Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C(N)=C2C(N=CN2)=NC=1.[CH3:11][C@@H:12]([O:24]CP(O)(O)=O)[CH2:13][N:14]1[C:18]2[N:19]=[CH:20][N:21]=[C:22]([NH2:23])[C:17]=2[N:16]=[CH:15]1.CC(C)([O-])C.[Mg+2].CC(C)([O-])C.C1(=O)O[C@H](C)CO1.CS(O)(=O)=O>CN(C=O)C.[OH-].[Na+].C1(C)C=CC=CC=1>[OH:24][C@H:12]([CH3:11])[CH2:13][N:14]1[CH:15]=[N:16][C:17]2[C:18]1=[N:19][CH:20]=[N:21][C:22]=2[NH2:23]
Reactant: C[C@H](Cn1cnc2c(N)ncnc21)OCP(=O)(O)O
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)O
Agent: C[C@@H]1COC(=O)O1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C[C@@H](O)Cn1cnc2c(N)ncnc21
Temperature: 130 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
Adenine to PMPA using Magnesium t-Butoxide. To a suspension of adenine (40 g, 0.296 mol) in DMF (41.9 ml) was added (R)-propylene carbonate (34.5 g, 0.338 mol) and sodium hydroxide (0.480 g, 0.012 mol). The mixture was heated at 130° C. overnight. The reaction was cooled to 100° C. and toluene (138 ml) was added followed by methanesulfonic acid (4.7 g, 0.049 mol) while maintaining the reaction temperature between 100-110° C. Additional toluene (114 ml) was added to create a homogeneous solution. The solution was cooled to 3° C. over 7 hours and then held at 3° C. for one hour. The resulting solid was isolated by filtration and rinsed with acetone (2×). The wet solid was dried in vacuo at 80° C. to yield 42.6 g (75%) of (R)-9-[2-(hydroxy)propyl]adenine (HPA) as an off-white solid. Mp: 188-190° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][CH2:11][C@H:12]1[CH2:14][O:13]1)[CH3:9].[C:15]([O:20][CH3:21])(=[O:19])[CH2:16][CH:17]=[CH2:18].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:13]1[CH2:14][C@@H:12]1[CH2:11][O:10][C@@H:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1/[CH:18]=[CH:17]/[CH2:16][C:15]([O:20][CH3:21])=[O:19])[CH3:9]
Reactant: C[C@@H](OC[C@H]1CO1)c1ccccc1Br
Reactant: C=CCC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C/C=C/c1ccccc1[C@@H](C)OC[C@H]1CO1
Temperature: 25 °C
Yield: 23 %

Procedure:
Under an argon atmosphere, a mixture of (2R)-2-{[(1R)-1-(2-bromophenyl)ethoxy]methyl}oxirane (1.00 g, 3.89 mmol) described in WO 2004/094362, methyl but-3-enoate (497 μL, 4.67 mmol), palladium acetate (II) (44 mg, 0.19 mmol), tris(2-methylphenyl)phosphine (59 mg, 0.19 mmol), and triethylamine (0.65 mL, 4.67 mmol) in acetonitrile (10 mL) was stirred with heating under reflux for 3 hours. The reaction solution was cooled to room temperature, filtered through Celite, and washed with acetonitrile. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a yellow oily substance (246 mg, yield 23%).
Reaction SMILES: C([C@H]1CC[C@H:7]([CH:10]2CC[C:13]3([C:32](=[O:33])[C:17]4(CC[CH:20]([C@H:23]5CC[C@H](CCC)[CH2:25][CH2:24]5)[CH2:19][CH2:18]4)C3=O)[CH2:12][CH2:11]2)[CH2:6]C1)CC.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[CH3:6][CH2:7][CH2:10][CH2:11][CH2:12][CH2:13][C:32](=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:23][CH2:24][CH3:25]
Reactant: CCC[C@H]1CC[C@H](C2CCC3(CC2)C(=O)C2(CCC([C@H]4CC[C@H](CCC)CC4)CC2)C3=O)CC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCC(=O)CCCCCC

