Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([CH3:24])[NH:16][C:15]([CH3:25])=[C:14]1[C:26]([O:28][CH2:29][CH3:30])=[O:27].B(Br)(Br)Br.C([O-])([O-])=O.[K+].[K+].C(O)C>ClCCCl>[CH3:24][C:17]1[NH:16][C:15]2([CH3:25])[CH:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:13]([C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:4]1[C:5]3[C:10]([CH:11]=[CH:12][C:3]=1[O:2]2)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1c(OC)ccc2ccccc12
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCCl
Product: CCOC(=O)C1=C(C)NC2(C)Oc3ccc4ccccc4c3C1C2C(=O)OCC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 2.25 g (5.5 mm) of diethyl 1,4-dihydro-4-(2-methoxy-1-naphthalenyl)-2,6-dimethyl-3,5-pyridinedicarboxylate 20 in 12.0 mL of dry 1,2-dichloroethane was stirred under Ar at 25° C. and treated with 2.40 g (7.68 mm) of BBr3.CH3SCH3 complex. After stirring at 25° C. for 20 hours, 10.0 g of anhydrous powdered K2CO3 and 100 mL of absolute ethanol were added. Stirring was continued for 60 hours at 25°. The reaction was quenched with saturated aqueous NH4Cl and extracted with 500 ml of CH2Cl2. The organic layer was washed with pH 7 phosphate buffer and brine, dried (anhydrous Na2SO4), filtered, evaporated and flash chromatographed (silica gel, 2% acetone in CH2Cl2).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[NH:7])[CH3:6])[CH2:3][CH2:2]1.Br[C:9](=[CH:13]OC)[C:10](=[O:12])[CH3:11].C(N(CC)CC)C.S(=O)(=O)(O)O>C(O)(C)C>[C:10]([C:9]1[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]([CH3:6])=[N:7][CH:13]=1)(=[O:12])[CH3:11]
Reactant: COC=C(Br)C(C)=O
Reactant: CC(=N)NC1CC1
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(=O)c1cnc(C)n1C1CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
In a 300 mL-volume glass vessel equipped with a stirrer, a thermometer and a dropping funnel, the isopropyl alcohol solution containing 15.9 g (0.162 mol) of N-cyclopropylacetamidine (which was prepared in the above-mentioned Reference Example 4), 19.3 g (0.108 mol) of 3-bromo-4-methoxy-3-buten-2-one and 16.4 g (0.162 mol) of triethylamine were placed. The mixture was heated to 80° C. under stirring for 8 hours for carrying out reaction. After the reaction was complete, 80 mL of sulfuric acid (2 mol/L) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The concentrate was washed with methyl isobutyl ketone, and the aqueous portion was taken out. The aqueous portion was made basic by adding an aqueous 48% sodium hydroxide, while the mixture was kept at a temperature of not higher than 40° C. The aqueous basic portion was subjected to extraction with methyl isobutyl ketone, and the extracted portion was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=2/1) to give 11.8 g (yield: 67%) of 5-acetyl-1-cyclopropyl-2-methylimidazole as pale yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:13]=[N:12]1.[NH2:22][C:23]1[C:24]([O:41][CH3:42])=[C:25]([CH:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:36]=1)[CH2:26][N:27]([CH3:33])[CH2:28][CH2:29][N:30]([CH3:32])[CH3:31]>>[C:37]([C:35]1[CH:34]=[C:25]([CH2:26][N:27]([CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])[CH3:33])[C:24]([O:41][CH3:42])=[C:23]([NH:22][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[CH:15]=[C:14]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:13]=[N:12]3)[CH:4]=2)[CH:36]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: COc1c(N)cc(C(C)(C)C)cc1CN(C)CCN(C)C
