Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:32])[CH2:8][CH:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:19]=1)[C:10]#[C:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].[CH3:35]I>C1COCC1.C(OCC)(=O)C>[CH3:35][N:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[C:7](=[O:32])[CH2:8][CH:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:19]=1)[C:10]#[C:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(C(C#Cc2ccccc2)CC(=O)Nc2nccs2)cc1OC1CCCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(C#Cc2ccccc2)CC(=O)N(C)c2nccs2)cc1OC1CCCC1
Temperature: 80 °C

Procedure:
To a solution of the compound from Example 22 (0.07 g, 0.16 mmol) in THF (2 mL) under an argon atmosphere was added 60% NaH/mineral oil suspension (0.008 g, 0.19 mmol), followed by methyl iodide (0.012 mL, 0.19 mmol). After heating at 80° C. for 0.25 h, the mixture was cooled to room temperature, was diluted with ethyl acetate, was washed with brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluting with 1:1 hexanes/ethyl acetate provided the title compound as a yellow resin (0.025 g, 34%). Anal. (C27H28N2SO3 ·0.375 H2O) calcd: C, 69.39; H, 6.20; N, 5.99. found: C, 69.52; H, 6.22; N, 5.78.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:28](=[O:38])[NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=2)=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:16])[CH2:5][NH:6]C(OC(C)(C)C)=O.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[CH3:1][O:2][C:3](=[O:39])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:28](=[O:38])[NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=2)=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:16])[CH2:5][NH2:6]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-3-tert-Butoxycarbonylamino-2-{[5-(3-hydroxy-benzylcarbamoyl)-3-phenyl-thiophene-2-carbonyl]-amino}-propionic acid methyl ester (0.148 g, 0.27 mmol) in DCM (5 mL) was added TFA (2.0 mL). The mixture was stirred at room temperature 1 h and evaporated. Isolate 0.23 g of crude product which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:23](=O)[CH3:24])[C:15]([O:17][CH2:18][CH:19]1[CH2:22][CH2:21][CH2:20]1)=[O:16].[NH2:26][C:27]([CH3:32])=[CH:28][C:29](=[O:31])[CH3:30]>C(O)C>[C:29]([C:28]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:14]([C:15]([O:17][CH2:18][CH:19]2[CH2:22][CH2:21][CH2:20]2)=[O:16])=[C:23]([CH3:24])[NH:26][C:27]=1[CH3:32])(=[O:31])[CH3:30]
Reactant: CC(=O)C=C(C)N
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(=O)OCC1CCC1
Solvent: CCO
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)OCC2CCC2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
960 mg (2.82 mmol) of cyclobutylmethyl 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-3-oxobutanoate are dissolved with 279 mg (2.82 mmol) of 4-aminopent-3-en-2-one in 10 ml of ethanol and heated under reflux under argon for 24 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. Concentration of the product fractions and crystallization from ethyl acetate result in 532 mg (44% of theory) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][NH:13][CH2:14][CH3:15]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]([CH2:14][CH3:15])[CH3:12])=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: CCNC
Reactant: O=C(O)c1ccc(Br)cc1F
Product: CCN(C)C(=O)c1ccc(Br)cc1F

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluorobenzoic acid and N-methyl-ethanamine.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.[I:22]I.[F:24][C:25]([F:51])([F:50])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]1[CH:42]=[CH:43][N:44]=[C:37]1[C:36]([NH:45][CH2:46][CH2:47][CH2:48][OH:49])=[N:35]2>C(#N)C>[I:22][C:42]1[N:38]2[C:39]3[C:34]([N:35]=[C:36]([NH:45][CH2:46][CH2:47][CH2:48][OH:49])[C:37]2=[N:44][CH:43]=1)=[CH:33][C:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]([F:24])([F:50])[F:51])=[CH:41][CH:40]=3
Reactant: OCCCNc1nc2cc(-c3ccccc3C(F)(F)F)ccc2n2ccnc12
Reactant: II
Agent: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: OCCCNc1nc2cc(-c3ccccc3C(F)(F)F)ccc2n2c(I)cnc12
Reaction time: 0.17 h
Yield: 82.1 %