Procedure:
1 mmol of 3,11-bis(trans-4-propylcyclohexyl)dispiro-[5.1.5.1]tetradecane-7,14-dione (obtainable according to Example 1) are stirred with 210 mg (1 mmol) of phosphorus pentachloride in 30 ml of carbon tetrachloride for 48 hours at room temperature. After pouring onto ice-water, the organic phase is worked up. After chromatographic purification, 3,11-bis(trans-4-propylcyclohexyl)-14,14-dichlorodispiro[5.1.5.1.]tetradecan-7-one is obtained, m.p. 159°, c.p. 266.7°-270.1°.
Reaction SMILES: Cl[CH:2]([OH:18])[CH:3]([OH:17])[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][O:8][C:7]2[CH:12]=[N:13][C:14]([CH3:16])=[N:15][C:6]1=2.C(N(CC)CC)C>[Pd].C(O)C>[OH:17][CH:3]([CH2:2][OH:18])[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][O:8][C:7]2[CH:12]=[N:13][C:14]([CH3:16])=[N:15][C:6]1=2
Reactant: Cc1ncc2c(n1)N(CC(O)C(O)Cl)C(=O)CO2
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ncc2c(n1)N(CC(O)CO)C(=O)CO2
Yield: 18.9 %

Procedure:
The solution of 2 g of γchloro-8-(2,3-dihydroxypropyl)-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one and 0.739 g of triethylamine in 50 ml of abs. ethanol is hydrogenated in the presence of 0.20 g of 5% palladium-on-charcoal catalyst at room temperature and atmospheric pressure. Then the catalyst is filtered out, the filtrate is evaporated, the residue is taken up in water and extracted with chloroform. The organic phase is dried and evaporated. The residue is triturated with petroleum ether and dried to give 0.33 g (19%) of the product, m.p.: 70°-72° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]1([C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][O:7]1)=[O:6]>S(=O)(=O)(O)O>[N+:1]([C:12]1[CH:13]=[C:14]2[C:9]([CH2:8][O:7][C:5]2=[O:6])=[CH:10][CH:11]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C1OCc2ccccc21
Agent: O=S(=O)(O)O
Product: O=C1OCc2ccc([N+](=O)[O-])cc21

Procedure:
Three portions of a mixture of concentrated nitric acid (0.6 ml. each portion) and concentrated sulfuric acid (0.66 ml. each portion) were added to a mixture of 3-(2,4-bis(dimethylamino)phenyl)-3-(4-dimethylamino)phenyl)phthalide (4.17 g.) and concentrated sulfuric acid (20 ml.) with cooling. After each addition the temperature was allowed to rise to room temperature. The resulting mixture was poured onto ice and the resulting mixture was basified, affording 3-(2,4-bis(dimethylamino)phenyl)-3-(4-(dimethylamino)phenyl)5 or 6-nitrophthalide (I: X= Y 4 = (CH3)2N, Y 2 = Z4 = Z7 = H, Z5 or Z6 = O2N and the other of Z5 or Z6 = H) or a mixture of both.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][C:3]=1[CH3:11].ClN1C(=O)CCC1=O.[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([C:29]([F:32])([F:31])[F:30])=[CH2:28])[CH:24]=[C:23]([Cl:33])[CH:22]=1.C(N(CC)CC)C>CN(C)C=O.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH2:28][C:27]([C:25]3[CH:24]=[C:23]([Cl:33])[CH:22]=[C:21]([Cl:20])[CH:26]=3)([C:29]([F:30])([F:32])[F:31])[O:8][N:7]=2)=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C=NO)ccc1Br
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.2 %

