Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:13]=[CH:14][CH:15]=2)[N:5]=[CH:6][C:7]=1[C:8]([O:10]CC)=[O:9].O>C1COCC1>[Cl:1][C:2]1[C:3]2[N:4]([CH:13]=[CH:14][CH:15]=2)[N:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1cnn2cccc2c1Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnn2cccc2c1Cl
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Dissolved ethyl 4-chloropyrrolo[1,2-b]pyridazine-3-carboxylate (Preparation 2 from Step 5B, 2 g, 8.90 mmol) in THF (12 mL) and added water (2 mL) followed by monohydrated lithium hydroxide (0.747 g, 17.81 mmol) and the resulting yellow mixture was sonicated to give a fine dispersion followed by heating to 55° C. and stirring vigorously for one hour. After removing the organics under vacuum, the resulting residue was dissolved in ˜50 mL of water and 6 N aqueous HCl added until acidic giving a yellow slurry of the product. The product was extracted with ethyl acetate, washed with brine, dried over Na2SO4, decanted and conc. in vacuo to afford 1.8 g (˜quant.) of a yellow solid as the title compound. LCMS (condition B): m/z=197.1, 199.0. HPLC (condition B): Retention time=2.59 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)([CH3:11])[CH2:9][OH:10])[CH:7]=1.C(N(CC)CC)C.[C:30]([Si:34]([CH3:37])([CH3:36])Cl)([CH3:33])([CH3:32])[CH3:31]>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@:8]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)([CH3:11])[CH2:9][O:10][Si:34]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:37])[CH3:36])[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(CN[C@@](C)(CO)c2cc(Br)ccc2F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN[C@@](C)(CO[Si](C)(C)C(C)(C)C)c2cc(Br)ccc2F)cc1

Procedure:
A solution of (R)-2-(5-bromo-2-fluoro-phenyl)-2-(4-methoxy-benzylamino)-propan-1-ol (6.95 g, 18.9 mmol) in dichloromethane (170 ml) was treated at room temperature with triethylamine (5.78 ml, 41.5 mmol), 4-dimethylaminopyridine (1.15 g, 9.43 mmol), and tert-butyldimethylchlorosilane (1.15 g, 37.7 mmol). After 16 hours at room temperature the reaction mixture was consecutively extracted with saturated sodium hydrogen-carbonate solution (100 ml), water (100 ml), and brine (100 ml). The aqueous layers were re-extracted with dichloromethane (100 ml). The combined organic layers were dried over sodium sulfate and evaporated at reduced pressure. After chromatography on Silicycle-Si-amine column using heptane as the eluent, [(R)-1-(5-bromo-2-fluoro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-(4-methoxy-benzyl)-amine was obtained as a colorless oil (8.0 g, 88% of theory). Mass (calculated) C23H33BrFNO2Si [482.51]; (found) [M+H]+=482, [M+2-H]+=484.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][N:27]([CH2:29][CH:30](OCC)[O:31]CC)[CH:28]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.Cl>CC(O)=O.O>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][N:27]([CH2:29][CH:30]=[O:31])[CH:28]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CCOC(Cn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)c1)OCC
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)c1
Temperature: 90 °C
Yield: 47.4 %

