4]=[CH:3]2)[CH:7]=[CH:8][CH:9]=[C:10]3[NH:12][CH2:13]1
Reactant: Nc1cccc2cccc(N)c12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1cc2c3c(cccc3c1)NCN2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15175.5 %

Procedure:
A solution of the above aldehyde (1.17 g, 4 mmol), distilled 1,8-diamino naphthalene (0.63 g, 4 mmol), p-toluenesulfonic acid (10 mg), and tetrahydrofuran (6 mL) was stirred for 0.5 h at room temperature. The mixture was basified with 1 mL saturated sodium carbonate, diluted with THF-ether (1:1) and washed with water. The extract was concentrated and the residual solid was recrystallized from THF-ether (1:1, 30 mL) to give the 2,3-dihydroperimidine (1.50 g, 87%): mp 165-167° C.; 1H NMR (CDCl3) 7.59(s, 4H), 7.45 and 6.9(2d, 4H), 7.1(m, 4H), 6.4(d, 2H), 4.7(bs, 2H), 4.45(t, 1H), 4.0(t, 2H), 2.0-1.5(m, 8H); IR 3385, 3360, 2225, 1601 cm-1.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=1)[C:12]([C:14]1[CH:22]=[C:21]2[C:17](/[C:18](=[CH:24]/O)/[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[CH2:37][CH2:36]1>CCOC(C)=O>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=1)[C:12]([C:14]1[CH:22]=[C:21]2[C:17](/[C:18](=[CH:24]/[NH:47][C:44]3[CH:45]=[CH:46][C:41]([N:38]4[CH2:37][CH2:36][N:35]([CH3:34])[CH2:40][CH2:39]4)=[CH:42][CH:43]=3)/[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Nc2cc(C(=O)c3cccc(NCc4ccccc4)c3)ccc2/C1=C/O
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(N/C=C3\C(=O)Nc4cc(C(=O)c5cccc(NCc6ccccc6)c5)ccc43)cc2)CC1
Temperature: 65 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
A small screw cap test tube was charged with 6-(3-Benzylamino-benzoyl)-3-[1-hydroxy-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one (prepared below, 0.021 g, 0.056 mmol) and THF (1 mL). To the resulting solution was added 4-(4-Methyl-piperazin-1-yl)-phenylamine (10.7 mg, 0.056 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature. The yellow solid was dissolved in 5 mL of a solvent mixture containing 98% EtOAc/2% i-prOH and washed with water (2×5 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was chromatographed over silica (95/5 chloroform/Hexanes w/0.5% NEt3) to afford the title compound in 51% yield (15.5 mg, 0.028 mmol).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]4[N:24]=[CH:25][CH:26]=[CH:27][C:15]=4[N:14]3[C:28]=2[C:29]2[CH:34]=[CH:33][C:32]([C:35]3([NH:39]C(=O)OC(C)(C)C)[CH2:38][CH2:37][CH2:36]3)=[CH:31][CH:30]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[ClH:47].O1CCOCC1>C(Cl)Cl>[ClH:47].[ClH:47].[ClH:47].[NH2:39][C:35]1([C:32]2[CH:33]=[CH:34][C:29]([C:28]3[N:14]4[C:15]5[CH:27]=[CH:26][CH:25]=[N:24][C:16]=5[NH:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[C:13]4=[N:12][C:11]=3[C:8]3[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:10][CH:9]=3)=[CH:30][CH:31]=2)[CH2:38][CH2:37][CH2:36]1
Reactant: CC(=O)Nc1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.5 %

Procedure:
tert-Butyl (1-{4-[2-(4-acetamidophenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (22.6 mg, 0.0369 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 6 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (21.5 mg, 93.5%) as pale yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 10.08 (s, 1H), 8.70 (br s, 2H), 8.64 (s, 1H), 8.11 (dd, J=4.8, 1.6 Hz, 1H), 7.95 (dd, J=7.8, 1.8 Hz, 1H), 7.58-7.49 (m, 4H), 7.44-7.36 (m, 3H), 7.34-7.28 (m, 3H), 7.17-7.10 (m, 1H), 6.89 (dd, J=8.0, 1.6 Hz, 1H), 6.75 (dd, J=7.8, 4.6 Hz, 1H), 2.65-2.39 (m, 4H), 2.26-2.13 (m, 1H), 2.04 (s, 3H), 1.89-1.75 (m, 1H); LCMS: 513 [M+H].
Reaction SMILES: I[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[C:10]([C:12]1[N:16]([CH3:17])[CH:15]=[N:14][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)#[CH:11].C(N(CC)CC)C>CN(C=O)C.[Cu]I>[CH3:17][N:16]1[C:12]([C:10]#[C:11][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=2[NH2:9])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]=[CH:15]1
Reactant: C#Cc1c(-c2ccccc2)ncn1C
Reactant: Nc1ncnc(I)c1N
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cnc(-c2ccccc2)c1C#Cc1ncnc(N)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.4 %

