Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([N:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].CCO>[Fe].O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([N:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]3)[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CCN(c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)ccc2[N+](=O)[O-])CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC1CCN(c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)ccc2N)CC1
Temperature: 80 °C
Yield: 53.8 %

Procedure:
A flask charged with 4-[3-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.080 g, 0.20 mmol) (as prepared in the previous step), ammonium chloride (0.10 g, 2.0 mmol), iron powder (0.055 g, 10 mmol), EtOH (1 mL) and water (0.5 mL) was heated at 80° C. for 30 min. The reaction was filtered though Celite, concentrated and eluted from a 10-g SPE cartridge (silica) with 20% EtOAc/hexane to give 0.040 g (50%) of the title compound as a yellow oil. 1H-NMR (400 MHz, CDCl3): δ 7.08 (d, 1H), 6.97 (dd, 1H), 6.72 (d, 1H), 5.89 (m, 1H), 4.75 (br s, 2H), 4.08 (m, 2H), 3.63 (m, 2H), 3.12 (m, 2H), 2.62 (m, 2H), 2.50 (m, 2H), 1.78 (m, 2H), 1.52 (s, 9H), 1.38 (m, 3H), 1.00 (d, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][O:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:19][CH2:18]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[N-:32]=[N+]=[N-].[Na+]>CN1C(=O)CCC1.C(Cl)Cl>[C:11]1([C:10]2[C:5]3[C:4]([N:17]4[CH2:22][CH2:21][CH:20]([CH2:23][O:24][CH2:25][CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[CH2:19][CH2:18]4)=[N:3][C:2]([NH2:32])=[N:7][C:6]=3[S:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1nc(N2CCC(COCCN3CCCC3)CC2)c2c(-c3ccccc3)csc2n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Nc1nc(N2CCC(COCCN3CCCC3)CC2)c2c(-c3ccccc3)csc2n1
Temperature: 150 °C
Yield: 20.6 %

Procedure:
2-Chloro-5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidine (0.4 g, 0.9 mmol) was dissolved in NMP (2 mL). Sodium azide (0.3 g, 4 mmol) was added and the reaction heated to 150° C. in the microwave for 30 minutes. The reaction mixture was diluted with DCM, washed with water, dried over Na2SO4 and concentrated at reduced pressure. The resulting residue was purified by basic prep HPLC (method 6) to afford 5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidin-2-amine as a brown gum (81 mg). LCMS RT=2.8 min. M+1=438.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=O.[CH3:11][O:12][C:13](=[O:34])[CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[CH3:11][O:12][C:13](=[O:34])[CH:14]=[CH:7][C:6]1[CH:9]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:10]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(Br)ccc1F
Solvent: CC#N
Product: COC(=O)C=Cc1cc(Br)ccc1F
Temperature: 95 °C
Yield: 100 %

Procedure:
A solution of 5-Bromo-2-fluoro-benzaldehyde (1.0 g, 4.9 mmol) in anhydrous acetonitrile (20.0 mL) was added methyl(triphenylphosphoranylidene)acetate (3.3 g, 9.0 mmol) and heated to 95° C. for 12 h. The mixture was cooled, filtered and concentrated under reduced pressure. Silica gel chromatography (5% Ethyl acetate/petroleum ether) gave the title compound as a white solid (1.27 g, 99%) which was used directly in the next step.
Reaction SMILES: [I:1][C:2]1[C:10]([I:11])=[C:9]([I:12])[CH:8]=[C:7]2[C:3]=1[C:4]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])([CH3:14])[C:5]([CH3:13])=[N:6]2.[CH2:23]1[CH2:29][S:26](=[O:28])(=[O:27])[O:25][CH2:24]1>>[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:4]1([CH3:14])[C:3]2[C:7](=[CH:8][C:9]([I:12])=[C:10]([I:11])[C:2]=2[I:1])[N+:6]([CH2:24][CH2:23][CH2:29][S:26]([O-:28])(=[O:27])=[O:25])=[C:5]1[CH3:13])([OH:22])=[O:21]
Reactant: O=S1(=O)CCCO1
Reactant: CC1=Nc2cc(I)c(I)c(I)c2C1(C)CCCCCC(=O)O
Product: CC1=[N+](CCCS(=O)(=O)[O-])c2cc(I)c(I)c(I)c2C1(C)CCCCCC(=O)O
Yield: 42 %