Procedure:
To a solution of acetal 263 (2.95 g, 5.61 mmol) in AcOH/H2O (20/20 mL) was added concentrated HCl (2 mL) and the reaction mixture was heated at 90° C. for 1 h. The reaction mixture was concentrated, diluted with water and 4M NaOH to pH 10 to form a precipitate that was collected by filtration, washed with water and dried under vacuum. The material was then purified by Biotage (SNAP 100 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 0/100 to 15/85, over 20 CV) to afford the title compound 264 (1.2 g, 2.66 mmol, 47% yield) as a brown solid. MS (m/z): 484.51 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([OH:12])=[CH:4][CH:3]=1.CI.[C:15]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH3:15])=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(Br)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1nc(Br)ccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
A mixture of methyl 6-bromo-3-hydroxypicolinate (4 g, 17.2 mmol), CH3I (7.15 g, 34.5 mmol) and K2CO3 (4.76 g, 34.5 mmol) in DMF (50 mL) was stirred at RT for 3 hours. After concentrated, the mixture was diluted with H2O and extracted with EtOAc (50 mL*3). The organic layer was dried over Na2SO4 and concentrated to give crude methyl 6-bromo-3-methoxypicolinate (4 g, yield: 90%). 1H-NMR (CDCl3, 400 MHz) δ 7.56 (d, J=8.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H). MS (M+H)+: 256/258.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21]3)[CH:17]=[CH:16][C:15]=2[N+:27]([O-])=O)=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]>C1COCC1.O.[Fe].CC(O)=O>[OH:26][CH2:25][C:22]1[CH:23]=[CH:24][N:20]([C:18]2[CH:17]=[CH:16][C:15]3[N:27]=[C:9]([C:5]4[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=4)[C:1]#[N:2])[CH2:10][C:11](=[O:12])[NH:13][C:14]=3[CH:19]=2)[CH:21]=1
Reactant: N#Cc1cccc(C(=O)CC(=O)Nc2cc(-n3ccc(CO)c3)ccc2[N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#Cc1cccc(C2=Nc3ccc(-n4ccc(CO)c4)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from 3-(3-cyano-phenyl)-N-[5-(3-hydroxymethyl-pyrrol-1-yl)-2-nitro-phenyl]-3-oxo-propionamide (Example M11) by reductive cyclization with Fe/HOAc in THF/H2O at 60° C. according to the general procedure J (method d). Obtained as a brown solid (18 mg).
Reaction SMILES: [N:1]1[C:2]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[C:15](O)(=[O:17])C.C([O-])(=O)C.[Na+].C=O>O>[OH:17][CH2:15][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][C:2]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cn2ccccc2n1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1nc2ccccn2c1CO
Temperature: 90 °C
Yield: 49 %

Procedure:
A mixture of 570 mg (3.0 mmol) ethyl imidazolo[1,2-a]pyridine-2-carboxylate, glacial acetic acid (0.8 mL) and 1 g (12 mmol) sodium acetate is treated with 6 mL 37% formaldehyde in water. The mixture is heated in a sealed tube at 90° C. for 6 hr and the acetic acid removed in vacuo. The residue is made basic by addition of 2M sodium hydroxide and extracted into 3×10 mL dichloromethane containing 1% methanol. The organic extract is dried over anhydrous MgSO4 and the solvent removed in vacuo to give the crude residue. The residue is flash chromatographed with initially 10% methanol in dichloromethane to afford 325 mg (49%) ethyl 3-(hydroxymethyl)-imidazolo[1,2-a]pyridine-2-carboxylate.
Reaction SMILES: OC1C2C(=C(O)C=CC=2)N=C(C([NH:15][C@H:16]([C:25]([NH:27][NH:28][C:29](=[O:37])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[OH:36])=[O:26])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=O)C=1.[C:38]([OH:50])(=O)/[CH:39]=[CH:40]/[C:41]1[CH:48]=[CH:47][C:45]([OH:46])=[C:43]([OH:44])[CH:42]=1>>[C:38]([NH:15][C@H:16]([C:25]([NH:27][NH:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[OH:36])=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)(=[O:50])/[CH:39]=[CH:40]/[C:41]1[CH:48]=[CH:47][C:45]([OH:46])=[C:43]([OH:44])[CH:42]=1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)NNC(=O)c1ccccc1O)c1cc(O)c2cccc(O)c2n1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Product: O=C(/C=C/c1ccc(O)c(O)c1)N[C@@H](Cc1ccc(O)cc1)C(=O)NNC(=O)c1ccccc1O
Yield: 24.9 %

Procedure:
N1-[Nα-(tert-butoxycarbonyl)-L-tyrosyl]-N2-(2-hydroxybenzoyl)-hydrazine (349 mg, 0.84 mmol) prepared in example 73, step A was deprotected following the indications of general procedure C and coupled with caffeic acid (230 mg, 1.3 mmol) using general procedure D. The final product was purified by flash chromatography eluting with 40% EtOAc/CH2Cl2 then successively 5% and 10% MeOH/CH2Cl2 to yield 100 mg, 25% of the title compound.
Reaction SMILES: [CH2:1]([N:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C@H:11]([C:26]2[CH:57]=[CH:56][C:29]([C:30]([NH:32][C@H:33]([C:41]([NH:43][C@H:44]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:31])=[CH:28][CH:27]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si](C(C)(C)C)(C)C)[CH:13]=2)[C@H:6]([CH3:58])[CH2:5]1)[CH:2]=[CH2:3].O.[F-].C([N+](CC)(CC)CC)C>C(#N)C>[CH2:1]([N:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C@H:11]([C:26]2[CH:57]=[CH:56][C:29]([C:30]([NH:32][C@H:33]([C:41]([NH:43][C@H:44]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:31])=[CH:28][CH:27]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C@H:6]([CH3:58])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1C[C@@H](C)N([C@H](c2ccc(C(=O)N[C@@H](Cc3ccccc3)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)C[C@@H]1C
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: O
Solvent: CC#N
Product: C=CCN1C[C@@H](C)N([C@H](c2ccc(C(=O)N[C@@H](Cc3ccccc3)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)cc2)c2cccc(O)c2)C[C@@H]1C
Yield: 58 %