Procedure:
6-Iodopyrimidine-4,5-diamine (Intermediate 89) (50 mg), CuI (2 mg), PdCl2dppf (16 mag), 5-ethynyl-1-methyl-4-phenyl-1H-imidazole (intermediate 26) (77 mg), and triethylamine (0.33 mL) in DMF (7 mL) were mixed together and then degassed. The reaction mixture was allowed to stir at ambient temperature under an inert atmosphere for 24 hours. The reaction mixture was filtered through diatomaceous earth, washing well with DCM and then MeCN. The organics were concentrated and the residue purified by chromatography on silica eluting with DCM:MeOH (9:1) to afford the title compound as a yellow solid (47 mg, 76%);
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12]([N+:17]([O-:19])=[O:18])=[C:13]([CH:16]=1)[CH:14]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][CH2:21][CH2:22][C:23]([N:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH3:26])=[O:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[C:1]([C:9]1[CH:10]=[CH:11][C:12]([N+:17]([O-:19])=[O:18])=[C:13]([CH:16]=1)[CH2:14][NH:20][CH2:21][CH2:22][C:23]([N:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH3:26])=[O:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C(=O)CCN)C1CCCCC1
Reactant: O=Cc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C(=O)CCNCc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-])C1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of 5-benzoyl-2-nitro-benzaldehyde (10 g, 0.0390 mol), a known compound (which may be prepared as disclosed in European Patent EP 371564) and 3-amino-N-cyclohexyl-N-methyl-propionamide (7.5 g, 0.0410 mol) in 1,2-dichloroethane (250 mL) was stirred at room temperature under nitrogen. Sodium triacetoxyborohydride (8.7 g, 0.0410 mol) was added, and the reaction mixture was stirred for 6 h at room temperature. Saturated NaHCO3 solution (200 mL) was then added. The organic layer was separated, dried, and evaporated. The resulting residue was purified by column chromatography on silica gel (eluent: 99:1 CH2Cl2:MeOH). The purest fractions were combined, and the solvent was evaporated to yield a residue.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.Cl.[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][NH2:28])=[CH:23][CH:22]=1>C(O)C.O1CCOCC1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=3)=[N:28]2)=[CH:23][CH:22]=1
Reactant: NNc1ccc(F)cc1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(SC)cc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2ccc(SC)cc2)nn1-c1ccc(F)cc1
Yield: 8.2 %

Procedure:
A mixture of ethyl 4-[4-(methylthio)phenyl]-2,4-dioxobutanoate (1 g) and 4-fluorophenylhydrazine hydrochloride (0.67 g) in ethanol (10 ml) and dioxane (10 ml) was refluxed for 5 hours. The solvent was evaporated, and the residue was dissolved in chloroform and washed with water. The organic layer was dried over magnesium sulfate and concentrated. The residue (1.6 g) was purified by column chromatography on silica gel (30 g) eluting with a mixture of toluene and ethyl acetate (20:1) to give ethyl 1-(4-fluorophenyl)-3-[4-(methylthio)phenyl]pyrazole-5-carboxylate (0.11 g).
Reaction SMILES: C([O:8][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][O:13][C:14](=[O:27])[C@H:15]([CH:24]([CH3:26])[CH3:25])[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])C1C=CC=CC=1>C(OCC)(=O)C.CO.[Pd]>[C:17]([NH:16][C@H:15]([C:14]([O:13][CH2:12][CH2:11][CH2:10][C:9]([OH:28])=[O:8])=[O:27])[CH:24]([CH3:26])[CH3:25])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCCC(=O)O
Reaction time: 2 h

