Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[S:12][C:13]3[CH2:14][N:15]([CH3:20])[CH2:16][CH2:17][C:18]=3[N:19]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:21]([O:24][CH2:25][C:26]1[C:27]([N:35]2[CH2:46][CH2:45][N:44]3[C:37](=[CH:38][C:39]4[CH2:40][C:41]([CH3:48])([CH3:47])[CH2:42][C:43]=43)[C:36]2=[O:49])=[N:28][CH:29]=[CH:30][C:31]=1B(O)O)(=[O:23])[CH3:22].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.O.C(#N)C>[C:21]([O:24][CH2:25][C:26]1[C:27]([N:35]2[CH2:46][CH2:45][N:44]3[C:37](=[CH:38][C:39]4[CH2:40][C:41]([CH3:48])([CH3:47])[CH2:42][C:43]=43)[C:36]2=[O:49])=[N:28][CH:29]=[CH:30][C:31]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[S:12][C:13]3[CH2:14][N:15]([CH3:20])[CH2:16][CH2:17][C:18]=3[N:19]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:23])[CH3:22]
Reactant: CN1CCc2nc(Nc3cc(Br)cn(C)c3=O)sc2C1
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3nc4c(s3)CN(C)CC4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 203b (178 mg, 0.50 mmol), {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (200 mg, 0.50 mmol), K3PO4 (212 mg, 1.0 mmol), sodium acetate (82 mg, 1.0 mmol), 1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium(II) (21 mg, 0.025 mmol), acetonitrile (10 mL), and water (0.5 mL). After bubbling nitrogen through the mixture for 30 minutes, it was heated at 100° C. under N2 protection for 1 h. Analysis of reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was diluted with dichloromethane (20 mL) and water (10 mL). The aqueous layer was separated and extracted with dichloromethane (2×20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80/1 to 30/1) to afford 203c (135 mg, 43%) as yellow solid. MS-ESI: [M+H]+ 584
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=1)[C:8](O)=[O:9])[CH3:3].C1C=CC2N(O)N=[N:29][C:27]=2C=1.C(N(CC)CC)C.CN>C(Cl)Cl>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=1)[C:8]([NH:29][CH3:27])=[O:9])[CH3:3]
Reactant: CSc1ccc(Oc2ccc(C(=O)O)cc2CN(C)C)cc1
Reactant: On1nnc2ccccc21
Agent: CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccc(Oc2ccc(SC)cc2)c(CN(C)C)c1
Reaction time: 0.5 h

Procedure:
The product from example 158 (480 mg, 1.51 mmol) WSCDI (377 mg, 2 mmol), HOBt.H2) (255 mg, 1.66 mmol) and triethylamine (0.53 mL, 3.78 mmol) were dissolved in DCM (0.03 M). After stirring for 30 min, MeNH2 (condensed, 2 mL) was added and the mixture stirred for a further 12 h. The mixture was then evaporated and the residue partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (3 times). The combined organic layers were dried (MgSO4) and evaporated to a yellow oil, which was purified by flash chromatography [SiO2; DCM/ MeOH/ 880 NH3 (93:7:1)]. The desired title amide was isolated as its hydrochloride salt (285 mg, 63%); Free base: δH(CDCI3, 400 MHz) 2.12 (6 H, s), 2.41 (3 H, s), 2.92 (3 H, d), 3.46 (3 H, s), 6.78 (1 H, brd), 6.84 (2 H, d), 7.20 (2 H, d), 7.63 (1 H, dd), 7.82 (1 H, d); MS m/z (ES+) 331 (MH+)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH2:10][CH2:9]1.[CH3:23][NH2:24]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12]([NH:24][CH3:23])[C:11]=2[CH2:10][CH2:9]1
Reactant: CN
Reactant: Cc1ccccc1N1CCc2c(Cl)nc3c(C)cccc3c21
Product: CNc1nc2c(C)cccc2c2c1CCN2c1ccccc1C
Yield: 71 %