Procedure:
To a mixture protected from light of Selectfluor (103 mg; 0.29 mmol; 1.4 eq) and iodine (63 mg; 0.248 mmol; 1.2 eq) in acetonitrile (1.8 ml) stirred for 10 min under argon is added 3-({7-[2-(trifluoromethyl)phenyl]imidazo[1,2-a]quinoxalin-4-yl}amino) propan-1-ol (80 mg; 0.207 mmol; 1 eq) prepared as in example 5. The reaction mixture is stirred at rt overnight. Filtration of solid side-products, concentration, dissolution in ethyl acetate, washing with brine, aqueous sodium carbonate and water, drying (magnesium sulphate) and purification by prep CCM on silicagel (dichloromethane/methanol 95:5) affords the title product as an orange oil (88 mg; 0.17 mmol; 82%).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][C:6]([CH3:10])(O)[C:5]1=[CH2:11])([CH3:3])=[CH2:2].[CH3:12][CH:13]([CH3:18])[CH:14]=[CH:15][O:16]C>P(=O)(O)(O)O>[CH:15]([CH:14]([CH:13]([CH3:18])[CH3:12])[CH2:11][C:5]1[CH:4]([C:1]([CH3:3])=[CH2:2])[CH2:8][CH2:7][C:6]=1[CH3:10])=[O:16]
Reactant: COC=CC(C)C
Reactant: C=C(C)C1CCC(C)(O)C1=C
Agent: O=P(O)(O)O
Product: C=C(C)C1CCC(C)=C1CC(C=O)C(C)C
Yield: 45 %

Procedure:
According to the procedure described in Example 7, by the reaction of 30.4 g of 3-isopropenyl-1-methyl-2-methylene-cyclopentan-1-ol with 50 g of methyl (3-methyl-1-butenyl) ether in the presence of 7 drops of 85% phosphoric acid there was obtained 2-(2-formyl-3-methylbutyl)-3-isopropenyl-1-methyl-cyclopent-1-ene in 45% yield; boiling point 0.005 = 55°-56° C; nD20 = 1.4808; IRfilm : νmax = 3280, 2725, 1725, 1642, 1460/40, 1390/70 and 890 cm-1. The compound has a cedar-like, woody, remotely floral fragrance.
Reaction SMILES: [NH3:1].C[O:3][C:4]([C:6]1[N:10]=[C:9]([CH2:11][Cl:12])[N:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:7]=1)=O>CO>[C:20]([C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[N:8]1[C:9]([CH2:11][Cl:12])=[N:10][C:6]([C:4]([NH2:1])=[O:3])=[N:7]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Reactant: N
Solvent: CO
Product: NC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Temperature: 25 °C

Procedure:
30 ml of concentrated aqueous ammonia solution is added dropwise at 30° in the course of 5 minutes, with stirring, to the suspension of 6.0 g (0.015 mole) of 1-(2-benzoyl-4-chlorophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester in 220 ml of methanol. There has formed after 4 hours a clear reaction solution, and a short time later a crystalline product commences to precipitate. Stirring is maintained for one hour at room temperature and for one hour at 0°-5°. The formed crystals are thereupon filtered off and recrystallised from 50 ml of methanol. The product is filtered off with suction and washed with methanol and hexane. After drying in vacuum, there is obtained 1-(2-benzoyl-4-chlorophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxamide, m.p. 128°-130°.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH2:8][CH3:9])[C:6]2[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:5]=2[N:4]=1.C(OC([N:23]1[CH:27]=[CH:26][C:25]([C:28]2[NH:29][CH:30]=[CH:31][N:32]=2)=[N:24]1)=O)(C)(C)C>>[CH2:8]([N:7]1[C:6]2[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:5]=2[N:4]=[C:3]1[CH2:2][N:32]1[CH:31]=[CH:30][N:29]=[C:28]1[C:25]1[CH:26]=[CH:27][NH:23][N:24]=1)[CH3:9]
Reactant: CCn1c(CCl)nc2cc(C#N)ccc21
Reactant: CC(C)(C)OC(=O)n1ccc(-c2ncc[nH]2)n1
Product: CCn1c(Cn2ccnc2-c2cc[nH]n2)nc2cc(C#N)ccc21

