Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([C:10]#[C:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:8][N:9]=1)[CH:5]=[O:6].[CH3:20][Mg]Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH3:20])[C:7]([C:10]#[C:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:8][N:9]=1
Reactant: Cc1ccc(F)cc1C#Cc1cnc(Cl)cc1C=O
Reactant: C[Mg]Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)ncc1C#Cc1cc(F)ccc1C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a solution of 2-chloro-5-((5-fluoro-2-methylphenyl)ethynyl)isonicotinaldehyde (705 mg, 2.6 mmol) in tetrahydrofuran (11 mL) cooled at −15° C. was added a solution of 3.0M methylmagnesium chloride in tetrahydrofuran (1 mL, 3.1 mmol) dropwise over 1 minute. The reaction mixture was stirred at this temperature for 15 minutes and then quenched with a few drops of saturated aqueous ammonium chloride solution, tetrahydrofuran was evaporated in vacuo, and the resulting residue was redissolved in dichloromethane (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a colorless oil that was redissolved in dichloromethane (10 mL) and treated with Dess-Martin periodinane (1.4 g, 3.4 mmol). The reaction mixture was stirred at room temperature for 1 hour, and then diluted with dichloromethane (100 mL) and washed with saturated aqueous sodium bicarbonate solution (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 40 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as a pale yellow solid (700 mg, 90%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C@H:2]([N:6]1CCC[C:7]1=[O:11])[C:3]([OH:5])=[O:4].C(I)C.[CH2:15]([S:22]CBr)[C:16]1[CH:21]=[CH:20]C=[CH:18][CH:17]=1>>[CH2:21]([C:16]1([CH2:15][SH:22])[CH2:17][CH2:18][N:6]([C@@H:2]([CH3:1])[C:3]([OH:5])=[O:4])[C:7]1=[O:11])[CH3:20]
Reactant: C[C@@H](C(=O)O)N1CCCC1=O
Reactant: BrCSCc1ccccc1
Solvent: CCI
Product: CCC1(CS)CCN([C@@H](C)C(=O)O)C1=O

Procedure:
Following the procedures of Examples 1C-1E, α(S)-methyl-2-oxo-1-pyrrolidineacetic acid was first alkylated with ethyl iodide and then with benzylmercaptomethyl bromide. Removal of the benzyl group in the usual way and purification by chromatography provided the title compound as a mixture of diastereomers. [α]D25 =-4.04° (c=1, methanol).
Reaction SMILES: Br[CH2:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13].[C:14]1([N:20]2[C:24]([SH:25])=[N:23][N:22]=[N:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na].O>CN(C)C(=O)C>[C:7]1(=[O:8])[N:3]([CH2:2][S:25][C:24]2[N:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:21]=[N:22][N:23]=2)[C:4](=[O:13])[C:5]2=[CH:12][CH:11]=[CH:10][CH:9]=[C:6]12
Reactant: O=C1c2ccccc2C(=O)N1CBr
Reactant: Sc1nnnn1-c1ccccc1
Agent: [Na]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C1c2ccccc2C(=O)N1CSc1nnnn1-c1ccccc1
Yield: 72 %

Procedure:
A solution of 2.40 g N-(bromomethyl)phthalimide (0.010 mol) and 2.00 g 1-phenyl-1H-tetrazole-5-thiol, sodium salt (0.010 mol) in 20 ml N,N-dimethylacetamide was stirred 0.5 hours. The slurry was then poured into water extracted with ethyl acetate, dried and concentrated in vacuo. The solid obtained was recrystallized from ethyl acetate/hexane to give 2.43 g (72.0%) of a colorless solid, m.p. 146°-7° C.
Reaction SMILES: [C:1]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:14]N1C(C)(C)C(=O)N(Br)C1=O>C1(C)C=CC=CC=1>[Br:14][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Br)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 18 h
Yield: 176.5 %