Reactant: Cc1ccc(C(=O)O)cc1-n1cc(-c2cccnc2)nn1
Product: COc1c(CN(C)CCN(C)C)cc(C(C)(C)C)cc1NC(=O)c1ccc(C)c(-n2cc(-c3cccnc3)nn2)c1

Procedure:
Example 10 was prepared by coupling 4-methyl-3-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid with N-(3-amino-5-tert-butyl-2-methoxy-benzyl)-N,N′,N′-trimethyl-ethane-1,2-diamine (see U.S. provisional application 60/526,569) in the same manner as Example 1. ESI MS m/z 554 [C32H41N7O2—H]−.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:17][C:6]2=[C:7]([C:12]3[NH:16][N:15]=[N:14][N:13]=3)[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:18])[CH2:3]1.[CH2:20](N(CC)CC)C.IC>CN(C=O)C.CCOC(C)=O.O>[CH3:1][C:2]1([CH3:19])[CH2:17][C:6]2=[C:7]([C:12]3[N:16]=[N:15][N:14]([CH3:20])[N:13]=3)[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:18])[CH2:3]1
Reactant: CCN(CC)CC
Reactant: CSc1sc(-c2nnn[nH]2)c2c1C(=O)CC(C)(C)C2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1sc(-c2nnn(C)n2)c2c1C(=O)CC(C)(C)C2
Reaction time: 8 h
Yield: 14.3 %

Procedure:
To solution of 6,6-dimethyl-3-methylthio-1-(tetrazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (62 mg, 0.21 mmol) in DMF (5 mL) containing triethylamine (58 μL, 0.42 mmol) was added iodomethane (13 μL, 0.21 mmol). After stirring for 1 h more iodomethane (39 μL, 0.63 mmol) was added and stirring continued overnight. Ethyl acetate (20 ml) and water (20 mL) were added and the organic layer separated, dried (Na2SO4) and evaporated. The residue was triturated with CH2Cl2:EtOAc (1:1) and the undissolved solid (26 mg; 0.08 mmol) collected by filtration and washed with EtOAc. The filtrate was chromatographed on silica gel, eluting with petrol:EtOAc (2:) to give the title compound (10 mg, 0.03 mmol) as a tan solid. Total mass=36 mg (56%), mp 233-235° C. Found C, 50.26; H, 5.23; N, 17.94%. C13H16N4S2O requires: C,50.63; H, 5.23; N, 18.17%. 1HNMR (250 MHz, CDCl3) δ 1.10 (6H, s), 2.45 (2H, s), 2.65 (3H, s), 3.11 (2H, s), 4.40 (3H, s). MS (ES+) 309 (M+1).
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([C:27]2[N:32]=[C:31]([C:33]([O:35][CH3:36])=[O:34])[CH:30]=[CH:29][C:28]=2O)[CH:20]=[CH:21][C:22]=1[C:23]([F:26])([F:25])[F:24])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1B(O)O>>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([C:27]2[N:32]=[C:31]([C:33]([O:35][CH3:36])=[O:34])[CH:30]=[CH:29][C:28]=2[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[CH3:38])[CH:20]=[CH:21][C:22]=1[C:23]([F:24])([F:26])[F:25])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(O)c(-c2ccc(C(F)(F)F)c(OCc3ccccc3)c2)n1
Reactant: Cc1ccccc1B(O)O
Agent: O=S(=O)([O-])C(F)(F)F
Product: COC(=O)c1ccc(-c2ccccc2C)c(-c2ccc(C(F)(F)F)c(OCc3ccccc3)c2)n1
Yield: 89 %

Procedure:
According to the triflate/Suzuki coupling steps described in examples 4.4 and 4.5 respectively, starting from 4.38 g (10.9 mmol) of methyl 6-[3-(benzyloxy)-4-(trifluoromethyl)phenyl]-5-hydroxypyridine-2-carboxylate and 1.8 g (13.1 mmol) of 2-methylphenylboronic acid, we obtain 4.63 g of methyl 6-[3-(benzyloxy)-4-(trifluoromethyl)phenyl]-5-(2-methylphenyl)pyridine-2-carboxylate in the form of a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]2[N:17]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:19][C:3]=12.Cl.[C@H:26]12[CH2:32][C@H:29]([NH:30][CH2:31]1)[CH2:28][O:27]2.C(N(CC)CC)C>C(O)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]3[N:17]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:19][C:3]3=[C:2]([N:30]3[CH2:31][C@@H:26]4[CH2:32][C@H:29]3[CH2:28][O:27]4)[N:7]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)c3cnn(CC(F)(F)F)c3n2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(-c2nc(N3C[C@@H]4C[C@H]3CO4)c3cnn(CC(F)(F)F)c3n2)cc1