Procedure:
1-(2-Methylphenyl)-4-chloro-6-methyl-2,3-dihydropyrrolo[3,2-c]quinoline (1.5 g. 4.9 mmol) and methylamine (33% in ethanol, 250 ml) were heated to 180° C. in a pressure vessel for 24 hours, then evaporated. Crystallisation from aqueous ethanol gave 1-(2-methylphenyl)-4-methylamino-6-methyl-2,3-dihydropyrrolo[3,2-c]quinoline (1.05 g, 71%). m.p. 165°-167°.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[NH2:3].[C:10]1([CH2:16][CH:17]=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N.[OH-].[Na+]>>[C:10]1([CH2:16]/[CH:17]=[N:3]\[NH:2][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NNc1ccncc1
Reactant: O=CCc1ccccc1
Agent: Cl
Agent: N
Agent: [Na+]
Product: C(\Cc1ccccc1)=N\Nc1ccncc1

Procedure:
React 4-hydrazinopyridine HCl with phenylacetaldehyde under literature conditions (J Chem Soc, 1959, pg 3830). Instead of NH3, neutralize with 1N NaOH and extract with CHCl3. Dry organics over MgSO4 and concentrate on rotovap to give N-[2-Phenyl-eth-(Z)-ylidene]-N′-pyridin-4-yl-hydrazine (7.3 g, approx quantitative) as a crude thick oil that can be used without further purification. Mass Spectrum (m/e): 212.02 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=3[CH:17]=2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3ccc(F)c(Cl)c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 3-chloro-4-fluorophenylboronic acid according to the coupling procedure described in example 1. 1H NMR (DMSO-d6): δ 8.22 (s, 1H), 7.26 (t, J=9.1 Hz, 1H), 7.09 (dd, J=8.7, 2.3 Hz, 1H), 7.03 (m, 2H), 6.91 (m, 1H), 6.88 (d, J=2.3 Hz, 1H), 3.26 (s, 3H), 1.97 (m, 4H), 0.82 (t, J=7.2 Hz, 6H); MS (ESI) m/z 363/365 ([M+H]+); MS (ESI) m/z 361/363 ([M−H]−); Anal. calcd for C19H20ClFN2O2: C, 62.90; H, 5.56; N, 7.72. Found: C, 62.65; H, 5.53; N, 7.58.
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:8]=[CH:9][C:10]([C:13](=O)[CH2:14][CH2:15][C:16](=O)[CH:17]([C:25]2[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][N:26]=2)[CH2:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:11][CH:12]=1)[C:3]([OH:6])([CH3:5])[CH3:4].C([O-])(=O)C.[NH4+:39].[OH-].[Na+]>C(O)(=O)C>[CH3:4][C:3]([OH:6])([CH3:5])[CH:2]([C:7]1[CH:12]=[N:11][C:10]([C:13]2[NH:39][C:16]([CH:17]([C:25]3[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][N:26]=3)[CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[OH:1]
Reactant: [NH4+]
Reactant: CSc1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccc(C(O)C(C)(C)O)cn2)nc1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CSc1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(C(O)C(C)(C)O)cn3)[nH]2)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 78.6 %

Procedure:
A mixture of 1-[5-(1,2-dihydroxy-2-methylpropyl)pyridin-2-yl]-5-[5-(methylsulfanyl)pyridin-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (0.49 g), ammonium acetate (0.39 g) and acetic acid (5 mL) was stirred at 80° C. for 3 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (0.37 g, yield 79%) was obtained as a colorless amorphous form from a fraction eluted with ethyl acetate. MS: 468 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[C@H:39]([CH3:40])[CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:41])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:42]2[CH:43]=[N:44][N:45]([CH2:47][CH2:48][O:49]C3CCCCO3)[CH:46]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O.C([O-])(O)=O.[Na+]>CO>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[C@H:35]([CH3:41])[CH2:36][CH2:37][CH2:38][C@@H:39]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:42]2[CH:43]=[N:44][N:45]([CH2:47][CH2:48][OH:49])[CH:46]=2)[N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCOC5CCCCO5)c4)c4ccccc43)cn12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCO)c4)c4ccccc43)cn12
Temperature: 60 °C
Yield: 81.5 %