Procedure:
t-Butyl ethyl malonate (25.00 g, 0.13 mol) was dissolved in toluene and warmed to 80° C. To the resulting solution was added 1,3-dibromo-5,5-dimethylhydantoin (25.00 g, 0.07 mol). The reaction was stirred at elevated (80° C.) temperature 18 hr. The reaction was cooled, concentrated and taken up in Et2O. The organic layer was washed with saturated NaHCO3 (2×), brine (3×), dried (MgSO4), filtered and concentrated. Purification by filtration on silica (70:30-heptane:ethyl acetate) yielded 33.0 g (93%) of a light yellow oil. NMR and MS indicated a mixture of three compounds, starting material (20%), monobrominated (55%) and dibromonated diesters (25%). The material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][CH2:22][S:23]([O-:26])(=O)=[O:24])[O:12]1.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)[Cl:45].CN(C)C=O.S(Cl)(Cl)=O>>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][CH2:22][S:23]([Cl:45])(=[O:26])=[O:24])[O:12]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CCS(=O)(=O)[O-])O[C@H]2n1cnc2c(Cl)ncnc21
Reactant: ClCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CCS(=O)(=O)Cl)O[C@H]2n1cnc2c(Cl)ncnc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 78.1 %

Procedure:
Tetrabutyl-ammonium 2-[(3aR,4R,6R,6aR)-6-(6-chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-ethanesulfonate (250.0 mg, 0.0003481 mol) was dissolved in methylene chloride (5.00 mL, 0.0780 mol) and N,N-dimethylformamide (100.0 μL, 0.001292 mol). Thionyl chloride (228 μL, 0.00313 mol) was added and the reaction was stirred at 0° C. for 45 minutes, concentrated in vacuo to dryness and followed by azeotroping with toluene. The residue was purified by flash chromatography (10% THF in DCM) to yield product (115 mg, 78%).
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1>CO.[Pd]>[CH3:1][O:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)[CH2:5][CH2:4]1
Reactant: CON1CC=C(c2ccc(N)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CON1CCC(c2ccc(N)cc2)CC1
Yield: 92.1 %

Procedure:
A solution of 4-(1-methoxy-1,2,3,6-tetrahydro-pyridin-4-yl)-phenylamine (as prepared in previous step) (40.8 mg, 0.200 mmol) in MeOH (5 mL) was hydrogenated over 10% Pd/C (20.4 mg) at 20 psi for 1h. The solution was filtered through a pad of Celite and concentrated to give 4-(1-methoxy-piperidin-4-yl)-phenylamine (38 mg, 92%) which was directly used in the next step without purification.
Reaction SMILES: CS(Cl)(=O)=O.Cl.Cl.Cl.N1C=C(C[N:15]2[C:21]3[CH:22]=CC(C4C=NC=CC=4)=[CH:25][C:20]=3[CH2:19][N:18]([C:32](=[O:37])[C:33](F)(F)F)[CH:17]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:16]2)N=C1>C(Cl)Cl.O>[C:16]([C:17]1[CH:38]=[CH:22][C:21]2[NH:15][CH2:16][C@@H:17]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:18]([C:32](=[O:37])[CH2:33][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:19][C:20]=2[CH:25]=1)#[N:15]
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc2c(c1)CN(C(=O)Cc1ccccc1)[C@H](Cc1ccccc1)CN2
Temperature: 25 °C
Reaction time: 16 h
Yield: 151.8 %

Procedure:
Methanesulfonyl chloride (3.68 mL, 47.6 mmol) was added dropwise as a solution in CH2Cl2 (20 mL) to a solution of Compound B (10 g, 36.6 mmol) in CH2Cl2 (130 mL) at 0° C. under argon. After stirring at rt for 16 hr the reaction was diluted with water (20 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×40 mL). The combined organic layers were washed with water (1×30 mL), KHSO4 (2×30 mL), water (1×30 mL), NaHCO3 (2×30 mL), brine (1×30 mL), dried over MgSO4, filtered and concentrated to afford a golden brown oil. The oil was crystalized from EtOAc/hexanes and the yellow solid triturated with hexane and dried to afford Compound C (10.6 g, 82%). MS:[M+H]+=351.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.CN1CCOCC1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29]>C(Cl)(Cl)Cl>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([N:25]=[C:2]=[O:4])=[CH:23][C:22]=1[C:28]([F:29])([F:30])[F:31]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 40 °C
Reaction time: 15 h
Yield: 161.2 %

