Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[CH2:9][CH2:10][N:11]([CH:19]([CH3:21])[CH3:20])C(=O)OC(C)(C)C)[CH:5]=[CH:6][CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[CH2:9][CH2:10][NH:11][CH:19]([CH3:20])[CH3:21])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCCOC(CCN(C(=O)OC(C)(C)C)C(C)C)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCOC(CCNC(C)C)c1cccc(Cl)c1
Reaction time: 1 h

Procedure:
tert-butyl 3-(3-chlorophenyl)-3-(3-methoxypropoxy)propyl(isopropyl)carbamate was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (10 mL) and allowed to stir for 1 hour. The solvent and reagent were evaporated before re-dissolving in CH2Cl2 and washing with NaHCO3 saturated solution. The crude 3-(3-chlorophenyl)-N-isopropyl-3-(3-methoxypropoxy)propan-1-amine was isolated (138 mg) and used as is. MS ESI+ve m/z 299 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH-].[K+].CS(C)=O.Br[CH2:18][CH2:19][CH2:20][Cl:21]>O>[Cl:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Oc1cccc2[nH]ccc12
Reactant: ClCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: ClCCCOc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
A mixture of 4-hydroxyindole (0.100 g, 0.75 mmol, 1.0 eq), powdered potassium hydroxide (0.042 g, 0.75 mmol, 1.0 eq), and DMSO (3 mL) was stirred at room temperature for 1 hour before 1-bromo-3-chloropropane (0.118 g, 0.75 mmol, 1.0 eq) was added. The above mixture was then stirred at room temperature for another 0.5 hour and then 15 mL of water was added to it. The resultant mixture was extracted with ethyl acetate (2×30 mL). The organic layer was collected, combined, washed with water (6×25 mL) and brine (2×20 mL), and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel using hexane/ethyl acetate (95/5) as an eluant to afford 4-(3-chloropropoxy)-1H-indole (0.130 g, yield: 83%).
Reaction SMILES: F[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].O.[NH2:22][NH2:23]>C(O)C>[NH:22]([C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])[NH2:23]
Reactant: NN
Reactant: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: O
Solvent: CCO
Product: NNc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
2-fluoroadenosine (4 g, 14 mmol) was dissolved in 100 mL ethanol in a 300 mL three-necked flask. Hydrazine hydrate (4.1 mL, 6 equivalents, 84 mmol) was added and the mixture was heated to reflux for 1 hour. The reaction mixture was allowed to cool to room temperature and stirred overnight (16 hours). The resulting white precipitate was isolated by filtration and dried in oven at 40° C. overnight to afford 2-hydrazinoadenosine (yield: 94%, 3.5 g, 96% purity).
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([O:23][CH3:24])([C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:12]2)=O)(C)(C)C.C(Cl)[Cl:26]>Cl.O1CCOCC1>[ClH:26].[CH3:24][O:23][C:11]1([C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:12][CH:13]2[NH:8][CH:9]([CH2:15][CH2:14]2)[CH2:10]1
Reactant: COC1(c2ncccc2C)CC2CCC(C1)N2C(=O)OC(C)(C)C
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: COC1(c2ncccc2C)CC2CCC(C1)N2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
3-Methoxy-3-(3-methyl-pyridin-2-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.09 g) was dissolved in a solution of hydrogen chloride in dioxane (4 N, 1.5 mL). The mixture was stirred for 1 hour at 50° C., DCM (3 mL) added and stirred for 5 minutes. The solvent was removed by evaporation under vacuum afford the title compound as a white solid. LCMS m/z 233.1 [M+H]+. R.T.=1.72 min (Analytical Method 3).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][C:16]2[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:15]=2[N:14]=1)=O)(C)(C)C.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>C(Cl)Cl>[OH:29][C:23]([C:25]([F:28])([F:27])[F:26])=[O:24].[I:22][C:20]1[CH:19]=[CH:18][C:16]2[NH:17][C:13]([C@@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[N:14][C:15]=2[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(I)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Ic1ccc2[nH]c([C@@H]3CCCN3)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring mixture of (S)-2-(5-Iodo-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (20 g, 48 mmol) in CH2Cl2 (200 mL) at 0° C. is added TFA (200 mL). The reaction mixture is stirred at room temperature for 2 hours and concentrated in vacuum. The residue is dissolved in CH2Cl2 and saturated aqueous NaHCO3, the organic layer is washed with saturated aqueous NaHCO3, dried over sodium sulfate and concentrated in vacuum to afford (S)-5-iodo-2-(pyrrolidin-2-yl)-1H-benzo[d]imidazole-TFA salt (12 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[CH2:3]1.[CH3:11]C(C)([O-])C.[K+].CI>C(O)(C)(C)C>[CH3:11][CH:6]1[C:4](=[O:5])[CH2:3][C:2]([CH3:10])([CH3:1])[CH2:9][C:7]1=[O:8]
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CI
Product: CC1C(=O)CC(C)(C)CC1=O
Reaction time: 2 h