Procedure:
A portion of the benzhydrylpiperazine from above (0.36 g, 0.44 mmol) was stirred with tetraethylammonium fluoride hydrate (0.12 g, 0.67 mmol) in 10 mL of acetonitrile for 1 hr. The solvent was removed and the residue purified by chromatography on silica gel with dichloromethane:ethanol to give 0.180 g (58%) of tert-butyl N-(4-((αR*)-α-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoyl)-L-phenylalanyl-L-leucinate as a white solid.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:21])[CH2:4][C:5]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1.[C:22](OC(=O)C)(=[O:24])[CH3:23].CCCCCC>C(OCC)(=O)C>[C:22]([O:1]/[N:2]=[C:3](\[NH2:21])/[CH2:4][C:5]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:6][CH2:7][C:8]2([O:9][CH2:10][CH2:11][O:12]2)[CH2:13][CH2:14]1)(=[O:24])[CH3:23]
Reactant: N=C(CC1(c2ccccc2)CCC2(CC1)OCCO2)NO
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)O/N=C(\N)CC1(c2ccccc2)CCC2(CC1)OCCO2
Yield: 85.17 %

Procedure:
A mixture of N-hydroxy-2-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-acetamidine (266) (600 mg, 2.01 mmol) and acetic anhydride (2 mL) was stirred at room temperature for 16 h (TLC, ethyl acetate:hexane=7:3/UV/SiO2, Rf=0.4). The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (2×25 mL), brine (25 mL), dried and concentrated in vacuo to get crude mass which was purified by CombiFlash using a gradient eluent mixture of ethyl acetate and hexane to get pure (Z)-(1-amino-2-{8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl}ethylidene)amino acetate (267) (585 mg, 85.17%) as a white sticky solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]#[C:22][CH2:23][CH2:24][CH:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)=[C:19]([O:38][CH3:39])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl.CCOCC>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]#[C:22][CH2:23][CH2:24][CH:25]4[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]4)=[C:19]([O:38][CH3:39])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1C#CCCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1ccc2c(c1C#CCCC1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
A solution of tert-butyl (Z)-4-(4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}but-3-ynyl)piperidine-1-carboxylate (0.0507 g, 0.0961 mmol) in methylene chloride (4 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (4 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with ether, and the precipitated solid was collected by filtration, and washed with ether. The resulting solid was dissolved in a small volume of water, and the solution was adjusted to pH 9 with saturated aqueous sodium hydrogencarbonatewas. The solution was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[4-(piperidin-4-yl)but-1-ynyl]benzofuran-3(2H)-one (0.0372 g, 91%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]([N:15]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[CH:28][C:27]=4[O:39][CH3:40])[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17][C:16]2=[O:41])[CH:12]=[CH:13][CH:14]=1.CCN(C(C)C)C(C)C.[Cl:51][CH2:52][C:53](Cl)=[O:54]>C(Cl)Cl>[Cl:51][CH2:52][C:53]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[CH:28][C:27]=4[O:39][CH3:40])[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17][C:16]2=[O:41])[CH:10]=1)=[O:54]
Reactant: O=C(Cl)CCl
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(N)c3)c2n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(NC(=O)CCl)c3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
