Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([CH3:22])([OH:21])[CH3:20])[CH:15]=3)[CH:10]=[N:9]2)[C:5](Br)=[CH:4][N:3]=1.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([CH3:22])([OH:21])[CH3:20])[CH:15]=3)[CH:10]=[N:9]2)[C:5]([C:28]2[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=2)=[CH:4][N:3]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(O)C#Cc1ccc2cnn(-c3nc(N)ncc3Br)c2c1
Product: Cn1cc(-c2cnc(N)nc2-n2ncc3ccc(C#CC(C)(C)O)cc32)cn1

Procedure:
5-bromo-4-(6-bromoindazol-1-yl)pyrimidin-2-amine (3 g) was reacted with 2-methyl-3-butyn-2-ol (1 eq) via General Procedure Sonagashira Coupling (See, Chinchilla, R.; Najera, C. (2007), “The Sonogashira Reaction: A Booming Methodology in Synthetic Organic Chemistry”, Chem. Rev. 107: 874-922) to afford 0.7 g of 4-[1-(2-amino-5-bromo-pyrimidin-4-yl)indazol-6-yl]-2-methyl-but-3-yn-2-ol following flash column chromatography. 4-[1-(2-amino-5-bromo-pyrimidin-4-yl)indazol-6-yl]-2-methyl-but-3-yn-2-ol (0.1 g) was reacted with 1-methyl-4-pyrazoleboronic acid pinacol ester via General Procedure Suzuki Coupling to afford 12.2 mg of 4-[1-[2-amino-5-(1-methylpyrazol-4-yl)pyrimidin-4-yl]indazol-6-yl]-2-methyl-but-3-yn-2-ol following reverse phase hplc purification. MS (Q1) 374. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.30 (s, 1H), 7.88-7.81 (m, 2H), 7.48 (s, 1H), 7.24 (dd, J=8.3, 1.1 Hz, 1H), 7.05 (s, 2H), 6.98 (s, 1H), 5.47 (s, 1H), 3.73 (s, 3H), 1.48 (s, 6H).
Reaction SMILES: [CH2:1]1[N:16]2[C:17]3[C:8]([O:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=42)=[CH:7][CH:6]=[CH:5][C:4]=3[C:3](=[O:18])[CH2:2]1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=O)[CH:20]=1>>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:2]2[C:3](=[O:18])[C:4]3[CH:5]=[CH:6][CH:7]=[C:8]4[C:17]=3[N:16]([CH:1]=2)[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:9]4)[CH:20]=1
Reactant: O=Cc1cccnc1
Reactant: O=C1CCN2c3ccccc3Oc3cccc1c32
Product: O=c1c(Cc2cccnc2)cn2c3c(cccc13)Oc1ccccc1-2
Yield: 87.2 %

Procedure:
According to Example 1<step 4>, 1,2-dihydro-3H-pyrido[3,2,1-kl]phenoxazin-3-one (1 g) prepared by the procedure described in literature (J. Org. Chem., 24, 1699 (1959)) was reacted with pyridine-3-aldehyde (0.7 g) to obtain the title compound (1.2 g; 88%). The chemical structure thereof is shown below.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH3:25])[NH:17][C:16](=O)[N:15]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O1CCOCC1.CCOC(C)=O>[CH2:23]([O:22][C:20]([C:19]1[C:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[F:7])=[N:15][C:16]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[N:17][C:18]=1[CH3:25])=[O:21])[CH3:24]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1c(-c2ccccc2F)nc(=O)[nH]c1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc(N2CCOCC2)nc1-c1ccccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
Morpholine (0.5 mL) was added to a stirred solution of ethyl 4-(2-fluorophenyl)-1,2-dihydro-6-methyl-2-oxopyrimidine-5-carboxylate (0.75 g, 2.72 mmol), PyBroP (1.4 g, 3 mmol), and triethylamine (1 mL) in 1,4-dioxane (20 mL) at room temperature. The solution was stirred at room temperature for 3 h and diluted with EtOAc. The solution was washed with saturated NH4Cl and saturated aqueous NaCl solution, and dried. The solvent was removed under reduced pressure, and the residue was purified by Biotage SP1 on packed silica gel column (5%-80% EtOAC/hexanes gradient) to give 4-(2-fluorophenyl)-6-methyl-2-morpholin-4-yl-pyrimidine-5-carboxylic acid ethyl ester as an oil (0.937 g, 64%). Mass Spec. LCMS 346 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl-].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][Zn+])=[CH:16][CH:15]=1>C1COCC1.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>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: Fc1ccc(C[Zn+])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Cc2ccc(F)cc2)c1
Temperature: 60 °C
Reaction time: 19 h
Yield: 88.4 %