Procedure:
4-Bromo-3-methyl-benzaldehyde oxime (1.3 g) (Example I2) and N-chlorosuccinimide (“NCS”) (1.8 g) were dissolved in N,N-dimethylformamide (15 ml). The reaction mixture was stirred at ambient temperature for 90 minutes. A solution of 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (1.3 g) (prepared according to WO 2005/085216) and triethylamine (1.9 ml) in N,N-dimethylformamide (15 ml) was added and the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with water and ethyl acetate and the phases were separated. The organic phase was washed twice with water and the aqueous phases were extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: cyclohexane/dichloromethane 4:1) to give 3-(4-bromo-3-methyl-phenyl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (1.57 g). 1H-NMR (400 MHz, CDCl3): 7.40 (m, 6H), 4.05 (d, 1H), 3.65 (d, 1H), 2.40 (s, 3H) ppm.
Reaction SMILES: [NH2:1][C@H:2]([CH:21]([CH3:23])[CH3:22])[C:3]([N:5]1[CH2:10][CH2:9][C@@:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([OH:11])[C:7]([CH3:20])([CH3:19])[CH2:6]1)=[O:4].C(N(CC)CC)C.C(Cl)Cl.[C:34](Cl)(=[O:42])[O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CCOC(C)=O>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C@@:8]2([OH:11])[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C@H:2]([NH:1][C:34](=[O:42])[O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:21]([CH3:23])[CH3:22])[CH2:6][C:7]2([CH3:19])[CH3:20])=[CH:17][CH:16]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)[C@@H](N)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)Oc1ccccc1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reaction time: 1 h
Yield: 59.8 %