Procedure:
With a waste gas absorption device, triphosgen (167 g, 0.56 mol, 0.5 eq) was dissolved in chloroform (500 mL). A solution of N-methyl morpholine (11.4 g, 0.11 mol, 0.1 eq) in chloroform (100 mL) was added dropwise into the above mixture at 5° C. After addition, a solution of 4-chloro-3-(trifluoromethyl)aniline (220 g, 1.13 mol, 1.0 eq) in chloroform (700 mL) was added dropwise at 10° C. The mixture was warmed to 40° C. and stirred for 15 hours, and then warmed to 50° C. and stirred for 5 hours, and then heated to 60-65° C. and refluxed for 5 hours. The solvent was removed under atmospheric pressure. The residue was distilled under vacuum (oil temperature 110-120° C., vacuum 200 Pa) and the fractions at 95-100° C. were collected to give the title compound (200 g, purity 98.7%, yield 84%) as a colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH2:24]([S:28]([NH2:31])(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([NH:31][S:28]([CH2:24][CH2:25][CH2:26][CH3:27])(=[O:30])=[O:29])=[O:21])=[CH:22][CH:23]=1
Reactant: CCCCS(N)(=O)=O
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCS(=O)(=O)NC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.4 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) in dichloromethane (5 mL) was added butane-1-sulfonic acid amide (44.2 mg, 0.32 mmol), N,N-dicyclohexylcarbodiimide (67.1 mg, 322 mmol) and 4-dimethylaminopyridine (40.1 mg, 0.32 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was then filtered and the filtrate was concentrated and purified by chromatography (SiO2, heptane:ethyl acetate 100:0 to 0:100) to give the title compound (17 mg, 12%) as a white solid. MS: m/e=428.1 [M−H].
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([O:15]CC3C=CC=CC=3)=[O:14])=[CH:11][CH:10]=2)=[CH:6][C:5]=1[O:27]CC1C=CC=CC=1)([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:6][C:5]=1[OH:27]
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccc(C(=O)O)cc2)cc1O
Reaction time: 8 h
Yield: 93 %

Procedure:
46.6 g of the benzyl 4-(4-nitro-3-benzyloxyphenoxy)benzoate (0.11 mol) prepared as described in Example 4 are dissolved in 500 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 5 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated using hydrogen at a pressure of 1 bar at room temperature in an autoclave with vigorous stirring; the reaction is terminated after 3 days. The pale violet solution is evaporated to half in a rotary evaporator and left to stand overnight at room temperature, during which the reaction product precipitates out in crystalline form. The reaction product is then separated off and dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 93%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:17]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])=[CH:16][N:15]([CH3:27])[C:4]=2[N:5]=[C:6]([N:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])[N:7]=1.C(O)(=[O:30])C>[OH-].[Na+].O>[CH2:9]([N:8]([CH2:12][CH2:13][CH3:14])[C:6]1[NH:7][C:2](=[O:30])[C:3]2[C:17]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])=[CH:16][N:15]([CH3:27])[C:4]=2[N:5]=1)[CH2:10][CH3:11]
Reactant: CCCN(CCC)c1nc(Cl)c2c(-c3c(C)cc(C)cc3C)cn(C)c2n1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCN(CCC)c1nc2c(c(-c3c(C)cc(C)cc3C)cn2C)c(=O)[nH]1
Yield: 81 %

Procedure:
4-Chloro-5-mesityl-7-methyl-N,N-dipropyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine (50 mg, 0.13 mmol) in aqueous sodium hydroxide (2M, 10 ml) was heated at reflux for 6 hours. The solution was cooled to room temperature and neutralized with acetic acid. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (50 ml×3). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (4:1) to give 39 mg (81%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:21][NH:22][CH3:23]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:22]([CH3:23])[CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reaction time: 3 h
Yield: 76.2 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.010 mole) 1,1'-carbonyldiimidazole (1.7 g, 0.010 mole) and dry tetrahydrofuran (150 ml) was stirred for 3 hrs. at room temperature with a stream of nitrogen bubbling through it. A solution of 1.0 g of dimethylamine in 25 ml of tetrahydrofuran was added and the reaction container was stoppered and the mixture was stirred overnight at room temperature. The tetrahydrofuran was evaporated and the residue triturated in water (50 ml) and filtered. The filter cake was recrystallized from isopropyl alcohol and then from ethanol, giving 2.4 g (32%) of white needles, mp 212°-213° C.
Reaction SMILES: C(O[CH:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.C[Si]([N:32]=[N+:33]=[N-:34])(C)C.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][C@H:5]1[N:32]=[N+:33]=[N-:34])(=[O:10])[CH3:9]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](N=[N+]=[N-])[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.8 %