Procedure:
As described previously, nucleophilic displacement of 2-Chloromethyl-1-ethyl-1H-benzoimidazole-5-carbonitrile with 3-(1H-Imidazol-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester followed by usual work-up provides 1-Ethyl-2-[2-(1H-pyrazol-3-yl)-imidazol-1-ylmethyl]-1H-benzoimidazole-5-carbonitrile; 1H NMR (CD3OD) δ 7.97 (s, 1H), 7.53 (brs, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 6.97 (d, J=6.3 Hz, 2H), 6.79 (br s, 1H), 6.10 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 0.88 (t, J=7.2 Hz, 3H); m/z 318 [M+1].
Reaction SMILES: N1C(C)=CC=CC=1C.[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C@@H:28]([OH:31])[CH2:29][Br:30])=[C:21]2[C:26]=1[NH:25][C:24](=[O:27])[CH:23]=[CH:22]2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.FC(F)(F)S(O[Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])(=O)=O>C(Cl)Cl>[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C@@H:28]([O:31][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:29][Br:30])=[C:21]2[C:26]=1[NH:25][C:24](=[O:27])[CH:23]=[CH:22]2)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=c1ccc2c([C@@H](O)CBr)ccc(OCc3ccccc3)c2[nH]1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reaction time: 0.08 h
Yield: 85.7 %

Procedure:
2,6-Lutidine (6.9 mL, 59.5 mmol) was added to a solution of (R)-8-(benzyloxy)-5-(2-bromo-1-hydroxyethyl)quinolin-2(1H)-one (10.1 g, 27.0 mmol) in DCM (100 mL) at 0° C. The reaction mixture was stirred for 5 minutes then tert-butyldimethylsilyl trifluoromethanesulfonate (tBuMe2SiOtf) (13.0 mL, 56.8 mmol) was added dropwise over 15 minutes. The mixture was stirred at 0° C. for 30 minutes, followed by RT overnight. After this time the reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with DCM (×3). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated under reduced pressure. Iso-hexane (500 mL) was added to the crude material and the resulting solid collected by filtration. The solid was recrystallised from ethyl acetate and petroleum ether (40:60) to afford the title compound (11.3 g, 85%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].CC1C=C[C:9]([O:12]C)=CC=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]>Cl>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:9]=[O:12])=[CH:17][C:16]=1[CH3:21]
Reactant: COc1ccc(C)cc1
Reactant: Cc1ccccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C=O)ccc1F
Temperature: 30 °C
Yield: 131.4 %

Procedure:
229.30 g of aluminum chloride (mol. wt. 133.34; 1,719.7 mmol), 110.0 g (4-Methylanisole (mol. Wt. 122.17; 900.4 mmol), and about 500 g of 2-fluorotoluene (mol. Wt. 110.13; 4,540.1 mmol) were charged to a 2 liter Parr®-brand 4522 stainless steel reaction vessel. To this mixture was added 5 drops of concentrated HCl. The vessel was sealed, heated to 30° C., and purged three times with carbon monoxide with the pressure of the vessel increased to 100 psi for each purging. After the third purge, the vessel was vented and a final introduction of CO was made at a pressure of about 550 psi, the pressure at which the reaction was maintained for the total reaction time of about 66 hours (the reaction temperature was maintained at 30° C. for the duration as well). Once the reaction was complete, the resultant mixture (exhibiting a greenish-brown color) was poured into about 500 mL of ice water (which turned the solution a yellow color), to which was added 500 mL of cyclohexane. The top, organic layer was removed and washed three times with water using a separatory funnel and dried over magnesium sulfate. The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 2-fluorotoluene, and left about 98.01 g of 4-fluoro-3-methylbenzaldehyde product (mol. Wt. 138.14; 709.5 mmol; yield of approximately 86.7%). The 4-fluoro-3-methylbenzaldehyde product may then be easily separated from any residual 4-methylanisole by conversion into its corresponding bisulfite adduct, filtration, and decomposition of the bisulfite adduct under acidic or basic conditions.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][CH2:29][O:30][P:31](=[O:48])([O:40]CC6C=CC=CC=6)[O:32]CC6C=CC=CC=6)[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]>CO.CCOC(C)=O>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][CH2:29][O:30][P:31](=[O:32])([OH:40])[OH:48])[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CCOP(=O)(OCc4ccccc4)OCc4ccccc4)c3)ccc1-2
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CCOP(=O)(O)O)c3)ccc1-2

