Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[CH2:13]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([Br:3])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2c(ccn2Cc2ccccc2)c1
Temperature: 30 °C
Yield: 80 %

Procedure:
In a suspension of 26.6 g of KOH in 200 ml of dimethylformamide, 20.1 g of solid 5-bromoindole was incorporated while being stirred. The mixture was stirred for 50 minutes at room temperature, and 25.4 g of benzyl chloride was dropwise added to the mixture over a period of 16 minutes at a temperature of not higher than 30° C. The reaction mixture was maintained at 30° C. in an oil bath for 5 hours with stirring. After completion of the reaction, 200 ml of water was added and the thus-formed aqueous phase was extracted with 120 ml of ether three times. The thus-obtained organic phase was washed with water and dried over sodium sulfate overnight. The dried product was concentrated to dryness and then recrystallized from isopropyl ether to give 23.5 g of N-benzyl-5-bromoindole. The yield was 80% by mole.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[C:5]([Cl:21])=[CH:4][N:3]=1.[CH2:22]([N:24]1[CH2:30][CH2:29][C:28]2[CH:31]=[C:32]([NH2:35])[CH:33]=[CH:34][C:27]=2[CH2:26][CH2:25]1)[CH3:23].Cl.C(=O)([O-])[O-]>COCCO.O1CCOCC1>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:7][C:2]([NH:35][C:32]2[CH:33]=[CH:34][C:27]3[CH2:26][CH2:25][N:24]([CH2:22][CH3:23])[CH2:30][CH2:29][C:28]=3[CH:31]=2)=[N:3][CH:4]=1
Reactant: CCN1CCc2ccc(N)cc2CC1
Reactant: Clc1ncc(Cl)c(Nc2ccc(N3CCOCC3)cc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCO
Solvent: C1COCCO1
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4)n3)cc2CC1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(4-morpholin-4-yl-phenyl)-amine (96 mg, 0.29 mmol) was added into a vial, followed by a solution of 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (52 mg, 0.27 mmol) in 2-Methoxyethanol (2.7 mL). 4 M of Hydrogen chloride in 1,4-Dioxane (0.10 mL) was added and the reaction was heated at 120° C. After 6 h, the reaction was cooled and Macroporous carbonate resin (3.16 mmol/g loading; 400 mg, 1.25 mmol) was added and the reaction was stirred overnight, then was concentrated in vacuo onto Celite, and chromatographed (24 g alumina column, DCM). 5-Chloro-N*2*-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-N*4*-(4-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine was isolated as a yellow powder (40 mg, 31%). m.p.=190-194° C.; LCMS (m/e) 479 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.04 (s, 1H), 7.23 (m, 1H), 7.16 (d, 1H, J=7.9 Hz), 7.04 (dd, 1H, J=2.1, 2.2 Hz), 7.00 (m, 2H), 6.82 (s, 1H), 6.72 (dd, 1H, J=2.2, 8.3 Hz), 3.81 (t, 4H, J=4.8 Hz), 3.12 (t, 4H, J=4.8 Hz), 2.89 (m, 4H), 2.62 (m, 4H), 2.57 (q, 2H, J=7 Hz), 1.09 (t, 1H, J=7 Hz).
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[CH:17]=2)=[C:12]([OH:23])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[BH4-].[Na+].[Cl-].[Na+].CCOCC>CO>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:21][CH2:20][CH2:19][CH:18]([OH:22])[CH:17]=2)=[C:12]([OH:23])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)(C)c1ccc(C2=CC(=O)CCC2)c(O)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1ccc(C2=CC(O)CCC2)c(O)c1
Reaction time: 0.5 h

Procedure:
To a -18° C. solution of 70.0 g (0.20 mol) of 3-[4-(1,1-dimethylheptyl]-2-hydroxyphenyl]-cyclohex-2-enone in 200 ml of methanol is added 7.6 g (0.20 mol) of sodium borohydride. The reaction mixture is stirred for 30 minutes and then added to one liter of saturated sodium chloride-one liter of ether. The ether extract is washed once with 500 ml of saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue is purified via column chromatography on 500 g of silica gel eluted with 50% ether-pentane to yield the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:17][C:18]#[N:19].O>CN(C=O)C>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([O:13][CH2:17][C:18]#[N:19])=[CH:11][CH:12]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCOc1ccc(-c2ccccc2)cc1
Temperature: 70 °C