Temperature: 120 °C
Yield: 118.9 %

Procedure:
To a Smith process vial containing a suspension of 4-chloro-6-(4-nitro-phenyl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidine (0.30 g, 0.84 mmol) and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (0.12 g, 0.88 mmol) in ethanol (4 mL) was added triethylamine (0.33 mL, 2.5 mmol). The mixture was heated in the microwave reactor for 15 minutes at 120° C. The precipitate was collected by Buchner filtration, washed with methanol, and dried under house vacuum to provide (1S,4S)-5-(6-(4-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane as a bright yellow powder (0.42 g, >100%). MS (ES+): 421.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=2)=[N:10][C:9]([Br:20])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:25]=[N+:26]=[N-].[Na+].CCOCC>C(O)(C(F)(F)F)=O.CCOC(C)=O.O>[N:1]([C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9]([Br:20])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(CO)cc2)c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)nc(-c2ccc(C=O)cc2)c1N=[N+]=[N-]
Reaction time: 0.67 h
Yield: 72.7 %

Procedure:
Methyl 3-amino-6-bromo-2-(4-(hydroxymethyl)phenyl)isonicotinate (5.7 g, 16.91 mmol) was dissolved in TFA (85 mL) and the solution was cooled in an ice bath. Sodium nitrite (2.57 g, 37 2 mmol) was added slowly with stirring to give a yellow solution with gas evolution. After 40 min, gas evolution had ceased and solid sodium azide (10.99 g, 169 mmol) was added in portions over about 5 min with gas evolution. Et2O (85 mL) was slowly added and a precipitate formed. After stirring for 0.5 hr, water was added and the mixture was extracted with EtOAc. The combined organic phases were washed with water (3×) and brine (1×) and then saturated Na2CO3 solution (until the aqueous phase was basic) and brine (1×). After drying the solvent with sodium sulfate, the solvent was removed. Flash chromatography (step gradient elution with DCM containing 40 to 0% hexane and then 10% EtOAc) afforded methyl 3-azido-6-bromo-2-(4-formylphenyl)isonicotinate (4.45 g, 12.3 mmol, 73% yield) as a fluffy yellow solid. 1H NMR (500 MHz, chloroform-d) δ ppm 10.10 (1H, s), 7.96-8.04 (2H, m), 7.90-7.96 (2H, m), 7.86 (1H, s), 4.03 (3H, s).
Reaction SMILES: [Mg].II.[CH2:4](Cl)/[CH:5]=[C:6](/[CH2:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])\[CH3:7].[CH2:15](Cl)[CH:16]=[CH2:17].[NH4+].[Cl-]>CCOCC>[CH3:7][C:6]([CH2:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])=[CH:5][CH2:4][CH2:17][CH:16]=[CH2:15]
Reactant: CC(C)=CCC/C(C)=C/CCl
Reactant: C=CCCl