Procedure:
Phosphoric acid dibenzyl ester 2-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-ethyl ester (180 mg, 0.26 mmol) was dissolved in methanol:EtOAc (1:1, 6 mL) and the solution was flushed with bubbling nitrogen. Palladium hydroxide (5% on carbon, 40 mg) was added and the reaction mixture was placed under hydrogen atmosphere (1 atm, balloon) overnight while rapidly stirred. Filtration over celite and concentration of the filtrate gave 482. Lyophilization of a solution in acetonitrile and 1% NH4OH in water gave 482 as the bis-ammonium salt.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].ClCCl>>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2NS(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccccc1C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-[2-(1-t-Butoxycarbonylpiperidin-4-yl)phenyl]methanesulfonamide (488 mg) was dissolved in trifluoroacetic acid-dichloromethane (10%, 50 mL) and stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure to give the title compound as a colourless gum (501 mg), δH (CDCl3) 1.97 (4H, br m), 3.03 (3H, s), 3.16 (2H, m), 3.48 (1H, m), 3.68 (2H, m), 7.25-7.43 (4H, m), 8.01 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.I[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:1][C:2]1[C:3]([F:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21])[CH2:8][CH2:7]2
Reactant: O=C1NCCc2ccc(F)c(Cl)c21
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccc(F)c(Cl)c2C1=O
Yield: 27.4 %

Procedure:
Using analogous reaction conditions as described in Example 1, 8-chloro-7-fluoro-3,4-dihydro-2H-isoquinolin-1-one (250 mg, 1.2562 mmol) was reacted with 3-iodo-4-methyl-pyridine (275.12 mg, 1.2562 mmol), 1,4-dioxane (10 mL), copper iodide (23.9 mg, 0.12562 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (60 mL, 0.3768 mmol) and potassium phosphate (665.7 mg, 3.1405 mmol) to afford the crude product. Purification by column chromatography on silica gel (40% ethylacetate in hexane) afforded 100 mg of the product (27.44% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]3)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>ClCCl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[N:11]1([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2cccc3nc(N)nc(N)c23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(N)c2c(OCCN3CCNCC3)cccc2n1
Reaction time: 16 h
Yield: 88 %

Procedure:
In a 100 mL round bottom flask 4-[2-(2,4-Diamino-quinazolin-5-yloxy)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (2.3 g; 5.9 mmol) was magnetically stirred in 20 mL of dichloromethane and trifluoroacetic acid (3 mL) was added dropwise at room temperature. After 16 hours, solids were filtered and rinsed with 10 mls of dichloromethane. Title compound was obtained 2.1 g (88% yield).
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][CH2:41][NH2:42])[CH2:34][CH2:33]1>>[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27]([NH2:28])=[O:29])[CH2:34][CH2:33]1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Reactant: CN1CCN(CCCCN)CC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CCN(C)CC3)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 4-(4-methyl-piperazin-1-yl)-butylamine by the procedure analogous to Example 1. MS (APCl, m/z): 515 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[NH:36][C:37]1[C:42]([Cl:43])=[CH:41][N:40]=[C:39](Cl)[N:38]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[NH:36][C:37]1[C:42]([Cl:43])=[CH:41][N:40]=[C:39]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)[N:38]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Fc1cccc(OCCCOCc2ccccc2)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4OCCCOCc4ccccc4)n3)cc2CC1

