Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:30]([O:32]C)=[O:31])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:30]([OH:32])=[O:31])[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=2)=[O:19])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])=[CH:34][CH:35]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)O)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
In 150 ml of methanol, was dissolved 30 g of methyl N-(4-methoxybenzoyl)-phenylalanyltyrosinate. After addition of 145 ml of 1 N sodium hydroxide, the mixture was stirred at 50° C. for 2 hours. The reaction mixture was neutralized with hydrochloric acid, concentrated and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was crystallized from ethyl acetate to give 23.9 g of N-(4-methoxybenzoyl)-phenylalanyltyrosine with a mp. 198°-200° C. in a yield of 82%. Analysis, calculated for C26H26O6N2 : C, 67.52; H, 5.67; N, a 6.06; found C, 67.17; H, 5.69; N, 5.95.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]=[CH2:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:17]=[CH2:18].CCN(C(C)C)C(C)C>CCOC(C)=O>[CH2:16]([N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH:14]=[CH2:15])[CH:17]=[CH2:18]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=CCNc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)N(CC=C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 55.1 %

Procedure:
A solution of N-propylphosphonic acid anhydride cyclic trimer (50% reagent in EtOAc solution, 1.26 mL, 2.14 mmol) was added to a degassed solution of (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid (230 mg, 1.07 mmol), N-allylaniline (142 mg, 1.07 mmol), and Hunig's Base (0.560 mL, 3.21 mmol) at 0° C. The reaction mixture was stirred under argon for 2 min at 0° C. and then warmed to rt and stirred for 1 hr. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-30% EtOAc/Hex to give (S)-tert-butyl 1-(allyl(phenyl)amino)-1-oxopent-4-en-2-ylcarbamate (195 mg, 0.590 mmol, 55.2% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.43 (t, J=7.4 Hz, 2H), 7.36 (t, J=7.3 Hz, 1H), 7.24 (d, J=7.5 Hz, 2H), 5.91-5.78 (m, 1H), 5.63-5.49 (m, 1H), 5.23 (d, J=8.4 Hz, 1H), 5.18-5.05 (m, 2H), 5.05-4.94 (m, 2H), 4.43-4.19 (m, 3H), 2.33-2.23 (m, 1H), 2.20-2.08 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.[Cl-].[CH2:9]([O:11][C:12]1([NH3+:15])[CH2:14][CH2:13]1)[CH3:10].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:9]([O:11][C:12]1([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH2:13]1)[CH3:10]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC1([NH3+])CC1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC1(NC(=O)c2ccccc2)CC1

Procedure:
Triethylamine (2.5 g, 25 mmol) is added dropwise at 0° to a solution of 1-ethoxycyclopropylammonium chloride (1.25 g, 9.15 mmol) and benzoyl chloride (1.4 g, 10 mmol) in dry tetrahydrofuran (20 ml). The precipitate is filtered off and the filtrate is evaporated in vacuo yielding a crystalline residue. Sublimation following by recrystallisation from cyclohexane gives N-(1-ethoxycyclopropyl)-benzamide, mp 108°-109° (0.95 g, 51%); NMR (60 MHz): δCDCl 3 = 0.90-1.38 (m, 4H), 1.16 (t, J=7 Hz, 3H), 3.77 (q, J=7 Hz, 2H), 7.0-8.0 (1 m and 1 br. s, total 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].C(O)(=[O:12])C.BrN1C(=O)CCC1=O.[OH-].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[CH2:6][O:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: C=Cc1cccc(Cl)c1
Reactant: CC(=O)O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Clc1cccc(C2CO2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of m-chlorostyrene (5.70 g, 41.0 mmol) and acetic acid (2.33 mL, 40.9 mmol) in dioxane (33 ml) and H2O (78 ml) at 0° C. was added N-bromosuccinimide (8.02 g, 45.0 mmol) in three portions. The reaction was allowed to warm to R.T. After 4 hours, 2N NaOH (60 ml) was added and the reaction was allowed to stir at RT overnight. The reaction mixture was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give 6.20 g of a slightly tinted oil which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Li]CCCC.Br[CH2:14][CH2:15][CH2:16][Cl:17].O>C1COCC1>[Cl:17][CH2:16][CH2:15][CH2:14][CH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: Cc1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: ClCCCCc1ccncc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
4-Methylpyridine (8.4 g, 90 mmol) and THF (40 mL) were mixed in dry glassware, flushed with nitrogen and cooled to −60° C. n-BuLi (1.6 M solution, 61.9 mL, 99 mmol) was added dropwise over 1.5 h. The temperature was not allowed to exceed −50° C. The mixture was then allowed to reach rt, THF (20 mL) was added and the mixture was then stirred at 45° C. for 2 h. Additional THF (20 mL) was added. This mixture was cooled to 0° C. and added dropwise through a cooled dropping funnel to a 65° C. solution of 3-bromo-1-chloropropane (14.9 g, 94.5 mmol) in THF (15 mL). The reaction mixture was slowly allowed to reach 0° C. overnight. Water (90 mL) was added, and the mixture was stirred for 10 min. The organic layer was separated and dried (Na2SO4) to give the sub-title compound in 97.6% yield.
Reaction SMILES: CS([Cl:5])(=O)=O.[N+:6]1([O-])[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+]>>[Cl:5][CH:14]1[C:15]2[N:6]=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:11][CH2:12][CH2:13]1
Reactant: [O-][n+]1cccc2c1CCCC2
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: ClC1CCCc2cccnc21
Temperature: 20 °C