Procedure:
600 mg (0.94 mmol) of 6-(4,5,6-triiodo-2,3-dimethyl-3H-3-indolyl)hexanoic acid was heated with 600 mg (4.7 mmol) of 1,3-propane sultone at 100° C. for 40 minutes. The raw product was column purified (Silica gel 60, 0-40% methanol-chloroform) to give 300 mg of 3-[3-(5-carboxypentyl)-4,5,6-triiodo-2,3-dimethyl-3H-1-indoliumyl]-1-propane sulfonate: 7.39 (1H, s, arom.), 4.31 (2H, m, NCH2), 3.27 (3H, s, CH3), 2.34-2.02 (2H, m, CH2), 2.19 (2H, t, CH2CO), 1.98-1.65 (4H, m, CH2), 1.31 (3H, s, CH3), 1.43-1.00 (4H, m, (CH2)3), 0.62-0.35 (2H, m, CH2).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH:8]([NH:10][C:11](=O)[CH3:12])[CH3:9])=[N:6][N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:3]1.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:9][C:8]1[N:10]=[C:11]([CH3:12])[N:6]2[C:7]=1[C:2](=[O:1])[NH:3][C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:5]2
Reactant: CC(=O)NC(C)c1nnc(-c2ccccc2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: Cc1nc(C)n2nc(-c3ccccc3)[nH]c(=O)c12

Procedure:
8.34 g (32.3 mmol) of N-[1-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazin-6-yl)ethyl]acetamide] (Example 14A) were dissolved in 330 ml of 1,2-dichloroethane and 4.5 ml (48.5 mmol) of phosphoryl chloride were added. The mixture was stirred under reflux for 24 h. After cooling, the precipitate was filtered off and washed with water and diethyl ether. The product was subsequently dried under high vacuum. This gave 4.6 g (59% of theory) of the product as a solid.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][CH2:10][OH:11])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[CH2:12]([C:14]1[O:18][C:17]([CH2:19][CH2:20][NH:21][C:22]([NH:24][C:25]2[S:26][C:27]([C:31]3[CH:36]=[C:35]([CH3:37])[N:34]=[C:33](S(C)=O)[N:32]=3)=[C:28]([CH3:30])[N:29]=2)=[O:23])=[N:16][CH:15]=1)[CH3:13]>>[CH2:12]([C:14]1[O:18][C:17]([CH2:19][CH2:20][NH:21][C:22]([NH:24][C:25]2[S:26][C:27]([C:31]3[CH:36]=[C:35]([CH3:37])[N:34]=[C:33]([O:11][CH2:10][CH2:9][N:3]4[CH2:8][CH2:7][O:6][CH2:5][CH2:4]4)[N:32]=3)=[C:28]([CH3:30])[N:29]=2)=[O:23])=[N:16][CH:15]=1)[CH3:13]
Reactant: OCCN1CCOCC1
Reactant: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(S(C)=O)n3)s2)o1
Agent: [H-]
Agent: [Na+]
Product: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(OCCN4CCOCC4)n3)s2)o1
Temperature: 70 °C

Procedure:
Sodium hydride (0.020 mg, 0.50 mmol) is added to a stirred solution of 2-morpholin-4-yl-ethanol (0.084 ml, 0.69 mmol) and 1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[5-(2-methanesulfinyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-urea (Example 40) (0.10 g, 0.23 mmol). The reaction is heated at 70° C. for 8 hours then allowed to cool and filtered. The filtrate is evaporated and the residue is dissolved in DCM (50 ml) and washed with water (3×50 ml). The product is extracted into 1M HCl and the aqueous phase is washed with DCM. The aqueous phase is then basified with aq. NaOH and the product is re-extracted into DCM. After drying (MgSO4) the solvent is removed to give the titled compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5]Br.[C:7](#[N:11])[CH2:8][C:9]#[N:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:8]1([C:7]#[N:11])([C:9]#[N:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCCCCBr
Reactant: N#CCC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC1(C#N)CCCC1
Yield: 53.3 %