Procedure:
Methyl 2-chloroisonicotinate (5.6 g, 32.64 mmol) and Pd(PPh3)4 (0.754 g, 0.65 mmol) were dissolved under nitrogen in THF (100 mL) and (4-fluorobenzyl)zinc(II) chloride (0.5 M in THF) (100 mL, 50.00 mmol) was added. The brown solution was stirred at 60° C. for 19 h. The reaction was quenched by addition of methanol (50.0 mL). The solution was diluted with EtOAc and washed with NH4Cl (aq) and water. The organic layer was evaporated, dissolved in DCM and washed with NH4Cl (aq) and then dried by passage through a phase separator. The solvent was evaporated to yield a brown oil. The compound was purified in 2 runs via Biotage, SNAP 340 g KP-SIL, eluent isocratic heptane/ethyl acetate 8:2 for 2 CV, then linear gradient heptane/ethyl acetate 8:2 to 5:5 over 5 CV to yield methyl 2-(4-fluorobenzyl)isonicotinate 7.08 g (88%) as a yellow oil. 1H NMR (400 MHz, cdcl3) δ 3.92 (s, 3H), 4.18 (s, 2H), 6.94-7.02 (m, 2H), 7.19-7.27 (m, 2H), 7.65-7.69 (m, 2H), 8.68-8.71 (m, 1H). MS m/z 246 (M+H)+
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5].[O:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Li])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[C:15]([O:14][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4](=[O:5])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:7]1)=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: [Li]c1ccccc1Oc1ccccc1
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccccc2Oc2ccccc2)C1
Temperature: 25 °C
Yield: 120.4 %

Procedure:
To a solution of (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (4.40 g, 16.2 mmol) in anhydrous THF (18 mL) at −10° C., was added dropwise the solution of 2-phenoxyphenyllithium prepared in Step 1 (80 mL, 32 mmol). The mixture was then warmed to rt, and stirred until no starting material remained (˜30 min). The reaction was quenched with 1 N HCl (˜30 mL) and extracted with Et2O (4×10 mL). The combined organic layers were washed with sat'd aq NaHCO3 and brine, and dried over Na2SO4. The solvent was removed to give (3R)-1-(tert-butoxycarbonyl)-3-(2-phenoxybenzoyl)piperidine (7.44 g, quantitative).
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](OCCCl)=[O:4].[C:15]([O:19][CH:20]([CH3:22])[CH3:21])(=[O:18])[CH2:16][OH:17].C(C1C=CC=CC=1)(C)(C)C>C(OCC)C>[OH:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:17][CH2:16][C:15]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[O:4]
Reactant: CC(C)OC(=O)CO
Reactant: O=C(OCCCl)C(O)c1ccccc1
Solvent: CCOCC
Solvent: CC(C)(C)c1ccccc1
Product: CC(C)OC(=O)COC(=O)C(O)c1ccccc1