Procedure:
(R)-2-amino-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one (500 mg, 1.33 mmol), triethylamine (0.371 mL, 2.66 mmol) and methylene chloride (10 mL) were mixed at 0° C. under nitrogen then a methylene chloride solution of phenyl carbonochloridate (209 mg, 1.33 mmol) was added dropwise via an addition funnel. The reaction was stirred for 1 hour, diluted with EtOAc, and washed consecutively with 1N HCl and sat'd sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated in vacuo to give a white glass which was purified over silica gel (3:1 to 1:1 hexanes/EtOAc) to obtain phenyl (R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (365 mg, 0.795 mmol, 59% yield) as a white glass. MS found: (M+H)+=459.32.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:15][CH:14]([O:16][C:17]2[C:18]([C:23]3[CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][CH2:27][CH:28]=3)=[N:19][CH:20]=[CH:21][N:22]=2)[CH2:13]1)=[O:11].FC(F)(F)C(O)=O>C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:13][CH:14]([O:16][C:17]2[C:18]([C:23]3[CH2:24][NH:25][CH2:26][CH2:27][CH:28]=3)=[N:19][CH:20]=[CH:21][N:22]=2)[CH2:15]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC=C(c2nccnc2OC2CN(C(=O)c3nc4ccccc4[nH]3)C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1nc2ccccc2[nH]1)N1CC(Oc2nccnc2C2=CCCNC2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl 3-(3-(1-(1H-benzo[d]imidazole-2-carbonyl)azetidin-3-yloxy)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (see EXAMPLE 10.72; 120 mg, 0.252 mmol) in DCM (2 mL) is added 2,2,2-trifluoroacetic acid (116 μL, 1.511 mmol). The reaction was stirred at room temperature 24 hours. The reaction was concentrated, and the residue dissolved in MeOH (2 mL) and applied to a Varian SCX ion exchange column (1 g). The salt was eluted with MeOH (2×5 mL) and the product eluted with 2.0 M NH3 in MeOH (2×5 mL). The NH3 containing fractions were concentrated to give the crude amine which was carried on to the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:4]([OH:6])=[O:5])[CH3:3].C(N(CC)CC)C.C[Si](Cl)(C)C.[CH:19]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1>ClCCl.O>[CH:19]1([C:24]([NH:1][CH:2]([CH3:3])[C:4]([OH:6])=[O:5])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Cl)C1CCCC1
Reactant: CC(N)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(NC(=O)C1CCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
16.8 g (0.189 mol) of D,L-alanine and 41.98 g (0.415 mol) of triethylamine are initially charged in 200 ml of dichloromethane. At 0° C., 45.07 g (0.415 mol) of trimethylsilyl chloride are added dropwise, and the mixture is stirred at room temperature for 1 h and then at 40° C. for 1 h. The solution is cooled to −100° C., and 25 g (0.189 mol) of cyclopentanecarbonyl chloride are added dropwise. The mixture is stirred at −10° C. for 2 h and at room temperature for 1 h. With ice-cooling, 100 ml of water are added dropwise, the mixture is stirred for 10 min. and the resulting precipitate is filtered off with suction. The precipitate is washed with 300 ml of water and then with 300 ml of diethyl ether and subsequently dried at 60° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14].O>N1C=CC=CC=1.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH:9][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=1[F:10]
Reactant: NNc1ccccc1F
Reactant: O=C(Cl)c1ccccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(NNc1ccccc1F)c1ccccc1F
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a stirred solution, under nitrogen of 35.2 g of 2-fluorophenylhydrazine in 250 ml of dry pyridine, cooled in an ice bath, was added, dropwise, 36.7 ml of 2-fluorobenzoyl chloride. The reaction mixture was stirred at ambient temperature for 21 hours. Upon dilution of the reaction mixture with water a precipitate was formed. Attempts to separate the precipitate by filtration, washing with pyridine, resulted in the formation of an oil. That portion of oil which did not pass into the filtrate was dissolved in dichloromethane and concentrated in vacuo. Upon standing, the filtrate separated into aqueous and organic phases. Treatment of the organic phase with toluene resulted in the formation of a precipitate. Recrystallization of the combined product from toluene yielded 49.2 g of 2-fluorobenzoic acid, 2-(2-fluorophenyl)hydrazide.
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH:24]([CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]2)[C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CN1CCOCC1.FC(F)(F)C(O)=O.[NH2:61][C@H:62]([C:74]([NH:76][C:77]12[CH2:86][CH:81]3[CH2:82][CH:83]([CH2:85][CH:79]([CH2:80]3)[CH2:78]1)[CH2:84]2)=[O:75])[CH2:63][C:64]([O:66][CH2:67][C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)=[O:65].Cl>C(OCC)(=O)C>[C:77]12([NH:76][C:74]([C@@H:62]([NH:61][C:29](=[O:30])[CH2:28][NH:27][C:25]([CH:24]([CH2:23][CH2:22][CH:19]3[CH2:20][CH2:21][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:17][CH2:18]3)[CH2:32][CH2:33][CH:34]3[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[CH2:38][CH2:39]3)=[O:26])[CH2:63][C:64]([O:66][CH2:67][C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)=[O:65])=[O:75])[CH2:78][CH:79]3[CH2:85][CH:83]([CH2:82][CH:81]([CH2:80]3)[CH2:86]1)[CH2:84]2
Reactant: N[C@@H](CC(=O)OCc1ccccc1)C(=O)NC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(CCC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)NCC(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCC(CCC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)NCC(=O)N[C@@H](CC(=O)OCc2ccccc2)C(=O)NC23CC4CC(CC(C4)C2)C3)CC1
Reaction time: 0.17 h
Yield: 68.3 %

Procedure:
Isobutyl chloroformate (1.7 g, 12.4 mmol) is added, at room temperature, to a solution of 2-[(4-[1-(tert-butoxycarbonyl)-4-piperidyl]-2-{2-[1-(tert-butoxycarbonyl)-4-piperidyl]ethyl}butanoyl)amino]acetic acid (compound 4) (6.9 g, 11 mmol) in 150 ml of ethyl acetate and N-methylmorpholine (5 g, 49.5 mmol). A white suspension is obtained. After stirring for 10 minutes, a solution of benzyl (3S)-3-amino-4-(1-adamantylamino)-4-oxobutanoate trifluoroacetate (6.9 g, 11.2 mmol) in 20 ml of ethyl acetate is added. Stirring is continued at room temperature for 18 hours. 2N hydrochloric acid is added. The organic phase is washed with water, dried over sodium sulphate and evaporated to give the crude product, which is purified by flash chromatography (20/1 dichloromethane/methanol) to give 6.6 g of a beige-coloured solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]1([CH:19]2[O:23][CH:22]([CH2:24][CH2:25][CH2:26][CH2:27]O)[CH2:21][O:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:48]1(=[O:58])[NH:52][C:51](=[O:53])[C:50]2=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]12>C1COCC1>[C:13]1([CH:19]2[O:23][CH:22]([CH2:24][CH2:25][CH2:26][CH2:27][N:52]3[C:51](=[O:53])[C:50]4=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]4[C:48]3=[O:58])[CH2:21][O:20]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OCCCCC1COC(c2ccccc2)O1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCCC1COC(c2ccccc2)O1
Reaction time: 8 h
Yield: 92.3 %