Procedure:
A mixture of 43.19 g of 1,4-dibromobutane, 13.2 g of malononitrile, 55.3 g of potassium carbonate and 1 liter of acetonitrile was refluxed for 42 hours, filtered while hot and evaporated to dryness giving a dark oil. This oil was vacuum distilled, giving 12.8 g 1,1-cyclopentanedicarbonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1.[Cl:17]N1C(=O)CCC1=O>C(#N)C>[Cl:17][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1ccc(OC)c2c1OCCO2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COC(=O)c1cc(Cl)c(OC)c2c1OCCO2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of intermediate (1) (0.118 mol) and N-chlorosuccinimide (0.125 mol) in ACN (350 ml) was stirred at room temperature for two days. The solvent was evaporated and the residue was partitioned between DCM (500 ml) and water (500 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. A part of the residue was crystallized from a mixture of DIPE and ACN, yielding methyl 7-chloro-2,3-dihydro-8-methoxy-1,4-benzodioxin-5-carboxylate (intermediate 2, mp. 99° C.)
Reaction SMILES: [BH4-].[Li+].[CH3:3][O:4][C:5]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:6]=1[CH2:7][N:8]1[C:12](=[O:13])[CH2:11][C:10]([CH3:18])([C:14](OC)=[O:15])[CH2:9]1>C1COCC1.O>[CH3:3][O:4][C:5]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:6]=1[CH2:7][N:8]1[CH2:9][C:10]([CH2:14][OH:15])([CH3:18])[CH2:11][C:12]1=[O:13]
Reactant: COC(=O)C1(C)CC(=O)N(Cc2ccc(OC)cc2OC)C1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2CC(C)(CO)CC2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Lithium borohydride (28 mg, 1.3 mmol) was added to a solution of methyl 1-(2,4-dimethoxybenzyl)-3-methyl-5-oxopyrrolidine-3-carboxylate (200 mg, 0.65 mmol) in THF (2 mL) at 0° C. The mixture was stirred at room temperature for 16 hours and then diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to give 1-(2,4-dimethoxybenzyl)-4-(hydroxymethyl)-4-methylpyrrolidin-2-one. MS ESI calc'd. for C15H22NO4[M+H]+ 280. found 280. 1H NMR (400 MHz, CD3OD): δ 7.08 (d, J=8.4 Hz, 1H), 6.52 (s, 1H), 6.46 (d, J=8.4 Hz, 1H), 4.40-4.31 (m, 2H), 3.79 (s, 3H), 3.77 (s, 3H), 3.30-3.20 (m, 3H), 2.88-2.86 (m, 1H), 2.43 (d, J=16.8 Hz, 1H), 2.08 (d, J=16.8 Hz, 1H), 1.04 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]1.Cl.N1C=CC=CC=1.Cl>>[CH2:20]([N:17]1[CH2:16][CH2:15][CH:14]([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([O:9][C:10]([F:11])([F:12])[F:13])[C:3]=2[OH:2])[CH2:19][CH2:18]1)[CH2:21][CH3:22]
Reactant: CCCN1CCC(c2cccc(OC(F)(F)F)c2OC)CC1
Agent: Cl
Solvent: c1ccncc1
Product: CCCN1CCC(c2cccc(OC(F)(F)F)c2O)CC1

Procedure:
Preparation according to Example 29: 4-[2-methoxy-3-(trifluoromethoxy)phenyl]-1-propylpiperidine (1.32 g, 4.16 mmol), pyridine hydrochloride (3 g). Yield: 0.7 g (55%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 203-205° C. MS m/z (relative intensity, 70 eV) 303 (M+, 11), 275 (15), 274 (bp), 145 (4), 117 (6).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH:17]2[CH2:18][CH2:19][N:14]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:9][CH:10]=3)[CH2:15][CH2:16]2)[CH2:24][CH2:23]1
Reactant: CN1CCNCC1
Reactant: O=C1CCN(c2ccc(CN3CCOCC3)cc2)CC1
Product: CN1CCN(C2CCN(c3ccc(CN4CCOCC4)cc3)CC2)CC1