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: C=CCCC=C(C)CCC=C(C)C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Degreased magnesium turnings (84 g., 3.5 mole) were suspended in absolute ether (100 ml.). The Mg was activated with one crystal of iodine. In the course of about 3 hours, 300 g. (1.75 mole) of geranyl chloride, then 268 g. (3.5 mole) of allyl chloride in 800 ml. of ether were added dropwise. The mixture was boiled for 4 hours, then it was cooled and poured into a solution of 200 g. of NH4Cl in 1 liter of ice water. The solution was extracted with ether. The extracts were treated as usual, after concentration, they gave 384 g. of crude 6,10-dimethyl-1,5,9-undecatriene which was used without further purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][N:6]2C(=O)C3[C:8](=CC=CC=3)[C:7]2=O)[CH2:3][CH2:2]1.O.NN.[F:20][C:21]1[C:30]([CH:31]([C:33]2[N:37]3[N:38]=[C:39](C(=O)C)[CH:40]=[CH:41][C:36]3=[N:35][N:34]=2)[CH3:32])=[C:29]([F:45])[CH:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][CH:25]=[N:26]2.Cl.[OH-].[Na+]>CO>[CH:1]1([CH2:4][O:5]/[N:6]=[C:7](/[C:39]2[CH:40]=[CH:41][C:36]3[N:37]([C:33]([CH:31]([C:30]4[C:21]([F:20])=[C:22]5[C:27](=[CH:28][C:29]=4[F:45])[N:26]=[CH:25][CH:24]=[CH:23]5)[CH3:32])=[N:34][N:35]=3)[N:38]=2)\[CH3:8])[CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1OCC1CC1
Reactant: CC(=O)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1
Agent: Cl
Agent: NN
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C/C(=N\OCC1CC1)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
2-(cyclopropylmethoxy)isoindoline-1,3-dione (300 mg, 1.42 mmol), and hydrazine monohydrate (35 μL, 0.71 mmol) in methanol (5 mL) was heated at 75° C. for 3 hr. The reaction mixture was cooled, and the precipitate was filtered off, and washed twice with minimum methanol. To the combined methanol solution was added 1-(3-(1-(5,7-difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (53.6, 100 mg, 0.28 mmol), followed by hydrochloride (1N in dioxane) dropwise to give a clear solution. The reaction mixture was stirred at rt overnight, LCMS showed the reaction was complete. 1N NaOH aqueous solution was added until pH 8-9. The mixture was concentrated, and purified by column chromatography to afford 109 mg (91% yield) of the title compound as a white solid. 1H-NMR (400 MHz, CDCl3) δ ppm 8.93 (dd, 1H), 8.33 (d, 1H), 7.96 (d, 1H), 7.75 (d, 1H), 7.59 (d, 1H), 7.41 (dd, 1H), 5.28 (q, 1H), 4.03 (d, 2H), 2.19 (d, 3H), 2.02 (s, 3H), 1.13-1.22 (m, 1H), 0.52-0.62 (m, 2H), 0.22-0.31 (m, 2H). LCMS (method A): [MH]+=423, tR=5.49 min.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@H:10]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[C@@H:9]([C:25]([O:27][CH3:28])=[O:26])[CH2:8][C@H:7]([O:29][CH2:30][C:31]([OH:33])=O)[CH2:6]1)=[O:4].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[O:33]=[C:31]([N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:30][O:29][C@@H:7]1[CH2:6][N:5]([C:3]([O:2][CH3:1])=[O:4])[C@H:10]([C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][CH2:18]2)=[O:12])[C@@H:9]([C:25]([O:27][CH3:28])=[O:26])[CH2:8]1
Reactant: C1CCNC1
Reactant: COC(=O)[C@H]1C[C@H](OCC(=O)O)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H]1C[C@H](OCC(=O)N2CCCC2)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of ((3S,5S,6S)-1,5-bis(methoxycarbonyl)-6-[(4-phenylpiperazin-1-yl)carbonyl]piperidin-3-yloxy)acetic acid (57 mg, 0.00012 mol), pyrrolidine (0.0308 mL, 0.000369 mol), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (163 mg, 0.000369 mol) in N,N-dimethylformamide (0.50 mL, 0.0064 mol) was added N,N-diisopropylethylamine (0.0857 mL, 0.000492 mol). The mixture was stirred at rt for 2 h, then diluted with ethyl acetate, washed with water, brine and dried. After concentrated to dry, the residue was used directly in next step.