Procedure:
A 6 mL aliquot of an ethyl ether solution containing 0.25 M 2-chloroethyl 2-hydroxy-2-phenylacetate, 0.25 M isopropyl glycolate, and 1.0% tert-butylbenzene was added to 0.43 g Lipase P30. After mixing for 5 d at room temperature, the conversion of 2-chloroethyl 2-hydroxy-2-phenylacetate to the title compound was estimated (by GC, Method B) to be approximately 15%. The GC peak assigned to the title compound was confirmed by HRMS: calcd for C12H12O5Tms (M--CH3) 309.1158, obsd 309.1171. In identical reactions substituting Lipase G, Lipase AK, Lipase MAP10, Protease M, Lipase AP12, or porcine pancreatic lipase for Lipase P30, the relative values for conversions at 5 d (Lipase P30 =100) were 17, 12, 12, 6, 4, and 2%, respectively.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[CH2:3][C:4]([NH:6][NH:7][C:8]([O:10][CH3:11])=[O:9])=[S:5].[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:19][O:18][C:14](=[O:17])[CH2:15][CH2:16][S:5]/[C:4](=[N:6]\[NH:7][C:8]([O:10][CH3:11])=[O:9])/[CH2:3][C:2]([CH3:13])([CH3:12])[CH3:1]
Reactant: C=CC(=O)OC
Reactant: COC(=O)NNC(=S)CC(C)(C)C
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCS/C(CC(C)(C)C)=N\NC(=O)OC
Yield: 92.7 %

Procedure:
A mixture of 20.5 g of 2-(3,3-dimethyl-1-thioxobutyl)hydrazinecarboxylic acid, methyl ester, 12.92 g of methyl acrylate, 1 ml of triethylamine and 300 ml of dry benzene was heated at reflux for 8 hours, then cooled and concentrated in vacuo. The residual oil was chromatographed through a bed of hydrous magnesium silicate, eluting with dichloromethane and evaporated, giving 27 g of (Z)-[1-[(3-methoxy-3-oxopropyl)thio]-3,3-dimethylbutylidene]hydrazinecarboxylic acid, methyl ester.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[F:25])#[N:17].[C:26]([O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)(=[O:30])/[CH:27]=[CH:28]/[CH3:29]>CN(C)C1C=CN=CC=1.ClCCl>[C:26]([O:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:24][C:21]2[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[C:19]([F:25])[CH:20]=2)=[O:37])=[CH:39][CH:40]=1)(=[O:30])/[CH:27]=[CH:28]/[CH3:29]
Reactant: C/C=C/C(=O)Oc1ccc(C(=O)O)cc1
Reactant: N#Cc1ccc(O)cc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C/C=C/C(=O)Oc1ccc(C(=O)Oc2ccc(C#N)c(F)c2)cc1
Reaction time: 8 h
Yield: 105.6 %

Procedure:
2.6 g of N,N'-dicyclohexylcarbodiimide were added while stirring within 5 minutes to a solution of 1.2 g of 4-cyano-3-fluorophenol, 1.2 g of 4-[(E)-but-2-enoyloxy]benzoic acid and 0.1 g of 4-(dimethylamino)pyridine in 50 ml of dichloromethane. The reaction mixture was stirred overnight, then filtered. The filtrate was washed with saturated sodium bicarbonate solution and with water and concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 9:1) and two-fold recrystallization of the fractions which were pure according to thin-layer chromatography gave 2.0 g of 4-cyano-3-fluorophenyl 4-[(E)-but-2-enoyloxy]benzoate. M.p. (C-N) 125° C. and cl.p. (N-I) 195° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].Cl.N1C=CC=CC=1.[OH:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH2:27]>C(OCCO)C>[OH:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: Cc1ccc(N)cc1O
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cccc2c(Nc3ccc(C)c(O)c3)c(C#N)cnc12
Temperature: 100 °C
Yield: 89 %

Procedure:
Using an analogous procedure to that described in Example 274. A reaction mixture of 328.0 mg (1.5 mmol) of 4-chloro-8-methoxy -3-quinolinecarbonitrile, 173.3 mg (1.5 mmol) of pyridine hydrochloride and 203.2 mg (1.7 mmol) of 3-hydroxy-4-methylaniline in 15 mL of 2-ethoxyethanol was heated at 100° C. for 1.5 hr. After the work up, 407.7 mg (89.4%) of the product was obtained as a yellow solid, m.p. 148-150° C., mass spectrum (electrospray, m/e): M+H 306.9.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:16][O:17][CH2:18][CH2:19][N:20]([CH3:28])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][N:22]=1>>[CH3:16][O:17][CH2:18][CH2:19][N:20]([CH3:28])[C:21]1[N:22]=[CH:23][C:24]([NH:27][C:13]([C:3]2[C:2]([CH3:1])=[N:6][N:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:4]=2)=[O:15])=[CH:25][CH:26]=1
Reactant: Cc1nn(-c2ccccc2)nc1C(=O)O
Reactant: COCCN(C)c1ccc(N)cn1
Product: COCCN(C)c1ccc(NC(=O)c2nn(-c3ccccc3)nc2C)cn1