Procedure:
Prepared from the product of Example 19 and N-methylpiperazine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[C:27]([CH2:29][C:30](OCC)=O)#[N:28]>>[C:27]([CH2:29][CH:30]1[NH:1][C:2]2[CH:7]=[N:6][C:5]([O:8][C:9]3[CH:10]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][CH:14]=3)=[CH:4][C:3]=2[N:19]1[C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)#[N:28]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)Nc1cccc(Oc2cc(Nc3ccc(O)cc3)c(N)cn2)c1
Product: CC(=O)Nc1cccc(Oc2cc3c(cn2)NC(CC#N)N3c2ccc(O)cc2)c1
Temperature: 195 °C
Yield: 78 %

Procedure:
The product from Step 3 (2.9 g, 8.3 mmol) and ethyl cyanoacetate (6 mL) were combined and heated to 195° C. in a sealed tube. The reaction mixture was cooled and the crude material was purified by chromatography (0-10% methanol in EtOAc) to give the title compound (2.6 g, 78%). MS (ES+) m/e 400 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].[H][H]>CO.C(Cl)Cl.[Pd]>[CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]([C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1)[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8]
Reactant: [H][H]
Reactant: COC(=O)CN(C(=O)C(F)(F)F)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CN(C(=O)C(F)(F)F)c1ccc(N)cc1
Yield: 100 %

Procedure:
The compound from step b above (3.05 g, 10 mmol) was dissolved in a mixture of methanol (100 mL) and methylene chloride (15 mL) and hydrogenated in the presence of 10% palladium on activated carbon (700 mg) using a hydrogen balloon at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated to give the title compound (2.74 g, ˜100%) which was used direct for the next step. 1H NMR (400 MHz, CDCl3) δ: 7.13 (d, 2H), 7.63 (d, 2H), 4.36 (s, 2H), 3.78 (s, 3H), 3.65 (brs, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([C:25](=[O:34])[NH:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:33].[ClH:33].[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:25]([C:18]2[C:19]([C:21]([F:22])([F:23])[F:24])=[N:20][C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:16][CH:17]=2)=[O:34])=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(C(=O)Nc3ccc(Cl)cc3)c(C(F)(F)F)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Cl)cc1)c1cnc(NC2CCNCC2)nc1C(F)(F)F

Procedure:
A solution of 4-[5-(4-chloro-phenylcarbamoyl)-4-trifluoromethyl-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.00 mmol) in 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 400.1 [M+H]+.
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=[O:4])[CH3:3].[I-].[K+].Cl[CH2:30][C:31]1[CH:35]=[CH:34][S:33][CH:32]=1>>[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:30][C:31]3[CH:35]=[CH:34][S:33][CH:32]=3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=[O:4])[CH3:3]
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1O
Reactant: ClCc1ccsc1
Agent: Cl
Agent: [I-]
Agent: [K+]
Product: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1ccsc1
Yield: 46 %

Procedure:
Using an analogous procedure to that described for the starting material in Example 1, 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (400 mg) was reacted in the presence of catalytic potassium iodide with 3-chloromethylthiophene (Journal of the Chemical Society 1958, 4202) (168 mg) to give 4-(3-acetoxy-4-methylanilino)-6-methoxy-7-(3-thienylmethoxy)quinazoline (210 mg, 46%).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14])[CH:2]=[CH2:3].[CH2:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]CC>>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14])/[CH:2]=[CH:3]\[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: C=CCN1C(=O)c2ccccc2C1=O
Reactant: C=CCCCCCCCCCCCCCC
Product: CCCCCCCCCCCCCC/C=C\CN1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 89.7 %