8-(3-Aminophenyl)-24(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (1b, 131 mg, 0.29 mmol) in DCM (5 mL) at 0° C. was treated with DIEA (0.13 mL, 0.72 mmol) and cooled in an ice bath at 0° C. The solution was then treated with 2-chloroacetyl chloride (Sigma Aldrich; 0.027 mL, 0.344 mmol) slowly dropwise over 10 min and stirred at 0° C. for 30 min. LC-MS indicated only trace amounts of the desired product. The reaction mixture was sonicated for 10 min to help dissolve the substrate and another 2 drops of 2-chloroacetyl chloride was added. After 30 min, LC-MS indicated 74% conversion to the desired product m/z (ESI, +ve ion) 533.9 (M+H)+ along with unreacted starting material. 2 more drops of 2-chloroacetyl chloride was added and the solution stirred for another 75 min resulting in clean conversion to the desired product. The reaction mixture was concentrated, treated with DMSO (8 mL) and purified on a Gilson preparatory HPLC (Gemini Phenomenex; 30×150 mm, 5μ, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water). The product containing fractions were concentrated under reduced pressure (rotary evaporator) and the resulting aqueous solution treated with a 10% aqueous solution of Na2CO3 and extracted with DCM (4×30 mL), dried over sodium sulfate and dried under vacuum overnight affording 2-chloro-N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acetamide (53.4 mg, 0.100 mmol, 35% yield) as a yellow solid. m/z (ESI, +ve ion) 533.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.50 (1H, s), 8.75 (1H, s), 8.17 (1H, s), 7.91 (1H, d, J=9.4 Hz), 7.75 (1H, d, J=8.2 Hz), 7.49-7.57 (2H, m), 7.25 (1H, d, J=9.0 Hz), 7.04 (1H, d, J=7.8 Hz), 6.53 (1H, d, J=2.2 Hz), 6.44 (1H, d, J=9.4 Hz), 6.04 (1H, br. s.), 4.25 (2H, s), 3.78 (3H, s), 3.06 (4H, br. s.), 2.40-2.48 (4H, m), 2.23 (3H, s).
Reaction SMILES: [Si:1]([O:8][C:9]([CH3:18])([CH3:17])[CH2:10][N:11]1[CH:15]=[C:14](I)[N:13]=[CH:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Mg]Br)C.[CH3:23][Sn:24](Cl)([CH3:26])[CH3:25]>C(Cl)Cl>[Si:1]([O:8][C:9]([CH3:18])([CH3:17])[CH2:10][N:11]1[CH:15]=[C:14]([Sn:24]([CH3:26])([CH3:25])[CH3:23])[N:13]=[CH:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(Cn1cnc(I)c1)O[Si](C)(C)C(C)(C)C
Reactant: C[Sn](C)(C)Cl
Agent: CC[Mg]Br
Solvent: ClCCl
Product: CC(C)(Cn1cnc([Sn](C)(C)C)c1)O[Si](C)(C)C(C)(C)C
Temperature: 10 °C
Yield: 74 %

Procedure:
To a mixture of 1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-iodo-1H-imidazole in DCM was added ethylmagnesium bromide at −78° C. The temperature of the mixture was allowed to warm up to about 10° C. slowly and cooled again. Trimethyltin chloride was added dropwise at −78° C. After the addition, the temperature was allowed to slowly warm up to room temperature. The reaction mixture was pouted into saturate NH4Cl solution, then extracted with DCM. The organic phase was washed with water twice, dried over anhydrous Na2SO4, and concentrated to give 1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(trimethylstannyl)-1H-imidazole (Yield=74%). LC-MS: m/z=419 [M+H+]
Reaction SMILES: [O:1]=[C:2]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:3][CH2:4][C:5]1[S:9][C:8]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C@H:19]3[CH2:24][CH2:23][C@H:22]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[O:12])=[N:7][N:6]=1.[BH4-].[Na+].CN(C=O)C.O>CO>[OH:1][CH:2]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:3][CH2:4][C:5]1[S:9][C:8]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C@H:19]3[CH2:20][CH2:21][C@H:22]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][CH2:24]3)=[CH:15][CH:14]=2)=[O:12])=[N:7][N:6]=1
Reactant: CC(C)(C)OC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(CCC(=O)c4ccccc4)s3)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(CCC(O)c4ccccc4)s3)cc2)CC1

