Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:19]3[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]3)[S:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: OC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: OC1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.7 %

Procedure:
To a solution of 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde (1.1 g, 3.9 mmol) in 1,2-dichloroethane (20 mL) was added piperidin-4-ol (5.4 mmol), and AcOH (3.9 mmol). After the reaction mixture stirred 10 min at room temperature, Na(OAc)3BH (4.6 mmol) was added and the mixture stirred 72 h at room temperature. The reaction was quenched by the addition of saturated aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude reaction was purified by silica gel chromatography (0-20% MeOH in CH2Cl2) to afford 1-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperidin-4-ol (0.6 g). MS (Q1) 369 (M)+
Reaction SMILES: [H-].[Na+].[CH3:3]I.[Br:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[NH:10][CH:9]=1>C1COCC1>[Br:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[N:10]([CH3:3])[CH:9]=1
Reactant: COc1ccc2c(CCBr)c[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(CCBr)cn(C)c2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A flask was charged with NaH (110 mg, 4.60 mmol), MeI (0.39 mL, 6.13 mmol) and THF (1.5 mL). The resulting grey suspension was stirred at rt for 5 min, then a solution of 3-(2-Bromo-ethyl)-6-methoxy-1H-indole (156 mg, 0.61 mmol) in THF (2.5 mL) was added dropwise. After stirring for 18 h at rt, the reaction mixture was concentrated, redissolved in DCM and washed with H2O (3×). The org. layer was dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield the title compound as an yellow oil which was used as such in the next step. LC-MS conditions B: tR=0.94 min, [M+H]+=no ionization.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].CS(O[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Br:20])(=O)=O.N1CCCN2CCCCCC=12>C1COCC1>[CH3:6][O:5][C:3](=[O:4])[CH2:2][S:1][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Br:20]
Reactant: CS(=O)(=O)OCCc1ccccc1Br
Reactant: COC(=O)CS
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CSCCc1ccccc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.5 %

Procedure:
A mixture of methyl 2-mercaptoacetate (2.2 g), 2-bromophenethyl methanesulfonate (5.7 g), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (3.7 g) and THF (30 ml) was stirred at ambient temperature for 1.5 hrs and separation method A and E yielded the title compound (4.4 g).
Reaction SMILES: [CH:1]([N:4]([CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[NH2:22][NH:23][C:24]([NH2:26])=[O:25].C(O)C.[OH-].[Na+]>O>[CH:1]([N:4]([CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)/[C:10](=[N:22]\[NH:23][C:24]([NH2:26])=[O:25])/[C:8]1=[O:9])([CH3:3])[CH3:2]
Reactant: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)C(C)C
Reactant: NNC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)N(CCN1C(=O)/C(=N/NC(N)=O)c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
A suspension of 10.00 g of 1-(2-diisopropylaminoethyl)isatin and 4.88 g of semicarbazide hydrochloride in 350 ml of a mixture of ethanol and water (2.5:1) was stirred for 2 hours at room temperature. The suspension was warmed to make a solution, and then 44.0 ml of a 1N-aqueous sodium hydroxide solution was added dropwise to the solution. The precipitates were collected by filtration and washed with water to obtain 10.56 g of (E)-1-(2-diisopropylaminoethyl)isatin 3-semicarbazone. The chemical properties of this product were identical with those of the product obtained by Examle 1.
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:15][C:14]=3[CH:29]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C(O)C.ClCCl.C(O)C>[C:1]1([N:7]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=4)=[N:15][C:14]=3[CH:29]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2sc(CNc3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: N=C(N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)O)c4ccccc4)ccc3s2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.45 g (0.84 mmol) of 2-[N-(4-amidinophenyl)aminomethyl]benzothiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide were dissolved in 15 mL of ethanol, mixed with 2 mL of 2N sodium hydroxide solution, and stirred for 4 hours at room temperature. Then the mixture was acidified with 3 mL of 2N hydrochloric acid and the solvent was distilled off. The crude product obtained was taken up in 5 mL dichloromethane/ethanol (2:1) and filtered to remove the insoluble sodium chloride. After the distillation of the solvent, the desired compound was obtained as a yellow foam. Yield: 0.26 g (67% of theory), C25H23N5O3S (473.55); Rf value: 0.47 (silica gel; methanol/5% aqueous sodium chloride=6:4); mass spectrum: (M+H)+=474.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(OC(=O)C)(C)C.[ClH:28]>O>[ClH:28].[ClH:28].[C:2]1([CH2:1][N:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCN1Cc1ccccc1
Reactant: C1COCCN1
Agent: Cl
Solvent: O
Solvent: CC(=O)OC(C)C
Product: c1ccc(CN2CCC(N3CCOCC3)CC2)cc1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
10.00 kg (52.84 mol) 1-benzylpiperidone (K) were taken and 9.21 kg (105.68 mol) morpholine (L) and 30.0 L isopropylacetate were added. Then the reaction mixture obtained was heated to reflux temperature (95° C.) using the water separator and stirred until no more water separated off. Then the mixture was hydrogenated at 4 bar and at an internal temperature of 60° C. in the presence of 0.50 kg Raney nickel catalyst. Then the solvent was completely distilled off in vacuo. Then 45.0 L ethanol were added and 10.87 kg (116.25 mol) ethanolic 10-mol hydrochloric acid were metered in. The resulting suspension was cooled to 20° C. and stirred for 30 minutes at 20° C. The product was centrifuged off and dried.
Reaction SMILES: [NH:1]1[C:5]([NH2:6])=[CH:4][CH:3]=[N:2]1.O.[N+:8]([CH:11]([CH:14]=O)[CH:12]=O)([O-:10])=[O:9].[Na].O>C(O)(=O)C>[N+:8]([C:11]1[CH:12]=[C:4]2[CH:3]=[N:2][NH:1][C:5]2=[N:6][CH:14]=1)([O-:10])=[O:9]
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: Nc1ccn[nH]1
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cnc2[nH]ncc2c1
Temperature: 90 °C
Yield: 90 %