Procedure:
At ambient temperature, 3 ml of methane sulfonyl chloride were added slowly to 1.49 g of 5,6,7,8-tetrahydroquinoline-N-oxide with stirring under an insert atmosphere. The mixture was heated for 4 hours at 80° to 82° C., then cooled to 20° C. and poured into 20 ml of a saturated solution of sodium bicarbonate. Then, sodium bicarbonate was added until an alkaline pH was obtained and after extracting with methylene chloride, washing with water, drying the re-united organic solutions and distillation to dryness under reduced pressure, 1.53 g of 8-chloro-5,6,7,8-tetrahydroquinoline were obtained in the form of an oil.
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:24])([CH3:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:13]=[CH:12][C:11]=1Br)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:26]([O:28][C:29]([N:31]1[CH:36]=[CH:35][C:34](=[O:37])[CH2:33][CH2:32]1)=[O:30])[CH3:27].[Cl-].[NH4+]>O1CCCC1.CCOCC>[CH2:26]([O:28][C:29]([N:31]1[CH2:32][CH2:33][C:34](=[O:37])[CH2:35][CH:36]1[C:11]1[CH:12]=[CH:13][C:14]([C:16]([CH3:24])([CH3:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:15][C:10]=1[O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:30])[CH3:27]
Reactant: CCOC(=O)N1C=CC(=O)CC1
Reactant: CCCCCCC(C)(C)c1ccc(Br)c(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCC(C)(C)c1ccc(C2CC(=O)CCN2C(=O)OCC)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
To 3.45 (0.142 mole) of magnesium is added a solution of 27.6 g (0.071 mole) of 2-benzyloxy-1-bromo-4-(1,1-dimethylheptyl)benzene in 71 ml of tetrahydrofuran, at such a rate that gentle reflux occurs. The Grignard solution is allowed to cool to 25° C. over 30 minutes, diluted with 71 ml of ether, the mixture cooled to -12° C. and 2.13 g (0.0112 mole) cuprous iodide is added followed by addition of 8.00 g (0.0473 mole) of N-ethoxycarbonyl-2,3-dihydro-4(1H)-pyridinone in 47 ml of ether over 20 minutes. The reaction is stirred 30 minutes longer at -12° C. and then added to 2 liters ether and 600 ml saturated ammonium chloride. The organic extract is washed with three 600 ml portions of saturated ammonium chloride, dried over magnesium sulfate and evaporated to an oil. This crude product is purified via column chromatography on 2 kg of silica gel eluting in 500 ml fractions with 50% ether-hexane to yield (fractions 17-24) 16.0 g (71%) of the title compound as an oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[N:13]=[C:12]([CH:14]=O)[CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C1(P(=[CH:37][C:38](=[O:40])[CH3:39])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[N:13]=[C:12]([CH:14]=[CH:37][C:38](=[O:40])[CH3:39])[CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CSc1ccc(Oc2cccc(C=O)n2)cc1
Solvent: c1ccccc1
Product: CSc1ccc(Oc2cccc(C=CC(C)=O)n2)cc1
Yield: 221.2 %