Procedure:
1,2,3,4,6-penta-O-acetyl-galactopyranose (1.17 g, 3 mmol) was dissolved in dry CH2Cl2 (15 ml), then trimethylsilyl azide (416 mg, 3.6 mmol) and SnCl4 (0.18 ml) were added under nitrogen. The mixture was stirred at room temperature for 24 hours. The reaction mixture was subsequently diluted with CH2Cl2 (40 ml), dried over MgSO4 and evaporated. The residue was purified by chromatography using hexane/EtOAc 8:7 v/v as the mobile phase to give 2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl azide (1.05 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@H:56](OC)[CH3:57])[C:7]([N:9]1[C@H:14]([C:15]2[NH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:27]=[C:28]5[C:52](=[CH:53][CH:54]=4)[C:32]4[NH:33][C:34]([C@@H:36]6[CH2:40][CH2:39][CH2:38][N:37]6[C:41](=[O:51])[C@@H:42]([NH:46][C:47](=[O:50])[O:48][CH3:49])[CH:43]([CH3:45])[CH3:44])=[N:35][C:31]=4[CH:30]=[CH:29]5)=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[C@@H:13]2[CH2:55][C@H:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4].CO[C@H:62]([CH3:72])[C@H:63](NC(OC)=O)[C:64](O)=O>>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:56]1[CH:57]=[CH:64][CH:63]=[CH:62][CH:72]=1)[C:7]([N:9]1[C@H:14]([C:15]2[NH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:27]=[C:28]5[C:52](=[CH:53][CH:54]=4)[C:32]4[NH:33][C:34]([C@@H:36]6[CH2:40][CH2:39][CH2:38][N:37]6[C:41](=[O:51])[C@@H:42]([NH:46][C:47](=[O:50])[O:48][CH3:49])[CH:43]([CH3:44])[CH3:45])=[N:35][C:31]=4[CH:30]=[CH:29]5)=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[C@@H:13]2[CH2:55][C@H:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]5)cc4)ccc3c2[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]5)cc4)ccc3c2[nH]1)C(C)C

Procedure:
Title compound was prepared by methods analogous to those described for methyl (S)-1-((S)-2-(7-(4-(2-((1R,3S,4S)-2-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate, substituting (R)-2-(methoxycarbonylamino)-2-phenylacetic acid for (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid. (ESI) m/z 823 [M+H]+.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[F:5][C:6]1[C:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21](I)=[CH:20][C:19]=2[F:25])=[C:8]([CH:13]=[CH:14][C:15]=1[F:16])[C:9]([O:11][CH3:12])=[O:10]>>[F:5][C:6]1[C:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:3]#[C:2][CH2:1][OH:4])=[CH:20][C:19]=2[F:25])=[C:8]([CH:13]=[CH:14][C:15]=1[F:16])[C:9]([O:11][CH3:12])=[O:10]
Reactant: C#CCO
Reactant: COC(=O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: COC(=O)c1ccc(F)c(F)c1Nc1ccc(C#CCO)cc1F
Yield: 94 %