Procedure:
A suspension of 1H-pyrazol-5-amine (0.804 g, 9.48 mmol) and sodium nitromalonaldehyde monohydrate (1.56 g, 9.96 mmol) in acetic acid (12 mL) was heated to 90° C. overnight. The reaction mixture was cooled to room temperature and poured into water (50 mL). The resulting solids were collected by filtration. The solids were washed with water (3×20 mL) and dried in vacuo to give 5-nitro-1H-pyrazolo[3,4-b]pyridine (1.40 g, 84%) as a solid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[C:8]([OH:15])[CH:7]=1)[CH3:2].C(OC(=O)C)(=O)C.Cl.C(Cl)Cl.[N:31]1C=CC=[CH:33][CH:32]=1>>[CH2:32]([NH:31][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][C:8]=1[OH:15])[CH3:33]
Reactant: c1ccncc1
Reactant: CCCCC(CC)COc1ccc(C(=O)O)c(O)c1
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CCCCC(CC)COc1ccc(C(=O)NCC)c(O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62 %

Procedure:
In 30 ml of pyridine was dissolved 3.00 g (11.3 mmol) of 4-(2-ethylhexyloxy)-2-hydroxybenzoic acid (compound 14), and 2.89 g (28.4 mmol) of acetic anhydride was added to the solution dropwise on an ice-water bath. After the dropwise addition, the mixture was stirred for 20 minutes, poured into 120 ml of a 12% aqueous solution of hydrochloric acid, and extracted with 150 ml of ethyl acetate. The organic layer was washed successively with three 150 ml portions of dilute hydrochloric acid, three 150 ml portions of water, and three 100 ml portions of a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, followed by concentration. The resulting crude product was dissolved in 10 ml of methylene chloride, and a few drops of DMF were added thereto. To the mixture was further added dropwise 1.57 g (13.2 mmol) of methylene chloride at room temperature, followed by stirring for 15 minutes. The solvent was removed by distillation under reduced pressure, and the oily residue was dissolved in methylene chloride. The solution was added to 10 ml of a 70% aqueous solution of ethylamine on an ice bath. After the inner temperature was raised to room temperature, 300 ml of dilute hydrochloric acid was added thereto, and the mixture was extracted with 300 ml of ethyl acetate. The organic layer was washed successively with three 300 ml portions of water and two 300 ml portions of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was recrystallized from hexane to obtain 2.06 g (62%) of N-ethyl-4-(2-ethylhexyloxy)-2-hydroxybenzamide represented by the following chemical formula (hereinafter referred to as compound 28) as white crystals. The analytical results are shown below. ##STR49##
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:20](=[O:21])[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[C:12]2=[O:13])=[C:4]([F:22])[CH:3]=1.C(OCC)(=O)C>C(O)(=O)C.[Fe]>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:22])=[C:5]([N:11]2[C:20](=[O:21])[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[C:12]2=[O:13])[CH:6]=1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc([N+](=O)[O-])c(Cl)cc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Reaction time: 0.17 h