Procedure:
28.0 g (0.2 mol) of dimedone were dissolved in 150 ml of absolute t-butanol and, at 40° C., 22.4 g (0.2 mol) of potassium t-butoxide were added a little at a time. After 2 hours, an equimolar amount of methyl iodide was added. After a further 2 hours, the solvent was removed under reduced pressure and the residue which remained was extracted 3 times with diethyl ether. The combined ether extracts were evaporated to dryness. Yield: 26.2 g (85%). The crude product was not purified further.
Reaction SMILES: [C:1]1([CH2:7][C@H:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C@H:10]([OH:17])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]([C:29]([F:32])([F:31])[F:30])=[CH:20][C@@H:21]1[C@H:23]([C:24](Cl)=[O:25])[C:22]1([CH3:28])[CH3:27].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:18][C:19]([C:29]([F:30])([F:31])[F:32])=[CH:20][C@@H:21]1[C@H:23]([C:24]([O:17][C@H:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C@H:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:9]2)=[O:25])[C:22]1([CH3:28])[CH3:27]
Reactant: O[C@@H]1C[C@@H](Cc2ccccc2)c2ccccc21
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)O[C@@H]1C[C@@H](Cc2ccccc2)c2ccccc21
Yield: 61.9 %

Procedure:
In the manner of Example 4, the reaction of 0.6 g (0.0027 mole) of trans-3-phenylmethyl-1-indanol (96% trans, 4% cis) and 0.704 g (0.0027 mole) of cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride (which may be prepared by method disclosed in U.S. Pat. No. 4,238,505, Example 7) in the presence of 0.214 g (0.0027 mole) of pyridine and 50 mL of toluene gave 0.75 g of trans-3-phenylmethyl-1-indanyl cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate. The ir and nmr spectra were consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[CH2:22]Cl.[NH:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[CH2:22][N:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: COc1ccc(S(=O)(=O)n2cc(CCl)c3cc(Br)ccc32)cc1
Reactant: C1CNCCNC1
Product: COc1ccc(S(=O)(=O)n2cc(CN3CCCNCC3)c3cc(Br)ccc32)cc1