Procedure:
A solution of diethyl azodicarboxylate (8.6 g, 49.4 mmol) in 40 mL of THF was slowly added to a cold (ice bath) solution of 17 (10.0 g, 45.0 mmol), triphenylphosphine (13.0 g, 49.5 mmol) and phthalimide (7.3 g, 49.7 mmol) in 60 mL of THF. After being kept at ambient temperature overnight, the solution was concentrated and the residue was triturated with ether (˜150 mL) to precipitate triphenylphosphine oxide which was then removed by filtration. The filtrate was concentrated to give an oily residue which was chromatographed on silica eluting with 33% ethyl acetate in hexane. Concentration of the pure product fractions followed by drying under vacuum afforded 14.6 g (92%) of the desired product as a semi-solid (a mixture of diastereomers): 1H NMR (CDCl3, 300 MHz, ppm) 7.85 (m, 2H), 7.71 (m, 2H), 7.46 (m, 2H), 7.36 (m, 3H), 5.90 (s, 0.4H), 5.78 (s, 0.6H), 4.3-4.0 (m, 2H), 3.68 (m, 3H), 1.9-1.3 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][NH:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:21])[CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][CH:9]=1.[Cl:24][C:25]1[N:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][NH:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:28]2[CH:29]=[N:30][C:25]([Cl:24])=[CH:26][CH:27]=2)[CH2:15][CH2:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[CH:10][CH:9]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(O)CCC(C)(C)C)cc1
Reactant: Oc1ccc(Cl)nc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)CCNC(=O)c1ccc(C(CCC(C)(C)C)Oc2ccc(Cl)nc2)cc1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
3-[4-(1-Hydroxy-4,4-dimethyl-pentyl)-benzoylamino]-propionic acid methyl ester (546 mg, 1.7 mmol) and 6-chloro-pyridin-3-ol (270 mg, 2.09 mmol) are combined in anhydrous toluene (10 mL), degassed, filled with nitrogen for 3 times, and cooled in an ice bath. Tributylphosphine (TBP) (630 uL, 2.55 mmol) is added to the reaction mixture under nitrogen at 0° C., followed by addition of 1,1′-(azodicarbonyl)-dipiperidine (ADDP) (643 mg, 2.55 mmol). The reaction mixture is allowed to warm to room temperature and stirred over night, the mixture is loaded on silica gel column. Chromatography gave the title compound (722 mg, 1.67 mmol).
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1.[CH:17]([N:20]=[C:21]=[O:22])([CH3:19])[CH3:18]>>[CH:17]([NH:20][C:21](=[O:22])[O:13][CH2:12][CH2:11][O:10][C:9]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][CH:3]=[C:2]([CH3:16])[CH3:1])=[CH:7][CH:8]=1)([CH3:19])[CH3:18]
Reactant: CC(C)=CCOc1ccc(OCCO)cc1
Reactant: CC(C)N=C=O
Product: CC(C)=CCOc1ccc(OCCOC(=O)NC(C)C)cc1