Procedure:
To a solution of Intermediate 124a (239 mg, 0.32 mmol) in MeOH (3.5 mL) was added pyridinium p-toluenesulfonate (160 mg, 0.64 mmol) and the reaction mixture was heated at 60° C. for 3 h. The resultant mixture was poured into water and a saturated aqueous solution of NaHCO3 was added. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 3-10% MeOH in DCM, to give the title compound (174 mg, 82%). LCMS (Method 4): Rt 3.22 min, m/z 667 [MH+].
Reaction SMILES: C([O:9][CH2:10][CH:11]([CH2:23][O:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[O:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])(=O)C1C=CC=CC=1.[CH3:35][C:36](=[CH2:38])[CH3:37].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:36]([CH:10]([CH:11]([CH2:23][O:24][S:25]([C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)(=[O:26])=[O:27])[O:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=1)(=[O:15])=[O:14])[OH:9])([CH3:37])([CH3:35])[CH3:38]
Reactant: Cc1ccc(S(=O)(=O)OCC(COC(=O)c2ccccc2)OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(OS(=O)(=O)c2ccc(C)cc2)C(O)C(C)(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of 13.8 g (34.5 mmol) of (-)-1,2-di-p-toluene-sulfonyl glycerol (see Formula (I) in Scheme 2) in 100 ml of dry methylenechloride is added to 100 ml of liquid isobutylene taken in a pressure bottle at -78° C. Concentrated sulfuric acid (0.2 ml) is added to the above reaction mixture, the contents are stirred, and the mixture is then allowed to warm to room temperature and stirred for 16 hours. The pressure is gradually released, and the solution is neutralized with aqueous sodium bicarbonate solution. The organic layer is separated, washed with water, and dried over Na2SO4. The solvent is removed on a rotary evaporator and the crude product is dried under reduced pressure. Recrystallization from absolute ethanol affords white crystals of (+)-t-butyl-2,3-di-p-toluenesulfonyl glycerol (see Formula (J) in Scheme 2), m.p. 70°-71° C. [α]D2 +3.44 (c, 5.9, CHCl3). 1H NMR (CDCl3)δ7.8 (m, 4H); 7.3 (m, 4H); 4.5 (m, 1H); 4.15 (d, 2H); 3.35 (d, 2H); 2.45 (s, 6H); 1.1 (s, 9H).
Reaction SMILES: [OH-].[Na+:2].[OH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@@:7]([CH3:19])([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:6](=[O:20])[C:5]=1[C:21]1[NH:26][C:25]2[CH:27]=[CH:28][C:29]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][C:24]=2[S:23](=[O:37])(=[O:36])[N:22]=1>C(O)C>[CH3:19][C@@:7]1([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O-:3])=[C:5]([C:21]2[NH:26][C:25]3[CH:27]=[CH:28][C:29]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][C:24]=3[S:23](=[O:37])(=[O:36])[N:22]=2)[C:6]1=[O:20].[Na+:2]
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Yield: 83 %

Procedure:
A solution of 7.54 M NaOH (20.2 mL, 0.152 mol) was added over 5 minutes to a solution of the product of Example 39-7 (71.72 g, 0.139 mol) in ethanol (1450 mL) at 30-35° C. The product precipitated and the slurry was cooled slowly to RT and the product was isolated by filtration and dried to give the title compound (62.24 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:28]1([CH2:34][S:35][CH:36]([C:40](O)=[O:41])[C:37](O)=[O:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[O:12][C:37](=[O:38])[C:36]([S:35][CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:40]([OH:41])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(C)=O)cc1Cl
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)cc1Cl