Procedure:
Following the allylic amide cross metathesis general procedure, 2-allylisoindoline-1,3-dione (5.50 mg, 0.0290 mmol) was treated with 1-hexadecene (63.8 mg, 0.290 mmol), 5.0 mol % of in situ-generated complex 2 (75.0 μL, 0.02 M, 1.50 i&mol; final substrate concentration=0.19 M) and allowed to stir for 1 h. The unpurified product is 85% Z (as determined by 400 MHz 1H NMR analysis). The resulting brown oil was purified by silica gel chromatography (96:2:2 hexanes:EtOAc:CH2Cl2) to afford 19g (9.80 mg, 0.0260 mmol, 87.0% yield, 85% Z isomer) as a white, crystalline solid. M.P. 56-60° C.; IR (neat): 2954(w), 2916 (s), 2849 (m), 1771 (w), 1698 (s), 1614 (w), 1464 (m), 1429 (m), 1400 (m), 1356 (w), 1335 (w), 1294 (w), 1189 (w), 1173 (w), 1155 (w), 1089 (w), 1071 (w), 1052 (w), 1024 (w), 962 (m), 930 (m); 1H NMR (400 MHz, CDCl3): 7.84 (2H, dd, J=5.4, 3.0 Hz), 7.70 (2H, dd, J=5.4, 3.0 Hz), 5.78-5.7 1 (1H, m), 5.54-5.44 (1H, m), 4.23 (2H, dd, J=6.2, 0.8 Hz), [diagnostic E isomer signal: 4.22 (1H, d, J=8 Hz)], 1.99 (2H, dd, J=13.6, 6.8 Hz), 1.43-1.19 (24H, m), 0.88 (3H, t, J=6.8 Hz); 13C NMR (100 MHz, CDCl3): 168.2, 135.6, 134.0, 132.4, 123.4, 123.3, 123.1, 77.4, 39.8, 32.3, 32.1, 29.9, 29.8, 29.8, 29.7, 29.7, 29.6, 29.6,−29.5, 29.3, 29.0,22.8, 14.3; HRMS (ESI+) [M+H]+ calcd for C25H38NO2: 384.2903, found: 384.2905.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1>ClC1C=CC=CC=1Cl>[N:5]([C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[C:1]=[O:2]
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reactant: O=C(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: O=C=Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 175 °C
Reaction time: 0.67 h
Yield: 98 %

Procedure:
200 g of phosgene are dissolved in 650 g of o-dichlorobenzene at 5° C. A hot solution of 44.6 g (≈0.2 mol) of 1-amino-anthraquinone in o-dichlorobenzene is added dropwise to the phosgene solution in the course of 90 minutes. During this addition, the temperature in the reaction mixture is allowed to rise slowly up to 25° C. and a stream of phosgene is continuously passed through the reaction mixture. A yellow product precipitates. The mixture is then heated to 175° C. in the course of a further 90 minutes whilst passing a stream of phosgene through, whereupon a clear solution forms. After 40 minutes at 175° C., the stream of phosgene is discontinued and nitrogen is passed through the reaction mixture. After a further 60 minutes, the mixture is cooled and, from 120° C., the solvent is distilled off under reduced pressure. The crystalline residue which remains (53 g, still contains small amounts of o-dichlorobenzene) consists of 1-isocyanato-anthraquinone to the extent of 92.1% (NCO titration according to the method in Houben-Weyl, volume 2 (1953), page 557), which corresponds to a yield of 98%. C15H7NO3 calculated: 72.29% C. 2.83% H 5.62% N; found: 72.2 72.3 2.7 2.8 5.5 5.6.
Reaction SMILES: Cl.[NH:2](C(OC(C)(C)C)=O)[C@H:3]([C:8]([NH:10][C@H:11]([C:16]([NH:18][C@H:19]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].COC(C)(C)C>C(OCC)(=O)C>[NH2:2][C@H:3]([C:8]([NH:10][C@H:11]([C:16]([NH:18][C@H:19]([C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:36])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: -12.5 °C
Reaction time: 1.25 h