Procedure:
A mixture of 29.9 g (0.122 mol) of 6-(4-(methylthio)phenoxy)picolinaldehyde and 42.7 g (0.134 mol) of triphenylphosphoranylidene-2-propanone in 750 mL of benzene was heated at reflux for 2.75 hours and cooled. The solvent was removed in vacuo leaving 77 g of an oily solid which was dissolved in methylene chloride and placed on a column of dry silica gel. The column was eluted with methylene chloride and the fractions containing the desired product were combined. The solvent was removed in vacuo leaving 32.5 g (93.7 percent of theoretical) of an oily product which slowly crystallized upon standing. The above named product melted at 71°-72.5° C.; Rf -0.53, (silica gel, 50:50 ethyl acetate-hexane), 1H NMR (CDCl3) 82.25 (s, 3H, CH3C(O)--), 2.4 (s, 3H, CH3S--) 6.7-7.75 (m, 9H, ArH and --CH=CH--).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][N:3]=1.P(Br)(Br)[Br:11]>ClCCl>[Br:11][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1cccnc1Cl
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Clc1ncccc1CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
To a solution of (2-chloropyridin-3-yl)methanol (800 mg, 5.6 mmol) in anhydrous dichloromethane (50 mL) was added dropwise phosphorus tribromide (1.0 mL, 11.2 mmol). The mixture was stirred at room temperature overnight. Dichloromethane was evaporated. Water (20 mL) was added. The mixture was treated slowly with a saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (3×20 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording 3-(bromomethyl)-2-chloropyridine (1.0 g, 80% yield). The product was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[C:16]([Br:18])[S:17][C:11]=2[N:10]=[C:9]1[CH:19](Br)[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>C(O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[C:16]([Br:18])[S:17][C:11]=2[N:10]=[C:9]1[CH:19]([NH:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: CCC(Br)c1nc2sc(Br)nc2c(=O)n1Cc1ccccc1
Solvent: CCO
Product: CCC(NCCN(C)C)c1nc2sc(Br)nc2c(=O)n1Cc1ccccc1

Procedure:
A solution of 6-benzyl-2-bromo-5-(1-bromopropyl)[1,3]thiazolo[5,4-d]pyrimidin-7(6H)-one (1-2, 1 equiv) and N,N-dimethylethylenediamine (3 equiv) in ethanol is heated at reflux for 18 h. The reaction mixture is concentrated, and the residue is partitioned between EtOAc and brine. The organic layer is dried (MgSO4) and concentrated to provide 6-benzyl-2-bromo-5-(1-{[2-(dimethylamino)ethyl]-amino}propyl)[1,3]thiazolo[5,4-d]pyrimidin-7(6H)-one (1-3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([OH:16])=O)=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:21]=2[C:22]([F:25])([F:24])[F:23])[O:11][N:10]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C.CN1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:16])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:21]=2[C:22]([F:24])([F:23])[F:25])[O:11][N:10]=1
Reactant: O=C(O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46820.8 %