Procedure:
The title compound was prepared by Method A using 3'-chloro-4'-methoxy acetophenone (0.979 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 171° C.; 1H NMR (400 MHz, DMSO-d6) δ3.93 (s, 3 H), 3.99 (s, 2 H), 6.68 (s, 1 H), 7.32 (m, 6 H), 7.77 (d, 1 H), 7.83 (d, 1 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]1>C(O)C>[CH3:9][O:8][C:6]1[N:7]=[C:2]([N:13]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]2)[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: OC1CCNC1
Reactant: COc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CCO
Product: COc1nc(N2CCC(O)C2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
2 g (0.0106 mol) of 6-chloro-2-methoxy-3-nitropyridine, 25 ml of ethanol and 1.9 g of 3-pyrrolidinol are charged to a fully equipped round-bottomed flask. The mixture is brought to 50° C. for one hour with stirring and the mixture is poured onto an ice/water mixture with stirring. The precipitate formed is filtered off and dried. 2 g of yellow powder are obtained.
Reaction SMILES: [C:1]([O:20][CH2:21][CH:22]([CH2:25][OH:26])[O:23]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C/C=C\CCCCCCCC.C(OCC(CO)O)C1C=CC=CC=1.[Si:40](Cl)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:20][CH2:21][CH:22]([CH2:25][O:26][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[OH:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(CO)OC
Agent: CN(C)c1ccncc1
Agent: OCC(O)COCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(O)COCc1ccccc1
Reaction time: 3 h
Yield: 100 %

Procedure:
1-O-Oleoyl-2-O-methyl-rac-glycerol (Compound 44) To a mixture of 1-O-benzyl-glycerol (27 mL, 0.16 mol) and t-butyldimethylsilyl chloride (25 g, 0.17 mol) in dry CH2Cl2 (250 mL) under N2 was added DMAP (0.8 g, 6.6 mmol) followed by the addition of TEA (23 ml, 0.17 mol). After 3 hours, the mixture was washed with H2O (2×100 mL), dried (MgSO4) and concentrated to give 1-O-benzyl-3-O-t-butyldimethylsilyl-rac-glycerol (40) (48.8 g, 100%) as a yellow oil. 1H NMR (360 MHz; CDCl3): (0.06 (6H, s, Me2Si), 0.89 (9H, s, ButSi), 3.48-3.56 (2H, m, 1-H2 or 3-H2), 3.64 (1H, dd, J 10 and 5.5 Hz, 1-H or 3-H), 3.68 (1H, dd, J 10 and 5 Hz, 1-H or 3-H), 3.86 (1H, quintet, J 5.5 Hz, 2-H), 4.56 (2H, s, —OCH2Ph) and 7.27-7.35 (5H, m, —Ph).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[C:7](I)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.CS(C)=[O:16].[OH-].[Na+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[Cu]I.O>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[C:7]([OH:16])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2cc(I)cnc2c1F
Reactant: CS(C)=O
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1cnc2c(F)c(F)ccc2c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
In a 3 L eggplant-shaped flask containing a stir bar, 7,8-difluoro-3-iodoquinoline (227.2 g, 0.78 mol), dimethylsulfoxide (600 mL), and water (600 mL) were introduced and sodium hydroxide (131.5 g, 2.34 mol), CuI (14.8 g, 0.078 mol), and 1,10-phenanthroline (28.1 g, 0.156 mol) were added. The mixture was further heated to 100° C. in an oil bath and was stirred for 24 hours. After cooling, the organic layer was removed by adding ethyl acetate and water. The thus obtained aqueous layer was neutralized with concentrated hydrochloric acid, and then the precipitated crystals were filtered and dried. On the other hand, after the filtrate was extracted with ethyl acetate, dried with magnesium sulfate, filtered and concentrated, the crude product obtained was purified by silica gel column chromatography (normal hexane:ethyl acetate) to obtain 133.7 g (95%) of 7,8-difluoro-3-hydroxyquinoline as a hazel solid combined with the previously obtained crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:14]1([C:20]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]3[CH:24]([CH2:25][NH:26][CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][C:10]([N:26]1[CH2:25][CH:24]2[CH:28]([C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:21][CH2:22][C:23]2=[O:29])[CH2:27]1)=[O:12]
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3c(Cl)cccc3Cl)CC12
Reaction time: 0.5 h
Yield: 18.6 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-(2,6-dichlorophenyl)acetic acid (1.43 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 30 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.3 g) and triethylamine (0.98 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred at 20° C. for 20 hours, then washed with distilled water (3×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 1.8 cm, height 23.5 cm), eluting with dichloromethane and collecting 15 cc fractions. Fractions 1 and 2 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of acetonitrile (5 cc) and isopropyl ether (4 cc). The crystals obtained are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-2-[(2,6-dichlorophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (0.62 g) melting at 201° C. is obtained.
Reaction SMILES: Br[C:2]1[N:3]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:4]2[N:5]=[C:6]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:7]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:8](=[O:11])[C:9]=2[N:10]=1.[C-:35]#[N:36].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:7]2[C:8](=[O:11])[C:9]3[N:10]=[C:2]([C:35]#[N:36])[N:3]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:4]=3[N:5]=[C:6]2[C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=2)=[CH:13][CH:14]=1
Reactant: [C-]#N
Reactant: O=c1c2nc(Br)n(-c3ccccc3)c2nc(-c2ccc(C(F)(F)F)cc2)n1-c1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: N#Cc1nc2c(=O)n(-c3ccc(Cl)cc3)c(-c3ccc(C(F)(F)F)cc3)nc2n1-c1ccccc1
Temperature: 200 °C
Yield: 68.9 %