Procedure:
With a procedure similar to example 16 above, 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C19H22N6O2 (m/e) 366, obsd 367 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:12]=[CH:13]/[C:14]([N:16]2[C@H:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][O:18][C:17]2=[O:27])=[O:15])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CO[CH2:30][N:31]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:32][Si](C)(C)C.C(O)(C(F)(F)F)=O.C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:37]([N:31]1[CH2:32][C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([F:1])[CH:3]=2)[C@H:13]([C:14]([N:16]2[C@H:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:19][O:18][C:17]2=[O:27])=[O:15])[CH2:30]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(/C=C/c1ccc(C(F)(F)F)c(F)c1)N1C(=O)OC[C@H]1c1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC[C@@H](c2ccccc2)N1C(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(C(F)(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 57.1 %

Procedure:
To a solution of 338 (2.10 g, 5.54 mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (1.98 mL, 7.75 mmol) dissolved in toluene (25 mL) and cooled to 0° C. A solution of TFA (0.0427 mL, 0.554 mmol) and benzene (1 mL) was added slowly over 15 min and the mixture was stirred for 4 h. The mixture was washed sequentially with satd. aq. NaHCO3, twice with water, dried, filtered and evaporated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (20-40% EtOAc) to afford 1.62 g (57.1%) of (R)-3-((3S,4R)-1-benzyl-4-(3-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-3-carbonyl)-4-phenyloxazolidin-2-one (340) as white foamy solid.
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([OH:4])[CH3:3].[C:6](NC(=O)C(Cl)(Cl)Cl)([CH3:9])([CH3:8])[CH3:7].C([O-])(O)=O.[Na+].[CH2:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>[B]>[C:6]([O:5][CH2:1][C@@H:2]([OH:4])[CH2:3][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(O)CO
Reactant: C1CCCCC1
Reactant: CC(C)(C)NC(=O)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [B]
Agent: [Na+]
Product: CC(C)(C)OC[C@@H](O)CC1CCCCC1
Reaction time: 21 h

Procedure:
(S)-1-(tert-Butoxy)-3-cyclohexyl-propan-2-ol was prepared according to the procedure described by Alan Armstrong et al., Tetrahedron Letters 1988, 29: 2483-2486. Three drops of boron trifuoride etherate were added to a solution of (S)-3-cylcolhexyl 1,2-propanediol (540 mg, 3.4 mmol) and tert-butyl 2,2,2-trichloroacetamide (670 μL, 3.8 mmol) in cyclohexane (7 mL) at ambient temperature. After stirring for 21 hours, a saturated solution of NaHCO3 was added to the reaction mixture and the mixture was extracted with EtOAc (2×). The EtOAc phases were combined, dried (MgSO4) and concentrated. The residue was chromatographed (silica gel; EtOAc/hexanes, 1:10) to afford a clear oil (235 mg, 32%). 1H NMR (CDCl3, 300 MHz) δ0.79-1.01 (m, 2H), 1.12-1.53 (m, 6H), 1.20 (s, 9H) 1.58-1.84 (m, 5H), 3.12 (dd, J=9, 9 Hz, 1H), 3.35 (dd, J=3, 9 Hz, 1H), 3.81 (m, 1H); MS (CI/NH3) m/z: (M+H)+ 215.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]1[C:19]([F:20])=[C:18]([O:21][CH2:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:15]=1[CH:25](O)[CH2:26][CH:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:29][CH2:28]1.O>C1(C)C=CC=CC=1>[F:13][C:14]1[C:19]([F:20])=[C:18]([O:21][CH2:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:15]=1[CH:25]=[CH:26][CH:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:29][CH2:28]1
Reactant: CCCCCC1CCC(CC(O)c2c(C)cc(OCC)c(F)c2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(C=Cc2c(C)cc(OCC)c(F)c2F)CC1