Procedure:
3-(2-chloro-6-fluorophenyl)-5-(1-(3-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylic acid (50 mg, 0.0001 mmol), Morpholine (9 mg, 0.0001 mmol), HOBt (14 mg, 0.0001 mmol) and EDCI (19 mg 0.00012 mmol) were dissolved in 1 mL dry DMF. N-Methylmorpholine (100 NL, 0.001 mmol) was added and the reaction mixture was stirred at room temperature overnight. Morpholine, HOBt, EDCI and N-Methylmorpholine were added again in the aforementioned ratios. The mixture was stirred at room temperature for 24 h. DMF was removed by evaporation. An aqueous solution of 5% citric acid was added. The precipitate was filtered and dried. The product (example B-35) was purified by pTLC (PE/EE 5/5) to give 26 mg of a yellow oil (yield 45%). Result of LC/MS MH+: 554.7; 1H NMR (CDCl3): 8.15 (1H, s, CH-pyraz.), 7.35-7.6 (6H, m, CH-arom), 7.15 (1H, t, CH-arom), 3.6 (4H, m, CH2-morpholine), 3.18 (4H, m, CH2-morpholine).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Br:10])=[CH:4][N:3]=1.N1C=CC=CC=1.[Cl:17][CH2:18][C:19](Cl)=[O:20]>CCOCC>[CH3:9][O:8][C:7]1[C:2]([NH:1][C:19](=[O:20])[CH2:18][Cl:17])=[N:3][CH:4]=[C:5]([Br:10])[CH:6]=1
Reactant: COc1cc(Br)cnc1N
Reactant: O=C(Cl)CCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: COc1cc(Br)cnc1NC(=O)CCl
Reaction time: 0.5 h

Procedure:
A solution of 2-amino-3-methoxy-5-bromopyridine (20.3 grams) in absolute ether (200 ml) is charged into a glass reaction vessel equipped with mechanical stirrer and addition funnel. The solution is cooled to a temperature of about 5° C and pyridine (20 ml) is added thereto. A solution of chloroacetyl chloride (11.3 grams) in ether (50 ml) is then slowly added, with stirring, to the flask over a period of about 30 minutes resulting in the formation of a precipitate. The temperature of the reaction mixture is kept below about 10° C during the addition of the chloroacetyl chloride and stirring is continued thereafter for a period of about 1 hour to ensure the completion of the reaction. The precipitate which has formed is then recovered by filtration and is washed first with aqueous potassium carbonate and then with water. The washed product is then dried in a vacuum desiccator to yield the desired product N-(3-methoxy-5-bromo-2-pyridyl)-α-chloroacetamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[N:11]([CH2:20][C:21]([OH:23])=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[NH:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[NH:41][CH2:42][CH2:43][CH2:44][CH2:45][NH2:46]>>[NH:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[NH:41][CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:21](=[O:23])[CH2:20][N:11]1[CH2:10][CH2:9][CH:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]1=[O:19]
Reactant: CC(C)(C)OC(=O)CC1CCN(CC(=O)O)C(=O)c2ccccc21
Reactant: NCCCCNc1nc2ccccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)CC1CCN(CC(=O)NCCCCNc2nc3ccccc3[nH]2)C(=O)c2ccccc21

Procedure:
Analogously to Example IX, compound 3 was reacted with 1.0 g (3.1 mmol) of compound 9 and the reaction product was purified by column chromatography (eluent: diethyl ether/MeOH/ammonia, 40/10/2.5), 0.78 g of white amorphous powder; ESI-MS [M+H+]: 520.
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:11][CH3:12])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[C:36]([NH:35][C:31]1[CH:30]=[C:29]([CH:26]2[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][CH2:20][NH:19][C:8](=[O:9])[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH3:12])[CH2:24][CH2:25]2)[CH:34]=[CH:33][CH:32]=1)(=[O:40])[CH:37]([CH3:38])[CH3:39]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CCC(C(=O)O)(c1ccccc1)c1ccccc1
Product: CCC(C(=O)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)(c1ccccc1)c1ccccc1