Procedure:
Iron powder (7.30 g, 130.7 mmol) is added portionwise to a mixture. of N-(4-chloro-2-fluoro-5-nitrophenyl)-1-cyclohexene-1,2-dicarboximide (10.6 g, 32.7 mmol) in acetic acid (100 mL) at 65° C. After the addition is complete, the reaction mixture is stirred for 10 minutes, and filtered through diatomaceous earth. The filtrate is concentrated in vacuo to obtain a dark solid. A mixture of the solid in an ethyl acetate/saturated sodium hydrogen carbonate solution is filtered through diatomaceous earth, and the phases are separated. The organic phase is washed sequentially with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as a yellow solid.
Reaction SMILES: N12CCC(CC1)CC2[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][CH:20]=[CH:19]3)=[CH:12][CH:11]=1.[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>CCOC(C)=O.CCO>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[N:21]12[CH2:22][CH2:28][CH:27]([CH2:19][CH2:20]1)[CH:26]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][CH:20]=[CH:19]4)=[CH:14][CH:15]=1)[CH2:25]2
Reactant: c1cc2cc(-c3ccc(OC4CC5CCN4CC5)cc3)ccc2[nH]1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: c1cc2cc(-c3ccc(OC4CN5CCC4CC5)cc3)ccc2[nH]1

Procedure:
The product of Example 3A (80 mg, 0.25 mmol) was treated with fumaric acid (29 mg, 0.25 mmol) in EtOAc/EtOH (v. 1:1, 4 mL) at ambient temperature for 10 h. The title compound was obtained as solid (57 mg, yield, 52%). 1H NMR (300 MHz, CD3OD) δ 1.78-2.16 (m, 3H), 2.25-2.39 (m, 1H), 2.46-2.54 (m, 1H), 3.14-3.45 (m, 5H), 3.69-3.81 (m, 1H), 4.80-4.89 (m, 1H), 6.46 (dd, J=3.0, 1.0, 1H), 6.68 (s, 2H), 7.02 (dt, J=8.8, 2.5 Hz, 2H), 7.23 (d, J=3.1 Hz, 1H), 7.31 (dd, J=8.5, 2.0 Hz, 1H), 7.43 (dt, J=8.4, 0.8 Hz, 1H), 7.58 (dt, J=9.2, 2.6 Hz, 2H), 7.71 (dd, J=1.7, 1.0 Hz, 1H) ppm. MS (DCI/NH3): m/z 319 (M+H)+. Anal. Calculated for C21H22N2O.C4H4O4: C, 69.11; H, 6.03; N, 6.45. Found: C, 69.23; H, 5.81; N, 6.59.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11]
Reactant: O=C1CCc2ccccc2N1
Reactant: BrCCCCCBr
Product: O=C1CCc2ccccc2N1CCCCCBr