Procedure:
Using essentially the same procedure as described in example 127, 5-Bromo-1-(4-methoxybenzenesulfonyl)-3-chloromethyl-1H-indole was reacted with homopiperazine to obtain the above derivative.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:60][CH3:61])=[C:10]([CH2:19][N:20]([CH2:22][C:23]3[CH:24]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[CH:35][C:36]([F:59])=[C:37]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:51][CH2:50][N:49](C(OC(C)(C)C)=O)[CH2:48][CH2:47]6)[CH:40]=5)[CH:38]=4)=[O:30])[CH:26]=[CH:27][CH:28]=3)[CH3:21])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:60][CH3:61])=[C:10]([CH2:19][N:20]([CH2:22][C:23]3[CH:24]=[C:25]([CH:26]=[CH:27][CH:28]=3)[C:29]([NH:31][CH2:32][C:33]3[CH:38]=[C:37]([C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]5[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]5)[CH:40]=4)[C:36]([F:59])=[CH:35][CH:34]=3)=[O:30])[CH3:21])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(C)Cc1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(C)Cc1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCNCC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To a solution of 1,1-dimethylethyl 4-{[5′-({[(3-{[{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}(methyl)amino]methyl}phenyl) carbonyl]amino}methyl)-2′-fluoro-3-biphenylyl]methyl}-1-piperazinecarboxylate (0.055 g, 0.066 mmol) in DCM (0.25 mL) was added TFA (0.25 mL) and stirred at room temperature for 30 min before was diluted with DCM, basified with NaHCO3 (sat. aq.). Organic layer was separated, dried over Na2SO4, filtered, concentrated, purified using a Gilson HPLC (with TFA), final product was basified with an amine cartridge to afford 0.015 g (31%) of the title compound. LC-MS m/z 733 (M+H)+; 1H-NMR (400 MHz, CD3OD) δ ppm 1.24 (t, J=7.40 Hz, 3 H) 1.48 (t, J=7.15 Hz, 3 H) 1.70-1.85 (m, J=10.79 Hz, 2 H) 2.01-2.11 (m, J=12.55, 1.76 Hz, 2 H) 2.56 (s, 3 H) 2.83-2.97 (m, J=7.28 Hz, 2 H) 3.46-3.58 (m, J=5.77 Hz, 8 H) 3.59-3.68 (m, 2 H) 3.92-4.00 (m, J=12.05 Hz, 2 H) 4.01-4.26 (m, J=29.11 Hz, 4 H) 4.26-4.35 (m, 1 H) 4.41-4.50 (m, 4 H) 4.61 (s, 2 H) 7.19 (dd, J=10.67, 8.41 Hz, 1 H) 7.39-7.45 (m, 1 H) 7.50-7.60 (m, 4 H) 7.61-7.70 (m, 2 H) 7.74 (s, 1 H) 7.86 (d, J=8.03 Hz, 1 H) 7.95 (s, 1 H) 8.25 (s, 1 H).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=1[F:20].[CH2:21]([NH:24][CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23].C(Cl)(Cl)Cl>O>[CH2:21]([N:24]([CH2:25][CH2:26][CH3:27])[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=1[F:20])[CH2:22][CH3:23]
Reactant: Fc1cc(F)c(-c2c(Cl)nc3nccn3c2Cl)c(F)c1
Reactant: CCCNCCC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCN(CCC)c1c(-c2c(F)cc(F)cc2F)c(Cl)nc2nccn12
Temperature: 80 °C
Yield: 83.1 %

Procedure:
A mixture of 0.095 g of 5,7-dichloro-6-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyrimidine and 0.12 g of di-n-propylamine was heated at 80° C. for one hour. The reaction mixture was allowed to cool, and chloroform and water were added thereto. The separated organic layer was dried over sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 0.095 g of 5-(di-n-propylamino)-6-(2,4,6-trifluorophenyl)-7-chloroimidazo[1,2-a]pyrimidine.
Reaction SMILES: [C:1]12[CH2:8][CH2:7][C:6]=1[CH:5]=[CH:4][C:3]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1([CH2:28][CH2:29][CH2:30][CH2:31][C:32]3[CH:33]=[C:34]4[C:37](=[CH:38][CH:39]=3)[CH2:36][CH2:35]4)[C:25]3[CH:24]=[C:23](Br)[CH:22]=[CH:21][C:20]=3[C:19]3[C:14]1=[CH:15][C:16](Br)=[CH:17][CH:18]=3)=[CH:2]2.[CH3:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([NH:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:42]=1>C1(C)C=CC=CC=1>[C:1]12[CH2:8][CH2:7][C:6]=1[CH:5]=[CH:4][C:3]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1([CH2:28][CH2:29][CH2:30][CH2:31][C:32]3[CH:33]=[C:34]4[C:37](=[CH:38][CH:39]=3)[CH2:36][CH2:35]4)[C:25]3[CH:24]=[C:23]([N:47]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:43]4[CH:42]=[C:41]([CH3:40])[CH:46]=[CH:45][CH:44]=4)[CH:22]=[CH:21][C:20]=3[C:19]3[C:14]1=[CH:15][C:16]([N:47]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:43]1[CH:42]=[C:41]([CH3:40])[CH:46]=[CH:45][CH:44]=1)=[CH:17][CH:18]=3)=[CH:2]2
Reactant: Cc1cccc(Nc2ccccc2)c1
Reactant: Brc1ccc2c(c1)C(CCCCc1ccc3c(c1)CC3)(CCCCc1ccc3c(c1)CC3)c1cc(Br)ccc1-2
Solvent: Cc1ccccc1
Product: Cc1cccc(N(c2ccccc2)c2ccc3c(c2)C(CCCCc2ccc4c(c2)CC4)(CCCCc2ccc4c(c2)CC4)c2cc(N(c4ccccc4)c4cccc(C)c4)ccc2-3)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an oven-dried three-neck round-bottom flask under nitrogen, were added 600 mL anhydrous toluene, 14.3 g 9-(4-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)butyl)-9-(4-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)butyl)-2,7-dibromo-9H-fluorene, and 9.2 mL 3-methyldiphenylamine. After the reaction mixture was degassed with strong nitrogen flow for 30 minutes, 6.44 g sodium tert-butoxide, 0.82 g tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3), and 0.54 g tri-tert-butyl phosphine in 15 mL toluene were added. The reaction mixture was heated to reflux. After three hours, the heating was turn off, and the reaction was allowed to cool down to room temperature. The reaction mixture was filter through a Celite/silica gel plug. The product (13.1 g) was purified by flash chromatography using hexane, 1% then 5% ethyl acetate in hexane solution. The structure was confirmed by NMR.
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)=[C:20]([CH3:32])[CH:19]=1)=[N:10][CH:11]=[N:12]2)[CH2:3][NH:4][CH3:5].[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[CH3:5][N:4]([CH2:3][C@@H:2]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)=[C:20]([CH3:32])[CH:19]=1)=[N:10][CH:11]=[N:12]2)[CH3:1])[C:33](=[O:35])[CH3:34]
Reactant: CNC[C@H](C)Oc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N(C)C[C@H](C)Oc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Yield: 64 %