Procedure:
0.55 g of p-toluenesulfonic acid monohydrate was added to the compound (7) having been dissolved in 120 mL of toluene, and the mixture was heated under stirring by using a Dean-Stork trap until completion of azeotrope of water. After terminating the reaction by adding water, the aqueous layer was extracted with toluene, washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography and then subjected to recrystallization to obtain 6.53 g of 1-(2,3-difluoro-4-ethoxy-6-methylphenyl)-2-(4-pentylcyclohexyl)ethene (Compound 1-1-3-18) as colorless crystals.
Reaction SMILES: [O:1]=[C:2]1[NH:5][C@H:4]([CH2:6][CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.C(N(CC)CC)C.[C:26]([Si:30]([CH3:33])([CH3:32])Cl)([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O.C(OCC)(=O)C>[Si:30]([N:5]1[C:2](=[O:1])[CH2:3][C@H:4]1[CH2:6][CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:33])[CH3:32]
Reactant: O=C1C[C@@H](CC=CC(=O)OCc2ccccc2)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1CC=CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
To a mixture of benzyl 4-[(2R)-4-oxoazetidin-2-yl]but-2-enoate (16 mg) and triethylamine (18 μl) in dimethylformamide (0.5 ml) was added tert-butyl-dimethylchlorosilane (15 mg) at 5° C. The mixture was stirred at the same temperature for one hour and at room temperature for 30 minutes. The resultant mixture was diluted with ethyl acetate (20 ml), washed with chilled dilute hydrochloric acid, a dilute aqueous sodium bicarbonate, and brine. Drying over magnesium sulfate and removal of the solvent left an oil (23 mg), which was chromatographed on a silica gel plate (developing solvent: 5% methanol in dichloromethane) to give benzyl 4-[(2R)-1-(tert-butyl-dimethylsilyl)-4-oxoazetidin-2-yl)but-2-enoate (13 mg).
Reaction SMILES: [OH:1][CH:2]([CH2:6][OH:7])[CH2:3][NH:4][CH3:5].[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][NH:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31](Cl)[N:30]=4)=[CH:25][CH:24]=3)[CH:17]=2)[NH:12][CH:11]=1)#[N:9]>>[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][NH:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([N:4]([CH2:3][CH:2]([OH:1])[CH2:6][OH:7])[CH3:5])[N:30]=4)=[CH:25][CH:24]=3)[CH:17]=2)[NH:12][CH:11]=1)#[N:9]
Reactant: CNCC(O)CO
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: CN(CC(O)CO)c1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using 2,3-dihydroxy-propyl-methylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 471 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:20][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=3)[CH2:11][CH:6]2[CH2:5][CH2:4]1.[F:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.Cl>C1COCC1.C(OCC)(=O)C.CCOCC>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:1][CH2:2][CH:3]2[CH2:20][N:7]3[CH2:8][CH2:9][N:10]([C:12]4[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=4)[CH2:11][CH:6]3[CH2:5][CH2:4]2)=[CH:24][CH:23]=1
Reactant: Oc1ccc(F)cc1
Reactant: OCC1CCC2CN(c3ncc(Cl)cc3Cl)CCN2C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(OCC2CCC3CN(c4ncc(Cl)cc4Cl)CCN3C2)cc1
Yield: 87.3 %