Procedure:
from 3,4-dihydroquinolin-2(1H)-one and 1,5-dibromopentane
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)([CH3:6])[C:4]#[N:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[F:1][C:2]([F:17])([F:18])[C:3]([CH3:6])([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH2:4][NH2:5]
Reactant: COc1ccc(CNC(C)(C#N)C(F)(F)F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNC(C)(CN)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) solution of 3,3,3-trifluoro-2-(4-methoxybenzylamino)-2-methyl propanenitrile (1.5 g, 5.81 mmol) in dry diether ether (50 ml) was added LiAlH4 (11.62 ml of a 2M solution in THF) and the resulting mixture was stirred at RT overnight. The reaction mixture was hydrolyzed by successive addition of water 15% KOH, and water. The resulting precipitate was filtered on Celite® (filter material) and the organic portion was washed with water, dried over MgSO4 and concentrated under reduced pressure to afford the title product; 1H NMR (400 MHz, Methanol-d4) δ 7.97 (1H, s), 7.85 (1H, s), 7.60 (1H, s), 3.97 (3H, s), 3.77 (1H, m), 3.56 (1H, m), 1.37 (3H, s)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:28](Cl)(=[O:37])[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28](=[O:37])[CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: O=C(Cl)CCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)CCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and hydrocinnamoyl chloride.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:15][CH:16](O)[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(S(F)(F)[F:33])CC>>[CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:15][CH:16]([F:33])[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)NCC(O)Cc1cccc(OCC2CCCCC2)c1
Product: CC(C)(C)OC(=O)NCC(F)Cc1cccc(OCC2CCCCC2)c1

Procedure:
tert-Butyl 3-(3-(cyclohexylmethoxy)phenyl)-2-hydroxypropylcarbamate and DAST are reacted together to give tert-butyl 3-(3-(cyclohexylmethoxy)phenyl)-2-fluoropropylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][NH:30][CH:31]([CH3:33])[CH3:32])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:34](Cl)(=[O:36])[CH3:35]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH:31]([CH3:33])[CH3:32])[C:34](=[O:36])[CH3:35])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(=O)Cl
Reactant: CC(C)NCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CC(=O)N(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(C)C
Yield: 49 %

Procedure:
The procedure described in Example 5 was repeated using N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(isopropylamino)ethoxy]quinazolin-4-amine and acetyl chloride to give the title compound in 49% yield; NMR spectrum (DMSO-d6) 1.19 (d, 6H), 2.07 (s, 3H), 3.77 (t, 2H), 4.06-4.14 (m, 1H), 4.34 (t, 2H), 5.31 (s, 2H), 7.21 (d, 1H), 7.27 (d, 1H), 7.32-7.39 (m, 2H), 7.57-7.63 (m, 2H), 7.69-7.75 (m, 1H), 7.86-7.91 (m, 1H), 8.01 (d, 1H), 8.46 (s, 1H), 8.60 (d, 1H), 10.00 (s, 1H); Mass spectrum MH+ 506.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:29]([OH:33])(=[O:32])[CH:30]=O>>[N:23]1([CH2:22][CH2:21][O:20][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:14]=2[CH2:13][CH2:12][N:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[CH:30]3[C:29]([OH:33])=[O:32])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1ccc(S(=O)(=O)NCCc2ccccc2OCCN2CCCCC2)cc1
Reactant: O=CC(=O)O
Product: Cc1ccc(S(=O)(=O)N2CCc3c(OCCN4CCCCC4)cccc3C2C(=O)O)cc1

Procedure:
4-Methyl-N-{2-[2-(2-piperidin-1-ylethoxy)phenyl]ethyl}benzenesulfonamide is reacted with glyoxylic acid in analogy to the method described for Example 20.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][NH:13][C:12]2=[O:22])=[CH:7][CH:6]=1.[CH3:23][O:24][C:25](=[O:34])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br>CN(C=O)C>[CH3:23][O:24][C:25](=[O:34])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:13]1[CH:14]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=2)[C:12]1=[O:22]
Reactant: COC(=O)CCCCCCCBr
Reactant: COc1ccc(-n2c(-c3ccccc3)c[nH]c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1cc(-c2ccccc2)n(-c2ccc(OC)cc2)c1=O