Procedure:
A cooled solution (−15° C.) of gaseous HCl (50.0 g, 1.37 mol) in ethyl acetate (250 g) was added to Boc-Leu-Leu-Lys(Z)-OBzl (50.0 g, 71.7 mmol) at −15 to −10° C. over 15 min. The mixture was stirred at −15 to −10° C. for 75 min and t-butyl methyl ether (310 g) was added over 25 min. The temperature was allowed to rise to about −8 to −5° C. and the excess HCl was removed under reduced pressure. Another portion of t-butyl methyl ether (310.0 g) was added over 15 min and the reaction temperature was maintained at −5° C. for approximately 2 h. The resulting solid product, H-Leu-Leu-Lys(Z)-OBzl.HCl was filtered and rinsed with t-butyl methyl ether then dried to give 41.8 g, 92.1%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][C:7](=[O:16])[C:6]=2[CH:17]=1.[BrH:18].C1(S[C:26]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[NH:27])C=CC=CC=1>CO>[BrH:18].[O:16]=[C:7]1[C:6]2[CH:17]=[C:2]([NH:1][C:26]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)=[NH:27])[CH:3]=[CH:4][C:5]=2[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[NH:8]1
Reactant: N=C(Sc1ccccc1)c1cccs1
Reactant: Nc1ccc2c(c1)C(=O)Nc1ccccc1O2
Agent: Br
Solvent: CO
Product: N=C(Nc1ccc2c(c1)C(=O)Nc1ccccc1O2)c1cccs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.3 %

Procedure:
To a solution of 2-amino-10H-dibenzo[b,f][1,4]oxazepin-11-one (Example 4, 100 mg, 0.44 mmol) in methanol was added thiophene-2-carboximidothioic acid phenyl ester hydrobromide (146 mg, 0.48 mmol). The mixture was stirred at room temperature for 24 hr. The solvent was evaporated to give a yellow solid that was recrystalized from a mixture of ethanol and diethyl ether to give a yellow solid (yield 50 mg, 43%). H1 NMR (DMSO d6) δ: 11.38 (bs, 1H), 10.67 (s, 1H), 9.77 (bs, 1H), 8.95 (bs, 1H), 8.19-8.18 (m, 1H), 8.10 (s, 1H), 7.85 (s, 1H), 7.71-7.68 (m, 1H), 7.55-7.53 (m, 1H), 7.40-7.43 (m, 2H), 7.21-7.18 (m, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[CH:19]12[CH2:26][CH2:25][CH:22]([CH:23]=[CH:24]1)[CH:21]1[C:27]([O:29][C:30](=O)[CH:20]21)=[O:28]>O>[C:10]([CH:2]([N:1]1[C:27](=[O:28])[CH:21]2[CH:20]([CH:19]3[CH2:26][CH2:25][CH:22]2[CH:23]=[CH:24]3)[C:30]1=[O:29])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([OH:12])=[O:11]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C1OC(=O)C2C3C=CC(CC3)C12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)C(Cc1ccccc1)N1C(=O)C2C3C=CC(CC3)C2C1=O
Temperature: 25 °C
Yield: 58 %

Procedure:
To a suspension of L-phenylalanine (502 mg, 3.0 mmol) in H2O (15 mL) was added a solution of K2CO3 (252 mg, 1.8 mmol) in H2O (3 mL) and the mixture was stirred until a homogeneous solution was obtained. Bicyclo[2.2.2]oct-5-en-2,3-dicarboxylic anhydride (452 mg, 2.5 mmol) was added and the mixture was heated to reflux temperature and allowed to react for 19 hrs. After cooling to room temperature, the reaction mixture was washed with EtOAc and acidified with conc. HCl until the pH reached 1. The aqueous phase was extracted with EtOAc and the organic phase washed with 5% HCl followed by brine and then dried over Na2SO4. Removal of the solvent gave a colorless solid which was recrystallized from EtOAc/hexane to yield the pure product as colorless crystals: 475 mg (58% yield), mp=161° C.