Procedure:
Following the procedure of Example 9, 2[4-(3-methyl-2-butenoxy)phenoxy]ethanol and isopropyl isocyanate are reacted together to give O-2-[4-(3-methyl-2-butenoxy)phenoxy]ethyl N-isopropylcarbamate, MS, m/e 307 (M+).
Reaction SMILES: Br[C:2]1[N:19]([CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]2)[C:5]2[C:6]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=3)=[N:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=1.[O:28]1[CH2:33][CH2:32][NH:31][C@@H:30]2[CH2:34][CH2:35][CH2:36][C@@H:29]12.[F-].[K+].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C.CS(C)=O>[Cl:18][C:16]1[CH:17]=[C:12]([C:6]2[C:5]3[N:19]([CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]4)[C:2]([N:31]4[CH2:32][CH2:33][O:28][C@@H:29]5[CH2:36][CH2:35][CH2:34][C@@H:30]45)=[N:3][C:4]=3[CH:9]=[C:8]([C:10]#[N:11])[N:7]=2)[CH:13]=[N:14][CH:15]=1
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: C1C[C@H]2NCCO[C@@H]2C1
Agent: [F-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 100 °C

Procedure:
To a vial was added 2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1, 90 mg, 0.202 mmol), (4aR,7aR)-octahydrocyclopenta[b][1,4]oxazine (51.5 mg, 0.405 mmol), potassium fluoride (58.8 mg, 1.01 mmol), DMSO (0.62 mL), and N,N-diisopropylethylamine (0.18 mL, 1.01 mmol). The vial was sealed and heated to 100° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 4-(5-chloropyridin-3-yl)-2-((4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C27H31ClN6O [M+H]+ 491. found 491.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][OH:14])[C@H:10]([CH2:15][OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[C:37](Cl)[N:36]=[N:35][C:34]=2[CH2:40][CH2:41][CH2:42][CH3:43])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:15][OH:16])[C@H:11]([CH2:13][O:14][C:37]2[N:36]=[N:35][C:34]([CH2:40][CH2:41][CH2:42][CH3:43])=[C:33]([C:30]3[CH:29]=[CH:28][C:27]([O:26][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:32][CH:31]=3)[CH:38]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CO)[C@H](CO)C1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of (±)-trans-3,4-bis-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.0 mmol, 462 mg) in THF (4.0 mL) at 0° C. was added NaH (60% dispersion in mineral oil, 2.5 mmol, 100 mg) and stirring continued for 10 min at room temperature, then 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine (Example 1, 1.0 mmol, 352 mg) was added. The resulting mixture was stirred at 50° C. for 1 hour, poured into water and extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The product was purified by column chromatography using 1% methanol in ethyl acetate to give (±)-trans-3-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester, which was dissolved in dichloromethane (1.0 mL), added 4.0 M HCl in dioxane (1.0 mL) and stirred at room temperature for 1 hour. Solvents were evaporated to give (±)-trans-{4-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-pyrrolidin-3-yl}-methanol dihydrochloride.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]1[C:8]([C@@H:14]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:15]([CH3:17])[CH3:16])=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)(=[O:4])=[O:3].[C:26](OC(=O)N[C@H](C1C(C(O)C)=CC(Cl)=CN=1)C(C)C)(C)(C)C>>[CH3:1][S:2]([O:5][CH:6]([C:7]1[C:8]([C@@H:14]([NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH:15]([CH3:17])[CH3:16])=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)[CH3:26])(=[O:3])=[O:4]
Reactant: CC(O)c1cc(Cl)cnc1[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)c1ncc(Cl)cc1COS(C)(=O)=O
Product: CC(OS(C)(=O)=O)c1cc(Cl)cnc1[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reaction time: 0.02 h

Procedure:
Procedure same as that for (S)-(2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloropyridin-3-yl)methyl methanesulfonate, using tert-butyl((1S)-1-(5-chloro-3-(1-hydroxyethyl)pyridin-2-yl)-2-methylpropyl)carbamate as a starting material. LC-MS tR=1.03 min in 1 min chromatography, MS (ESI) m/z 407.4 [M+H]+.