Procedure:
Prepared from 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and [2-(3-Benzyloxy-propoxy)-6-fluoro-phenyl]-(2,5-dichloro-pyrimidin-4-yl)-amine in an analogous manner to Example 1221d. Title compound was isolated as a white solid, HPLC purity 99%, LCMS 516.27 (M-benzyl), 1H-NMR (DMSO-d6, 400 MHz) δ 9.63 (s, 1H), 9.32 (s, 1H), 8.47 (s, 1H), 8.09 (s, 1H), 7.38-7.35 (m, 1H), 7.28-7.25 (m, 4H), 7.18-7.15 (m, 3H), 7.14-7.12 (d, 1H), 7.01-6.99 (m, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.24 (s, 2H), 4.08-4.05 (m, 2H), 3.80-3.72 (m, 2H), 3.58-3.50 (m, 2H), 3.35-3.31 (m, 7H), 3.20-2.90 (m, 6H), 1.85-1.81 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[S:7][C:8](B(O)O)=[CH:9][C:5]=2[CH:4]=1.Br[C:16]1[CH:29]=[CH:28][C:19]([O:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[S:7][C:8]([C:16]3[CH:17]=[CH:18][C:19]([O:20][CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:28][CH:29]=3)=[CH:9][C:5]=2[CH:4]=1
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Reactant: COc1ccc2sc(B(O)O)cc2c1
Product: COc1ccc2sc(-c3ccc(OCCN4CCCC4)cc3)cc2c1
Yield: 47 %

Procedure:
The title compound was prepared in 47% yield by essentially following the procedures in Example 1, Part B, from 5-methoxybenzo[b]thiophene-2-boronic acid (Part B) and 1-(2-(4-bromophenoxy)ethyl)pyrrolidine.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2.C(OCC)(=O)C.[H][H]>C(O)C.[Pd]>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2
Reactant: FC(F)(F)c1ccccc1C=C1c2ccccc2CCc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: FC(F)(F)c1ccccc1CC1c2ccccc2CCc2ccccc21
Reaction time: 17 h

Procedure:
Add 5-(2-trifluoromethyl-benzylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.16 g, 0.45 mmol) to a mixture of 10% Pd/C (0.075 g) suspended in absolute ethanol (4.0 mL) and ethyl acetate (2.0 mL) and hydrogenate under a balloon of hydrogen at room temperature and pressure. Stir for 17 h, remove the catalyst via filtration through a pad of Celite. Evaporate the filtrate and pass through a plug of silica gel equilibrated with hexanes. Concentrated the filtrate to give the title product. MS (m/e): 352 (M+). Analysis for C23H19F3: Calcd: C, 78.39 H, 5.43. Found: C, 78.84 H, 5.11.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=[O:13].CN(C)C=O.[H-].[Na+].[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25](S(C)(=O)=O)[N:24]=1>O>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25]([O:1][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]=2[CH:12]=[O:13])[N:24]=1
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2ccc3ccccc3c2C=O)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 47.7 %

Procedure:
8.6 g (0.05 mol) of 2-hydroxynaphthalene-1-aldehyde are introduced into 50 ml of dry dimethylformamide and admixed by stirring, at 0°-5° C., with 1.5 g (0.05 mol) of 80% strength sodium hydride added a little at a time. 10.9 g (0.05 mol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine are then added at room temperature, and the mixture is heated to 90° C. and stirred at that temperature for 6 hours. The solution thus obtained is poured into water. The aqueous mixture is extracted with methylene chloride, carefully washed with water, dried over sodium sulfate and concentrated under reduced pressure. The crude product is further purified by stirring out with cold toluene, leaving 7.4 g of 2-(4,6-dimethoxypyrimidin-2-yloxy)naphthalene-1-aldehyde of m.p. 123°-125° C.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][OH:7])(=[O:5])[OH:4])[CH3:2].[CH2:8](O)[CH2:9][CH2:10][CH3:11]>O>[CH2:1]([P:3]([CH2:6][OH:7])(=[O:4])[O:5][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2]
Reactant: CCP(=O)(O)CO
Reactant: CCCCO
Solvent: O
Product: CCCCOP(=O)(CC)CO
Yield: 66.6 %

Procedure:
405.5 g of ethylhydroxymethylphosphinic acid (prepared according to example 1) are admixed with 1115 g of butanol and the water of condensation is removed with a water trap by boiling at atmospheric pressure. After the esterification has ended, the butanol is separated off in vacuo and the residue is vacuum distilled via a Vigreux column to obtain 392 g of n-butyl ethylhydroxymethylphosphinate in a 79% yield.