Procedure:
The procedure described in Example 104 was repeated using 5-[(1S)-1-methyl-2-(methylamino)ethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (obtained as described in Example 109, preparation of starting materials) and acetic anhydride to give the title compound in 64% yield; NMR spectrum (CDCl3) 1.55 (d, 3H), 2.08 (s, 3H), 2.30 (s, 3H), 2.53 (s, 3H), 3.08 (s, 3H), 3.56 (dd, 1H), 3.93 (dd, 1H), 5.09 (m, 1H), 6.92 (d, 1H), 7.12 (m, 3H), 7.50 (m, 2H), 7.65 (m, 1H), 7.70 (s, 1H), 8.27 (s, 1H), 8.62 (s, 1H); Mass spectrum: MH+ 472.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([CH3:14])[CH:3]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([CH3:14])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)c2c(F)ccc(F)c2n1
Product: Cc1cc(Cl)c2c(F)ccc(F)c2n1
Temperature: 25 °C

Procedure:
4-Hydroxy-5,8-difluoro-2-methylquinoline (5.4 g) in phosphoryl chloride (60 ml) was boiled for 4 h. The mixture was cooled to room temperature, excess phosphoryl chloride removed at reduced pressure, the residue dissolved in ethyl acetate, washed with sodium hydrogen carbonate, dried (Na2SO4) and solvent removed at reduced pressure. The title compound (5.35 g) was isolated as a brown powder. (Method B). 1H NMR δ: 2.61 (3H, s), 7.46 (1H, m), 7.66 (1H, m), 7.81 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][CH:14]([C:19]1[CH:20]=[CH:21][C:22]([C:25]([OH:28])([CH3:27])[CH3:26])=[N:23][CH:24]=1)[CH2:15][CH:16]1[CH2:18][CH2:17]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:12][CH2:13][CH:14]([C:19]1[CH:24]=[N:23][C:22]([C:25]([OH:28])([CH3:26])[CH3:27])=[CH:21][CH:20]=1)[CH2:15][CH:16]1[CH2:18][CH2:17]1)=[O:6]
Reactant: CC(C)(O)c1ccc(C(CN)CC2CC2)cn1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: CC(C)(O)c1ccc(C(CNC(=O)c2cccc(Cl)c2Cl)CC2CC2)cn1

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 2-(5-(1-amino-3-cyclopropylpropan-2-yl)pyridin-2-yl)propan-2-ol was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=407.1, tR (minutes, Method F)=1.98. [α]D20=+23.89 (c=3.0 mg/mL,CHCl3)
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=3)=[C:16]([CH3:27])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:35][CH2:36][CH2:37][OH:38].O>CN(C)C=O>[C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=3)=[C:16]([CH3:27])[N:15]([CH2:35][CH2:36][CH2:37][OH:38])[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: OCCCBr
Reactant: CSc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(CCCO)c2C)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-(β-D-glucopyranosyloxy)-5-methyl-4-[(4-methylthiophenyl)methyl]-1H-pyrazole (0.020 g) and cesium carbonate (0.11 g) in N,N-dimethylformamide (0.5 mL) was added 3-bromopropanol (0.022 mL), and the mixture was stirred at 40° C. overnight. To the reaction mixture was added water, and the mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol), and successively by column chromatography on silica gel (eluent: dichloromethane/methanol=5/1) to give 3-(β-D-glucopyranosyloxy)-1-(3-hydroxypropyl)-5-methyl-4-[(4-methylthiophenyl)methyl]-1H-pyrazole (0.011 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[CH:35]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:26]2[CH:27]=[CH:28][C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:25]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: O=Cc1ccc2ccccc2c1
Product: Clc1cccc2c(-c3cccc(NCc4ccc5ccccc5c4)c3)c(-c3ccccc3)nnc12