Reaction SMILES: [CH2:1]([Zn]CC)C.COCCOC.ICI.[OH:15][CH2:16]/[CH:17]=[C:18](\[C:20]1[CH:21]=[C:22]([CH2:31][CH2:32][C:33](=[O:38])[CH2:34][CH2:35][CH2:36][CH3:37])[C:23]2[O:27][CH2:26][C:25]([CH3:29])([CH3:28])[C:24]=2[CH:30]=1)/[CH3:19]>ClCCl.CCCCCC.C(OCC)(=O)C>[OH:15][CH2:16][C@H:17]1[CH2:19][C@@:18]1([C:20]1[CH:21]=[C:22]([CH2:31][CH2:32][C:33](=[O:38])[CH2:34][CH2:35][CH2:36][CH3:37])[C:23]2[O:27][CH2:26][C:25]([CH3:29])([CH3:28])[C:24]=2[CH:30]=1)[CH3:1]
Reactant: CC[Zn]CC
Reactant: CCCCC(=O)CCc1cc(/C(C)=C\CO)cc2c1OCC2(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCC(=O)CCc1cc([C@@]2(C)C[C@@H]2CO)cc2c1OCC2(C)C

Procedure:
Following General Procedure C and using 1.57M diethylzinc in anhydrous dichloromethane (10 mL, 15.7 mmol), 1,2-dimethoxyethane (1.63 mL, 15.7 mmol), diiodomethane (2.53 mL, 31.4 mmol), 1-[5-((Z)-3-hydroxy-1-methyl-propenyl)-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl]-heptan-3-one (Intermediate 800.18 g, 0.55 mmol), 4A° molecular sieves powder (0.4 g) and (4S-trans)-2-butyl-N,N,N′,N′-tetramethyl[1,3,2]dioxaborolane-[4,5]dicarboxamide (0.34 g, 1.17 mmol) in 3 mL of anhydrous dichloromethane followed by flash column chromatography using 20% ethyl acetate in hexane, the title compound was obtained as a brown oil (0.16 g,85%). It was used as such for the next step.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:22][C:23](=O)[C:24]#[C:25][CH2:26][O:27][CH2:28][CH3:29]>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:23](=[O:22])[CH:24]=[C:25]([CH2:26][O:27][CH2:28][CH3:29])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Reactant: CCOCC#CC(=O)OC
Solvent: ClC(Cl)Cl
Product: CCOCc1cc(=O)nc2n1C[C@@H](COc1ccc(C3CCCCC3)cc1)O2

Procedure:
The title compound was prepared from (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine and 4-ethoxy-but-2-ynoic acid methyl ester employing the procedure described in Example 94. [α]D25 −9.80 (c 0.5, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13](O)[CH3:14])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.C1(P([N:35]=[N+:36]=[N-:37])(C2C=CC=CC=2)=O)C=CC=CC=1.O>C1(C)C=CC=CC=1>[N:35]([CH:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][C:4]=2[N+:18]([O-:20])=[O:19])=[CH:8][CH:9]=1)[CH3:14])=[N+:36]=[N-:37]
Reactant: CC(O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(N=[N+]=[N-])c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.1 %

Procedure:
To the product from Example 164b (0.30 g, 1.0 mmol) in toluene (20 mL) was added diphenylphosphoryl azide (0.36 g 6.26 mmol), followed by 1,8-diazabicyclo[4.3.0]undec-7-ene (0.19 g, 1.3 mmol). The mixture is stirred at 25° C. for 18 h. The reaction was poured into water and extracted with ethyl acetate. The combined organic layers are washed with 5% HCl, sat. NaCl (1×), dried over sodium sulfate, filtered and concentrated under vacuum giving the crude title compound. The crude product was purified by silica gel chromatography, eluting with hexanes/ethyl acetate/methanol (85:15:5) to provide the title compound (300 mg, 94%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN([C:20]([O:24][N:25]1N=NC2C=CC=N[C:26]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O>C(Cl)Cl>[CH3:20][O:24][N:25]([CH3:26])[C:14]([CH:10]1[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a solution of 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (10 g, 43 mmol) in DCM (60 mL) was added HATU (19 g, 50 mmol) in portions, The mixture was stirred at room temperature for 0.5 h. Then DIPEA (12.9 g, 100 mmol) and N, O-dimethylhydroxylamine hydrochloride (5.0 g, 51.5 mmol) were added in the mixture. The mixture was stirred at room temperature overnight. Water (40 mL) was added and the mixture was extracted by DCM (100 mL*3). The organic layer was washed with brine (5 mL) and dried over sodium sulfate. Concentration and purification by column chromatography on silica gel (eluted: petroleum ether/ethyl acetate=20/1-10/1) to give tert-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (10 g, 84%).