Procedure:
Example 12 was prepared from 2,2-diphenylbutanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.44–7.39 (m, 2H), 7.37–7.28 (m, 8H), 7.27–7.20 (m, 3H), 6.89 (d, 1H, J=7.4 Hz), 6.43 (t, 1H, J=4.5 Hz), 3.35–3.27 (m, 2H), 2.90–2.82 (m, 2H), 2.51 (septet, 1H, J=6.8 Hz), 2.49–2.35 (m, 4H), 2.24 (t, 2H, J=6.3 Hz), 1.89 (t, 2H, J=10.2 Hz), 1.75–1.68 (m, 2H), 1.66–1.58 (m, 2H), 1.57–1.45 (m, 2H), 1.24 (d, 6H, J=6.7 Hz), 1.27–1.23 (m, 2H); ESMS m/e: 526.3 (M+H)+.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])=[N:25][CH:26]=[N:27]2)=[CH:22][C:21]=1[O:39][CH3:40])(O)=[O:14].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>CN(C)C1C=CN=CC=1.CN(C=O)C>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:24]2[C:23]3[C:28](=[CH:29][C:20]([O:19][CH2:18][CH2:17][CH2:16][C:13]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[O:14])=[C:21]([O:39][CH3:40])[CH:22]=3)[N:27]=[CH:26][N:25]=2)=[C:32]([F:38])[CH:33]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCC(=O)O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.3 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (94 mg, 4.9 mmol) was added to a mixture of 7-(3carboxypropoxy)4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (164 mg, 0.4 mmol), morpholine (0.11 g; 1.26 mmol) and 4-dimethylaminopyridine (200 mg, 1.64 mmol) in DMF (5 ml). The reaction mixture was stirred at ambient temperature for 24 hours and the volatiles were removed by evaporation. Water was added to the residue and the aqueous mixture was extracted with methylene chloride (3×30 ml). The extracts were combined and the solvent removed by evaporation. The residue was triturated with ether and the precipitate was collected by filtration. The solid was purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (100/8/1). The purified product was triturated with acetone, collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-morpholinocarbonylpropoxy)quinazoline (88 mg, 46%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[NH:8][CH:9]([CH3:11])[CH3:10].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>O1CCCC1>[Cl:18][C:17]1[C:12]([C:4]2[CH:5]=[CH:6][C:7]3[N:8]([CH:9]([CH3:11])[CH3:10])[C:23](=[O:24])[NH:1][C:2]=3[CH:3]=2)=[N:13][CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)Nc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1N
Solvent: C1CCOC1
Product: CC(C)n1c(=O)[nH]c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21

Procedure:
37.4 g of 2-[3-amino-4-(1-methylethylamino)-phenyl]-3-chloro-5-trifluoromethylpyridine and 27.6 g of carbonyldiimidazole were heated at reflux temperature for four hours in 200 ml of anhydrous tetrahydrofuran, after which the reaction mixture was concentrated. The residue was treated with 100 ml of 10% strength hydrochloric acid and the mixture was extracted three times with 100 ml of methylene chloride each time. The combined organic phases were washed twice with 50 ml of water each time, dried over sodium sulfate and concentrated. The crude product was stirred with ether, then separated off and dried. Yield: 29.8 g (74%) of colorless crystals; m.p.: 192-193° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:4]([CH2:9][OH:10])[O:3]1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:11])[O:3][C@H:4]([CH2:9][O:10][S:13]([CH3:12])(=[O:15])=[O:14])[C@@H:5]([CH2:7][O:8][S:13]([CH3:12])(=[O:15])=[O:14])[O:6]1
Reactant: CC1(C)O[C@H](CO)[C@@H](CO)O1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC1(C)O[C@H](COS(C)(=O)=O)[C@@H](COS(C)(=O)=O)O1
Reaction time: 3 h
Yield: 66 %

Procedure:
The starting material (1) (3,4-O-isopropylidene-D-mannitol) was reacted with sodium periodate and potassium borohydride as described in J. Chem. Soc., Perkin Trans. I., 1972, 275 (the contents of which are herein incorporated by reference) to yield compound (2) in 92% yield. Compound (2) (5.1 g) was dissolved in pyridine (40 ml) and cooled in ice. To this solution was added methanesulphonyl chloride (18 ml), dropwise with stirring. The mixture was allowed to stand at room temperature for 3 hours, after which time it was added to a solution of sodium bicarbonate. This solution was then extracted with dichloromethane (5×50 ml) and the combined extracts were dried (MgSO4) and concentrated in vacuo. The residue obtained was recrystallised from ethanol to give 2,3-O-isopropylidene-1,4-di-O-methanesulphonyl-D-threitol (3), (6.6 g, 66%), m.p. 83°-85° C.