Procedure:
A solution of 0.50 g (1.58 mmol) of (7RS,9aSR)-7-hydroxymethyl-2-(3,5-dichloro-pyridin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine in 40 mL of THF with 0.266 g (2.32 mmol) of 4-fluorophenol, 0.498 g (1.90 mmol) of triphenylphosphine, and 0.30 mL (1.90 mmol) of diethyl azodicarboxylate was stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate and treated with excess HCl(g) in ether. The solvent was evaporated and the residue washed repeatedly with 1:1 ethyl acetate:ether. The white powder was dissolved in chloroform, washed with 1M NaOH (2×), dried (magnesium sulfate), filtered and evaporated. The crude product was purified by flash silica gel chromatography with 50:50 ethyl acetate: hexane to give 0.566 g (87%) of title compound. mp (—HCl) 247-248° C. 13C NMR (base, CDCl3): δ27.1, 29.0, 36.4, 49.0, 54.4, 54.8, 58.6, 60.7, 71.7, 115.36, 115.47, 115.59, 115.89, 122.3, 124.0, 138.2, 155.1, 155.6, 156.6, 158.8. HRMS calc for C20H22Cl2FN3O: 409.1124, found: 409.1141.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].Br[CH2:12][C@@H:13]([CH3:16])[CH2:14][Cl:15]>>[Cl:15][CH2:14][C@H:13]([CH3:16])[CH2:12][O:10][C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: Oc1cc(F)c(F)cc1F
Reactant: C[C@@H](CCl)CBr
Product: C[C@@H](CCl)COc1cc(F)c(F)cc1F

Procedure:
Prepared by Procedure U and Scheme AK using 2,4,5-trifluorophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[C:7]([NH2:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:18](OC)(OC)(OC)[CH2:19][CH2:20][CH2:21][CH3:22]>Cl.N1C=CC=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:18]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: CCCCC(OC)(OC)OC
Reactant: CC(C)CNc1c(N)cnc2cc(Br)ccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCc1nc2cnc3cc(Br)ccc3c2n1CC(C)C
Temperature: 25 °C
Yield: 43.9 %

Procedure:
7-Bromo-N4-isobutylquinoline-3,4-diamine (39.4 g of crude material), trimethyl orthovalerate (32 g, 0.20 mol), and pyridine hydrochloride (0.31 g, 2.7 mmol) were combined with anhydrous toluene (500 mL) and heated to reflux for 30 min. The reaction was cooled to room temperature, concentrated, and the residue was purified by chromatography on silica gel (75% ethyl acetate in hexane to 100% ethyl acetate gradient) to afford 21.2 g of 7-bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinoline as a yellow solid.
Reaction SMILES: [Cl-:1].[NH3+:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[NH+:11][CH:12]=[CH:13][CH:14]=1)=O.[Cl-].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:29][C:26]([CH:27]=O)=[CH:25][CH:24]=2)=[C:19]([N+:30]([O-:32])=[O:31])[CH:18]=1.Cl>C(O)(C)C>[ClH:16].[ClH:1].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:29][C:26]([CH:27]=[C:6]3[CH2:5][CH2:4][CH2:3][N:2]=[C:7]3[C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)=[CH:25][CH:24]=2)=[C:19]([N+:30]([O-:32])=[O:31])[CH:18]=1
Reactant: [NH3+]CCCCC(=O)c1ccc[nH+]c1
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2[N+](=O)[O-])o1
Reactant: [Cl-]
Agent: Cl
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc(Cl)ccc1-c1ccc(C=C2CCCN=C2c2cccnc2)o1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
3-(5-Ammoniopentanoyl)pyridinium chloride (109 mg, 0.43 mmol) and 5-(4-chloro-2-nitrophenyl)furfural (131 mg, 0.52 mmol) were combined in a reaction vessel and treated with isopropanol (6 mL). The reaction vessel was sealed and the reaction was heated to 80° C. with stirring overnight. The reaction was then cooled to room temperature, concentrated under reduced pressure and treated with saturated NaHCO3(aq). This mixture was then extracted three times with EtOAc. The EtOAc extracts were washed with brine, combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The recovered material was eluted through a 20 gram column of silica gel with 10.5:7:7:1:0.1 hexane:MtBE:CH2Cl2:MeOH:NH4OH (800 mL). One sample was recovered. This material was dissolved into methanol and treated with 2 equivalents of 6 N HCl(aq). This solution was concentrated under reduced pressure and the recovered material re-crystallized from a mix of isopropanol and ether. The crystals were recovered by vacuum filtration, washed with a 20% solution of isopropanol in hexane, and then with ether, then dried under vacuum giving 95 mg (47%) of a yellow solid. LC-MS: RT=5.65 min, [M+H]+=394.0.