Reaction SMILES: [CH2:1]([Zn]CC)C.CCCCCC.FC(F)(F)C(O)=O.ICI.[CH2:22]([O:24][C:25]([C:27]1[C:28]([CH3:42])=[N:29][N:30]([C:32]2[C:37]([CH2:38][O:39][CH:40]=[CH2:41])=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:31]=1)=[O:26])[CH3:23].Cl>ClCCl>[CH:40]1([O:39][CH2:38][C:37]2[C:32]([N:30]3[CH:31]=[C:27]([C:25]([O:24][CH2:22][CH3:23])=[O:26])[C:28]([CH3:42])=[N:29]3)=[N:33][CH:34]=[CH:35][CH:36]=2)[CH2:1][CH2:41]1
Reactant: C=COCc1cccnc1-n1cc(C(=O)OCC)c(C)n1
Reactant: CC[Zn]CC
Agent: Cl
Solvent: ICI
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: CCOC(=O)c1cn(-c2ncccc2COC2CC2)nc1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1.0 M diethylzinc in hexane (365.7 mL, 3.5 mmol) is added under nitrogen to dichloromethane (0.9 mL). The solution is cooled to 0° C. and a solution of trifluoroacetic acid (268.4 μL, 3.5 mmol) in dichloromethane (0.9 mL) is added very slowly. After 20 min a solution of diiodomethane (286.1 mL, 3.5 mmol) in dichloromethane (0.9 mL) is added. After an additional 20 min, a solution of 3-methyl-1-(3-vinyloxymethyl-pyridin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (510 mg, 1.8 mmol) in dichloromethane (0.9 mL) is added. The mixture is stirred at room temperature overnight. 5% HCl is added and the aqueous layer is extracted with ethyl acetate. The organic layer is separated, dried over sodium sulfate and the solvent is eliminated under reduced pressure. The crude is purified by normal phase Isco chromatography using hexane and ethyl acetate as eluents (5-20% in ethyl acetate) to get 310 mg of ethyl 1-[3-(cyclopropoxymethyl)-2-pyridyl]-3-methyl-pyrazole-4-carboxylate. MS (m/z): 302 (M+1)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:6])[CH3:5].[N+](=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][O:6][CH:4]([CH3:5])[CH2:3][O:2][CH3:1])[CH3:14]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: COCC(C)O
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCCCCCC
Product: CCOC(=O)COC(C)COC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a solution of 1-methoxy-2-propanol (900 mg, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixture is stirred at rt for 30 min. The reaction mixture is diluted with heptane, filtered through celite, and the filtrate is evaporated and the residue is vacuum distilled at 133° C. to give 1.03 g of the product 473. 1H NMR (CDCl3) δ 4.20 (q, 2H), 3.72 (m, 1H), 3.45 (dd, 1H), 3.37 (dd, 1H), 3.35 (s, 3H), 1.27 (t, 3H), 1.19 (d, 3H).
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1C=CC=CC=1.CCOCC>[CH3:1][NH:3][CH2:4][C:5]1([N:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CN1CCN(C2(CNC=O)CCCCC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: CNCC1(N2CCN(C)CC2)CCCCC1

Procedure:
1-(1-Formylaminomethylcyclohexyl)-4-methylpiperazine (5.97 g, 0.025 mole) was dissolved in dry benzene (100 ml) and added dropwise to a stirred suspension of lithium aluminum hydride (3.8 g; 0.1 mole) in dry ether (200 ml). The suspension was refluxed for four days and excess lithium aluminium hydride decomposed by the dropwise addition of water (8 ml), 30% sodium hydroxide solution (6 ml) and water (28 ml). The ether/benzene layer was separated, dried (Na2SO4) and evaporated to yield an amber, mobile oil (5.2 g. 93.0%) which failed to crystallise or produce stable salts. Distillation of this oil in vacuo gave 1-(1-methylaminomethylcyclohexyl)-4-methylpiperazine as a colourless oil.