Procedure:
0.159 g of tert-butyl trans-(4-{4-[5-(3-oxo-3-phenylpropyl)[1.3.4]thiadiazol-2-ylcarbamoyl]phenyl}cyclohexyl)acetate (0.3 mmol, 1 eq.) is placed in 5 mL of methanol with stirring. The reaction medium is cooled on an ice bath and 0.012 g of sodium borohydride (0.33 mmol, 1.1 eq.) is added. 3 mL of DMF are added. After stirring for 16 hours, the reaction medium is cooled on an ice bath and 0.023 g of sodium borohydride (0.6 mmol, 2 eq.) and 3 mL of DMF are added. After stirring for 2 hours, the reaction medium is poured into water and extracted twice with ethyl acetate. The organic phase is washed three times with water, dried over magnesium sulfate and evaporated to give 0.146 g of tert-butyl trans-(4-{4-[5-(3-hydroxy-3-phenylpropyl)-[1.3.4]thiadiazol-2-ylcarbamoyl]phenyl}cyclohexyl)acetate,
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]1([C@@H:14]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C@H:20]3[C@@H:15]2[CH2:16][CH2:17][CH2:18][N:19]3C(OC(C)(C)C)=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].[C:37]([O:41][C:42]([NH:44][C@@H:45]1[CH2:50][CH2:49][CH2:48][CH2:47][C@@H:46]1[C:51]([OH:53])=O)=[O:43])([CH3:40])([CH3:39])[CH3:38].C(N(CC)CC)C.CCOC(OC(OCC)=O)=O>O>[C:37]([O:41][C:42](=[O:43])[NH:44][C@@H:45]1[CH2:50][CH2:49][CH2:48][CH2:47][C@@H:46]1[C:51]([N:19]1[C@@H:20]2[C@@H:15]([C@H:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=32)[CH2:16][CH2:17][CH2:18]1)=[O:53])([CH3:38])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Agent: CCOC(=O)OC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1C(=O)N1CCC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 26.1 %

Procedure:
TFA (1 ml) was added to tert-butyl (4aR*,5R*,10bR*)-5-phenyl-3,4,4a,5,6,10b-hexahydrobenzo[h]-1,6-naphthyridine-1(2H)-carboxylate (195 mg, 0.54 mmol), and the mixture was stirred at room temperature for 3 min. Ice water was added to the reaction mixture, basified with 8N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (3 ml), (1S,2R)-2-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid (131 mg, 0.54 mmol) and triethylamine (109 mg, 1.1 mmol) were added, DEPC (88 mg, 0.54 mmol) was added at 0° C., and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with 6% aqueous sodium hydrogen carbonate solution and saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (30 g), and eluted with hexane-ethyl acetate (9:1-4:1, v/v) to give the title compound (69 mg, 26%) as a colorless amorphous form.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][OH:21])[O:17][N:16]=1.Cl[C:23]1[C:28]([C:29]#[N:30])=[CH:27][CH:26]=[CH:25][N:24]=1.[H-].[Na+].Cl>O.CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:23]2[N:24]=[CH:25][CH:26]=[CH:27][C:28]=2[C:29]#[N:30])[O:17][N:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CO)on1
Reactant: N#Cc1cccnc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1cc(COc2ncccc2C#N)on1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.2 %

Procedure:
To a mixture of [3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolyl]methanol (2.00 g), 2-chloro-3-cyanopyridine (1.16 g) and N,N-dimethylformamide (60 mL) was gradually added sodium hydride (60%, oil, 335 mg) under ice-cooling. After stirring the reaction mixture at room temperature for 90 min., water was added to the reaction mixture. The mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (2.61 g, 96%) of 2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]nicotinonitrile from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 139-140° C.
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([NH:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=2)=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[N:27]3[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]3=[N:25][N:24]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NNc2ccc(F)cn2)CC1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nnc3ccc(F)cn23)CC1
Reaction time: 2 h
Yield: 80.7 %

Procedure:
Hexachloroethane (990 mg, 4.18 mmol) was added portionwise to a solution of Intermediate 4a (707 mg, 2.09 mmol), triphenylphosphine (1.103 g, 4.18 mmol) and triethylamine (1.2 mL, 8.36 mmol) in dry THF (30 mL) at RT. The mixture was stirred for 2 h. The resulting precipitate was filtered off and the filtrate evaporated. The residue was purified by SCX-2, eluting with MeOH followed by 2M NH3 in MeOH, to give a pale orange coloured solid. This was triturated (diethyl ether) to give the title compound as a buff-coloured solid (540 mg, 80%). LCMS (Method 1): Rt 2.79 min, m/z 321 and 221(-Boc) [MH+].