Procedure:
The product is produced as described in example 1 from 2.4 g of NaH (80% suspension in mineral oil), 21.3 g of 1-(4-methoxyphenyl)-5-phenyl-4-imidazolin-2-one, 160 cc. of DMF 19 g of 8-bromocaprylic acid methyl ester and 2.4 g of NaJ. Eluant in chromatographic purification: hexane/ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:18])[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2ccc(F)cc2)CC1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 83.3 %

Procedure:
To a solution of 8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decan-8-ol (1.95 g, 7.73 mmol) in THF (30 mL) was added 3 M HCl (10 mL). The mixture was stirred at 50° C. for 1.5 h, and then poured into EtOAc (50 mL) and aqueous NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, hexane to 60:40 hexane/EtOAc) to give the title compound (1.34 g, 83%) as a colorless solid:
Reaction SMILES: C(O[C:4]([CH:6]1[C:14](=[O:15])[C:13]2[CH:12]=[N:11][CH:10]=[CH:9][C:8]=2[C:7]1=[O:16])=[O:5])C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:25][C:4]([CH:6]2[C:14](=[O:15])[C:13]3[CH:12]=[N:11][CH:10]=[CH:9][C:8]=3[C:7]2=[O:16])=[O:5])[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cccc(N)c1
Reactant: CCOC(=O)C1C(=O)c2ccncc2C1=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1cccc(NC(=O)C2C(=O)c3ccncc3C2=O)c1
Temperature: 25 °C

Procedure:
5,7-Dioxo-6,7-dihydro-5H-[2]pyrindine-6-carboxylic acid ethyl ester (18 g) (see, Robin D. Allan and Joyce Fong, Aust. J. Chem., Vol. 36, Pp. 1221-1226, 1983), m-anisidine (17.7 ml) and acetic acid (9 ml) were suspended in toluene (1,000 ml). This mixture was refluxed for 110 minutes under nitrogen. The mixture was cooled to room temperature and the precipitate (ppt) was collected with suction. The ppt was washed with toluene and dichloromethane and dried under reduced pressure to give a brown powder (21.6 g). ESI−MS: m/z 297 (MH+); 1H-NMR (DMSO-d6): δ3.74 (3H, s), 6.54 (1H, dd, J=8.5 Hz, J=2.5 Hz), 7.00 (1H, bd, J=8.5 Hz), 7.17 (1H, t, J=8.5 Hz), 7.42 (1H, t-like, J=ca 2.5 Hz), 7.73 (1H, d, 5 Hz), 8.71 (1H, s), 8.91 (1H, d, J=5 Hz), 10.65 (1H, brs).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][OH:10].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.Cl>N1C=CC=CC=1.CO>[S:17]([C:6]([S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18])([NH:7][CH2:8][CH2:9][OH:10])[C:5]([S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18])([S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18])[NH:4][CH2:3][CH2:2][OH:1])([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCNCCNCCO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)C(NCCO)(C(NCCO)(S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N,N′-bis(2-hydroxyethyl)-ethylenediamine (Aldrich, 14.8 g, 100 mmol) and pyridine (Fluka, 200 mL) was stirred at 0° C. under nitrogen while a solution of toluene-4-sulfonyl chloride (Fluka, 77 g, 400 mmol) dissolved in pyridine (Fluka, 100 mL) was dropped into the solution over a period of 75 minutes. The temperature was slowly raised to room temperature and continued stiffed for 4 hours. Solution was poured into a mixture of ice (250 mL) and hydrochloric acid (concentrated, 250 mL) while stirring to afford a dark sticky oil. Solvents were removed by decantation, product crude washed with water, decanted and re-dissolved in methanol (250 mL). The resulting slurry was isolated by filtration and the crude product was re-dissolved in hot methanol (60° C., 600 mL) and cooled down. Solid product was filtered off and dried in vacuo. Yield 36.36 g (47.5%). Product was verified by NMR.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1>>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:19][CH:20]=1)#[N:25]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: N#Cc1ccc(CN(c2ccc(C#N)cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[(4-cyanophenyl)amino]pyrimidine and α-bromo-p-tolunitrile