Procedure:
8-Bromo-1-(4-chloro-phenyl)-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one (10.0 mg, 0.0183 mmol), potassium cyanide (110 mg, 1.68 mmol) and 18-crown-6 (12.0 mg, 0.0454 mmol) are added to a microwave tube with 1 mL of dry acetonitrile. The tube is capped and heated to 200° C. for 45 min in microwave reactor. The reaction mixture is then filtered and the filtrate is evaporated to dryness. The crude material is purified by column chromatography, yielding 6.2 mg (69%) of the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.64 (m, 5H), 7.52 (d, 2H), 7.38 (m, 4H), 7.12 (d, 2H). HPLC-MS calculated for C25H13ClF3N5O (M+H+) 492.1. Found: 492.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([N:39]=[C:40]=[O:41])[CH:36]=[CH:37][CH:38]=1>CO.CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH:30][C:40]([NH:39][C:35]2[CH:36]=[CH:37][CH:38]=[C:33]([O:32][CH3:31])[CH:34]=2)=[O:41])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Solvent: CO
Solvent: CC#N
Product: COc1cccc(NC(=O)Nc2nc3nc(NCCCN4CCN(C)CC4)ncc3cc2-c2c(Cl)cccc2Cl)c1
Yield: 69 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2, 3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.334 g of 3-methoxyphenyl isocyanate according to the general procedure of Example 37 to give 0.920 g of 1-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-(3-methoxy-phenyl)-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=595; mp 87.5-92.5 ° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:28])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([C:26]#[N:27])([CH3:25])[CH3:24])[CH:18]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[C:29]([N:34]=[C:35]=[S:36])(=[O:33])[O:30][CH2:31][CH3:32].O>CS(C)=O>[C:26]([C:23]([C:19]1[CH:18]=[C:17]([C:16]([NH:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:35]([NH:34][C:29](=[O:33])[O:30][CH2:31][CH3:32])=[S:36])=[N:7][CH:6]=2)=[O:28])[CH:22]=[CH:21][CH:20]=1)([CH3:24])[CH3:25])#[N:27]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc(N)nc3)c2)c1
Reactant: CCOC(=O)N=C=S
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)c3cccc(C(C)(C)C#N)c3)c2)cn1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (4.32 g, 11.6 mmol) in DMSO (100 mL) was added ethyl isothiocyanatocarbonate (1.64 mL, 13.9 mmol), and the mixture was stirred at room temperature for 21 hr. Water (300 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (250 mL, 50 mL). The combined organic layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give ethyl ({5-[3-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)phenoxy]pyridin-2-yl}carbamothioyl)carbamate as a yellow amorphous solid. The obtained compound was used in the next reaction without further purification.