Procedure:
The title compound was prepared by Sonogashira reaction of propargyl alcohol and methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate by the general procedure of Example 1, Step A. The oil resulting from workup was purified by chromatography on silica gel (20% EtOAc/PE as eluant), to give methyl 3,4-difluoro-2-[2-fluoro-4-(3-hydroxy-1-propynyl)anilino]benzoate as a pale yellow solid (94%); m.p. (Et2O/hexane) 116-120° C. 1H NMR [400 MHz, (CD3)2SO] δ 8.79 (s, 1 H), 7.79 (ddd, J=8.3, 5.9, 2.0 Hz, 1 H), 7.30 (dd, J=12.2, 1.8 Hz, 1 H), 7.26-7.17 (m, 1 H), 7.15 (dd, J=8.5, 1.6 Hz, 1 H), 6.92 (ddd, J=8.8,8.8,4.7 Hz, 1 H), 5.31 (br s, 1 H), 4.28 (s, 2 H), 3.81 (s, 3 H). Anal. calcd. for C17H12F3NO3: C, 60.9; H, 3.6; N, 4.2. Found C, 61.4; H, 3.9; N, 4.7. Step B: Preparation of Methyl 3,4-difluoro-2-[2-fluoro-4-(3-hydroxypropyl)anilino]benzoate
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[Cl:8][C:6]1[CH:7]=[C:2]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:13]=2[CH3:12])[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: Cc1ccncc1B(O)O
Reactant: Clc1cc(Br)c2nccn2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1-c1cc(Cl)nn2ccnc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 34.6 %

Procedure:
A microwave vial was charged with a mixture of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (1.1 g, 4.73 mmol), 4-methylpyridin-3-ylboronic acid (0.648 g, 4.73 mmol), tetrakis(triphenylphosphine)palladium(0) (0.547 g, 0.473 mmol), dioxane (14 mL), and K3PO4 (7.10 mL, 14.20 mmol) (2.0 M water solution) was stirred at room temperature for 5 min. under nitrogen. The resulting mixture was heated to 100° C. for 8 h in microwave. The reaction mixture was cooled to room temperature, quenched with water, and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by BIOTAGE® (20-80% EtOAc/CH2Cl2, 1.5 L, then 20%-65% B/CH2Cl2, 0.9 L; B: 10% MeOH/CH2Cl2) to give 400 mg (34%) product. 1H NMR (400 MHz, CD3OD) δ ppm 9.00 (1H, s), 8.80 (1H, d, J=5.79 Hz), 8.38 (1H, d, J=1.51 Hz), 8.04 (1H, d, J=6.04 Hz), 7.96 (1H, d, J=1.51 Hz), 7.86 (1H, s), 2.73 (3H, s); LC/MS: Rt=0.98 min. LC/MS (Condition A): 245.11/247.08.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.Cl[S:20]([C:23]1[C:24]([F:34])=[CH:25][C:26]([F:33])=[C:27]([CH:32]=1)[C:28]([O:30][CH3:31])=[O:29])(=[O:22])=[O:21].N12CCN(CC1)CC2>C1COCC1>[CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1)[S:20]([C:23]1[C:24]([F:34])=[CH:25][C:26]([F:33])=[C:27]([CH:32]=1)[C:28]([O:30][CH3:31])=[O:29])(=[O:22])=[O:21]
Reactant: COC(=O)c1cc(S(=O)(=O)Cl)c(F)cc1F
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: COC(=O)c1cc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)c(F)cc1F
Yield: 45 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (378 mg, 1.54 mmol) prepared in Example 14a, methyl 5-(chlorosulfonyl)-2,4-difluorobenzoate (500 mg, 1.85 mmol), 1,4-diazabicyclo[2.2.2]octane (208 mg, 1.85 mmol) and THF (15.0 mL), to yield the title compound (332 mg, 45%) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Cl[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][N:30]=1>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][N:30]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: Clc1ccncn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccncn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-chloropyrimidine in Step 4. LC-MS Method 2 tR=1.167, m/z=374; 1H NMR (CDCl3) 1.06 (s, 3H), 1.11 (s, 3H), 1.49 (d, 3H), 2.11 (s, 1H), 2.17 (s, 2H), 2.21 (m, 1H), 2.35 (m, 1H), 2.80 (m, 1H), 5.66 (m, 1H), 7.02 (d, 2H), 7.21-7.36 (m, 5H), 7.54 (d, 1H), 7.78 (d, 2H), 8.68 (d, 1H), 9.16 (s, 1H).