Procedure:
To a solution of 4-(N-Boc-L-valyloxy)butyric acid benzyl ester (1.2 g, 3 mmole) in ethyl acetate/methanol (5 ml/5 ml) was added palladium black (20 mg). The reaction mixture was kept under hydrogen at atmospheric pressure for 2 hr. The suspension was filtered through Celite and dried, giving the title product, 840 mg.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([OH:24])=[C:21]([C:25]#[N:26])[C:20](=[O:27])[NH:19][C:18]=3[S:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:2].[BH4-].[Na+]>CO.ClCCl>[OH:24][C:22]1[C:23]2[C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[CH2:1][OH:2])=[CH:14][CH:13]=3)=[CH:16][S:17][C:18]=2[NH:19][C:20](=[O:27])[C:21]=1[C:25]#[N:26]
Reactant: N#Cc1c(O)c2c(-c3ccc(-c4ccccc4C=O)cc3)csc2[nH]c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: N#Cc1c(O)c2c(-c3ccc(-c4ccccc4CO)cc3)csc2[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(2′-formyl-1,1′-biphenyl-4-yl)-4-hydroxy-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (0.03 g, 0.08 mmol) in MeOH (2 mL) and dichloromethane (0.5 mL) was added NaBH4 (0.012 g, 0.32 mmol) in a single portion. The reaction was stirred at room temperature for 18 h. It was then cooled to 0° C. in an ice bath, quenched by slow addition of 1N HCl (10 mL) and extracted with dichloromethane (3×10 mL). The organic layers were dried with anhydrous sodium sulfate, concentrated and purified by RP-HPLC to give the title compound as a white solid. MS (ESI) m/e 372.9 (M−H)+; 1H NMR (400 MHz, DMSO-d6): δ ppm 12.42 (br s, 1H), 7.60 (dd, 1H), 7.50 (d, 2H), 7.32–7.42 (m, 4H), 7.26 (dd, 1H), 7.07 (s, 1H), 4.46 (s, 2H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:15]=[C:14]([O:16][CH2:17][C:18]#[CH:19])[C:13]([F:20])=[CH:12][C:5]=1[C:6]([O:8]CC#C)=[O:7].Cl>CO>[Cl:3][C:4]1[CH:15]=[C:14]([O:16][CH2:17][C:18]#[CH:19])[C:13]([F:20])=[CH:12][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: C#CCOC(=O)c1cc(F)c(OCC#C)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#CCOc1cc(Cl)c(C(=O)O)cc1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
To a mixture of 30 ml of methanol and 30 ml of a 15% aqueous sodium hydroxide solution was added 19 g of 2-propynyl 2-chloro-5-fluoro-4-(2-propynyloxy)benzoate obtained above, and then stirred at 50° C. for 2 hours. The reaction mixture was made acidic by addition of hydrochloric acid. Then, a produced solid was collected by filtration. The solid was washed with a MTBE-hexane mixed solvent, and 10 g of 2-chloro-5-fluoro-4-(2-propynyloxy)benzoic acid was obtained.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:32])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:50])[C@@H:15]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([O:42][Si](C(C)(C)C)(C)C)[CH2:36]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:32])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:50])[C@@H:15]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([OH:42])[CH2:36]2)=[CH:10]1
Reactant: CCC(Oc1ccccc1F)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(Oc1ccccc1F)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 73.3 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.26 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(2-fluorophenoxy)butyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described inExample 55, above] and 25.9 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 635 mg of the title compound as white crystals, melting at between 136° and 138° C.
Reaction SMILES: [C:1]([N:9]1[CH2:20][CH2:19][C:12]2[N:13]=[N:14][C:15]([NH:17][NH2:18])=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C>[C:1]([N:9]1[CH2:20][CH2:19][C:12]2[N:13]=[N:14][C:15]([NH:17][N:18]=[C:21]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cc2c(nn1)CCN(C(=O)c1ccccc1)C2
Reactant: O=C1CCCCCCCCCCC1
Solvent: CCO
Product: O=C(c1ccccc1)N1CCc2nnc(NN=C3CCCCCCCCCCC3)cc2C1

Procedure:
A suspension of 2.7 g of 6-benzoyl-3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine and 1.8 g of cyclododecanone in 20 cc of absolute ethanol is heated on a water bath for 30 minutes, whereby a dissolution and reprecipitation clearly occurs. The resulting title compound is recrystallized from a mixture of 160 cc of methanol and 30 cc of dimethyl formamide. M.P. 222°-225° (decomp.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([CH3:20])[CH2:18][NH2:19].CCN(C(C)C)C(C)C>C(O)(C)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:19][CH2:18][CH:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])[CH3:20])[CH:7]=1
Reactant: COc1ccccc1C(C)CN
Reactant: Clc1cc(Cl)ncn1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1C(C)CNc1cc(Cl)ncn1
Reaction time: 18 h
Yield: 77 %