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and naphthalene-2-carbaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 471.9.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>>[CH2:18]([NH:20][C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22])[CH3:19]
Reactant: CCN=C=O
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 69.9 %

Procedure:
Beginning with 0.15 gm (0.65 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.067 mL (0.85 mMol) ethyl isocyanate, 0.137 gm (70%) of the title compound were recovered essentially by the procedure of Example 122. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13](Br)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[CH3:19][C:20]1([CH3:29])[CH2:25][CH2:24][C:23](B(O)O)=[CH:22][CH2:21]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([C:23]3[CH2:24][CH2:25][C:20]([CH3:29])([CH3:19])[CH2:21][CH:22]=3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]
Reactant: CC1(C)CC=C(B(O)O)CC1
Reactant: COC(=O)C1(c2ccc(N)c(Br)c2)CCOCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1(c2ccc(N)c(C3=CCC(C)(C)CC3)c2)CCOCC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
To a mixture of 4-(4-amino-3-bromo-phenyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (as prepared in the previous step, 1.45 g, 4.61 mmol), 4,4-dimethylcyclohexen-1-ylboronic acid (782 mg, 5.08 mmol) and dichloro(1,1-bisdiphenylphosphino-ferrocene palladium (II) (Pd(dppf)Cl2) dichloromethane adduct (337 mg, 0.461 mmol) in 40 mL of DMF was added K3PO4 (3.91 g, 18.4 mmol). The resulting mixture was stirred at 70° C. for 18 h under Ar. After cooling to RT, the mixture was treated with 150 mL of EtOAc, washed with H2O (3×30 mL) and brine (30 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-2% EtOAc/DCM) to afford 1.14 g (72%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C21H29NO3, 344.2 (M+H). found 344.4.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>O>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCCC
Solvent: O
Product: C=CCCCCCCCC

Procedure:
To a 250 ml high pressure kettle for polymerization, 80 ml of n-hexane, 8 g of catalyst obtained as above, 30 ml of 1-decene and 0.144 ml of water as a co-catalyst are added. 1-decene oligomerization is carried out under a condition of a temperature of 80° C. and a pressure of 1.0 MPa for 5 hours, after which the reaction is stopped and the catalyst is filtered out, the solvent n-hexane is removed by distillation under ambient pressure, and then unreacted monomer 1-decene and part of the dimers are removed by distillation under reduced pressure to produce the final oligomer. The conversion of 1-decene is 58.8 wt %. The oligomer has a kinematic viscosity at 40° C. of 14.82 mm2/s.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:11])[CH2:9][NH2:10])=[CH:4][CH:3]=1.Cl[C:13]1[S:17][N:16]=[C:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[N:14]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH3:11])[CH2:9][NH:10][C:13]2[S:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[N:14]=2)=[CH:6][CH:7]=1
Reactant: COc1cccc(Cc2nsc(Cl)n2)c1
Reactant: C[C@H](CN)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cccc(Cc2nsc(NC[C@@H](C)c3ccc(F)cc3)n2)c1
Temperature: 180 °C
Yield: 83.9 %

Procedure:
To a solution of (S)-2-(4-fluorophenyl)propan-1-amine (96 mg, 0.62 mmol, 1.5 equiv) and 5-chloro-3-(3-methoxybenzyl)-1,2,4-thiadiazole (100 mg, 0.42 mmol, 1.0 equiv) in NMP (0.8 mL) in a microwavable vial was added K2CO3 (230 mg, 1.68 mmol, 4.0 equiv). The mixture was heated by microwave for 15 minutes at 180° C. and then allowed to cool to room temperature. Purification by silica gel across a gradient of 10-30% EtOAc/Hexanes provided the title compound (126 mg, 84%). m/z=358.0 [M+H]+.