Procedure:
As shown in step 4-v of Scheme 4, a mixture of 4,6-dichloropyrimidine (817 mg, 5.49 mmol), 2-(2-methoxyphenyl)-1-propanamine (0.997 g, 6.03 mmol), and DIEA (2.13 g, 2.87 mL, 16.5 mmol) in isopropanol (5.0 mL) was stirred for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue purified by medium pressure chromatography on silica gel (25% EtOAc in hexanes) to give 6-chloro-N-(2-(2-methoxyphenyl)propyl)pyrimidin-4-amine as a colorless solid (Compound 2012, 1.18 g, 77% yield): 1H NMR (CDCl3) δ 8.31 (s, 1H), 7.23 (dd, J=12.0, 4.5 Hz, 2H), 7.03-6.87 (m, 2H), 6.41 (s, 1H), 5.42 (s, 1H), 3.89 (s, 3H), 3.67-3.18 (m, 3H), 1.35 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:40][CH3:41])[C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=[O:39])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34](I)[CH:33]=2)=[C:8]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][N:29]=2)[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:14])[CH:9]=1)[CH3:2].[CH2:42]([OH:57])[CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][C:55]#[CH:56].CCN(CC)CC>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1COCC1>[CH2:1]([N:3]([CH2:40][CH3:41])[C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=[O:39])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:56]#[C:55][CH2:54][O:53][CH2:52][CH2:51][O:50][CH2:49][CH2:48][O:47][CH2:46][CH2:45][O:44][CH2:43][CH2:42][OH:57])[CH:33]=2)=[C:8]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][N:29]=2)[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:14])[CH:9]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(I)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: C#CCOCCOCCOCCOCCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C#CCOCCOCCOCCOCCO)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 13 h
Yield: 78.8 %

Procedure:
To a slurry of 2-(5-(diethylamino)-2-(3-iodobenzamido)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide (385 mg, 0.57 mmol), 3,6,9,12-tetraoxapentadec-14-yn-1-ol (175 mg, 0.75 mmol), Et3N (3 mL) and THF (2 mL) was added bis(triphenylphosphine)palladium(II)dichloride (12 mg, 0.017 mmol) and CuI (10 mg, 0.053 mmol) and purged well with nitrogen. The reaction mixture was stirred for 13 hours, then concentrated under vacuum and combined with the crude product from another run (0.15 mmol scale). Purification by flash chromatography on silica gel eluting (1% to 5% MeOH in DCM) gave the title compound (349 mg). 1H NMR (400 MHz, CDCl3, ppm) δ□ 12.51 (s, 1H), 8.83 (d, J=5.3 Hz, 1H), 8.42 (d, J=9.0 Hz, 1H), 8.21 (s, 1H), 7.99 (t, J=1.6 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.75-7.68 (m, 2H), 7.65 (s, 1H), 7.60 (d, J=7.3 Hz, 1H), 7.58-7.54 (m, 2H), 7.48 (t, J=7.6 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 6.98 (d, J=2.6 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H), 4.76 (d, J=5.9 Hz, 2H), 4.48 (s, 2H), 3.82-3.80 (m, 2H), 3.72-3.70 (m, 2H), 3.67-3.63 (m, 4H), 3.60 (s, 4H), 3.53-3.51 (m, 2H), 3.32 (quar, J=7.2 Hz, 4H), 2.90 (s, 1H), 1.13 (t, J=6.8 Hz, 6H). MS (ES, m/z): 777.4 [M+H]+.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br.CCO.O.[K+].[Br-]>O>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:15]1[C:14]2[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:13]=2[O:12][CH:11]([CH2:10][CH2:9][OH:1])[C:16]1=[O:17]
Reactant: Clc1cccc(CBr)c1
Reactant: COc1ccc2c(c1)NC(=O)C(CCO[Si](C)(C)C(C)(C)C)O2
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)N(Cc1cccc(Cl)c1)C(=O)C(CCO)O2

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-6-methoxy-3-oxo-2H-1,4-benzoxazine by methods F and G, alkylating with 3-chlorobenzyl bromide, in 80% overall yield. Isolated by crystallization from EtOH/water to afford a white powder, MS (Cl) 348 (MH+); IR (KBr) 3501, 3053, 3021, 2959, 2933, 2876, 2838, 1664, 1618, 1600, 1575, 1512, 1466, 1445, 1435, 1390, 1361, 1337, 1313, 1272, 1237, 1201, 1173, 1107, 1078, 1049, 1030 cm-1 ; 1H NMR (CDCl3) δ 7.27-7.20 (m, 3H), 7.13 (m, 1H), 6.94 (d, J=8.8 Hz, 1H), 6.52 (dd, J=9.1, 2.7 Hz, 1H), 6.41 (d, J=2.7 Hz, 1H), 5.12 (d, J=16.2 Hz, 1H), 4.79 (dd, J=8.2, 5.4 Hz, 1H), 3.92 (m, 2H), 3.68 (s, 3H), 3.39-2.16 (m, 2H), 2.17 (t, J=5.9 Hz, 1H). Anal. Calc'd for C18H18ClNO4.0.25 H2O: C 61.37, H 5.29, N 3.98. Found: C 61.35, H 5.14, N 3.95.