Procedure:
To a solution of 4-phenylphenol (3.4 g, 20 mmol) in DMF (75 ml) was added sodium hydride (0.88 g of a 60% dispersion in oil, 22 mmol). The mixture was stirred at 70° C. under nitrogen until a clear solution was obtained, then cooled to 50° C. To the mixture was added chloroacetonitrile (1.5 ml, 24 mmol). A precipitate formed immediately. The mixture was cooled to room temperature, poured into water (300 ml), and extracted with ether. The ether extracts were dried (MgsO4), filtered and evaporated. Recrystallization of the residue from methanol provided [1,1'-biphenyl]-4yloxyacetonitrile, mp 81°-83° C.
Reaction SMILES: CCCCCC.[H-].C([Al+]CC(C)C)C(C)C.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29](OCC)=[O:30])=[CH:23][C:22]=1[NH:34][C:35](=[O:51])[CH2:36][CH:37]1[C:50]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[O:44][C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)([CH3:20])([CH3:19])[CH3:18].Cl>O1CCCC1>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][OH:30])=[CH:23][C:22]=1[NH:34][C:35](=[O:51])[CH2:36][CH:37]1[C:50]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[O:44][C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)CCc1ccc(C(C)(C)C)c(NC(=O)CC2c3ccccc3Oc3ccccc32)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CCCO)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: -78 °C
Reaction time: 1.25 h
Yield: 66.7 %

Procedure:
5.96 ml (5.96 mmol) of a 1.0M hexane solution of diisobutylaluminum hydride were added dropwise, over a period of 10 minutes, to 14 ml of a tetrahydrofuran solution containing 702 mg (1.49 mmol) of N-[2-t-butyl-5-(2-ethoxycarbonylethyl)phenyl]-2-(9H-xanthen-9-yl)-acetamide (prepared as described in Preparation 17) which had previously been cooled at -78° C. The mixture was stirred for 75 minutes at this temperature and then for 45 minutes at room temperature. At the end of this time, the reaction solution was poured into a mixture of dilute aqueous hydrochloric acid and ice, and was then extracted with diethyl ether. The organic extract was washed with water, and then the solvent was removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 30 g of silica gel. Elution with a 5:4 by-volume mixture of methylene chloride and ethyl acetate afforded 427 mg (yield 67%) of the title compound as crystals, melting at 185°-186° C. (after recrystallization from a mixture of methylene chloride and diethyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([C:16]3[CH2:21][CH2:20][N:19](C)[CH2:18][CH:17]=3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:23]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].[NH4+].[OH-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([C:16]3[CH2:21][CH2:20][NH:19][CH:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:17]=3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:23]=1
Reactant: CN1CC=C(C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Reactant: CCOC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1C=C(C2c3ccc(Cl)cc3CCc3cccnc32)CCN1
Temperature: 80 °C
Yield: 26.7 %

Procedure:
Dissolved 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-N-methyl-1,2,5,6-tetrahydropyridine (1.24 g, 3.82 mmol) in 100 mL of dry toluene, and added ethyl chloroformate (0.91 mL, 9.54 mmol) via syringe. Heated at 80° C. for 46 hours under a nitrogen atmosphere. Cooled to room temperature, and added 1N NH4OH. Extracted with ether. Purified crude product by flash chromatography on silica gel eluting with 10% EtOAc-CH2Cl2. Combined appropriate fractions, and evaporated to give 0.39 g (27% yield) of ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1,2,5,6- tetrahydropyridinecarboxylate as an oil. mass spectrum: (Cl, CH4) m/e 383 (M+1) ##STR48##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1I.CC1(C)C(C)(C)OB([C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=2[C:28](OC)=[O:29])O1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:3]=1[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[C:28](=[O:29])[NH:8]2
Reactant: Nc1nccc(Cl)c1I
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C(=O)OC)c1
Product: COC(=O)c1ccc2c(c1)c(=O)[nH]c1nccc(Cl)c12
Yield: 48.5 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 1 using 4-chloro-3-iodopyridin-2-amine (510 mg, 2.0 mmol) and dimethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isophthalate (705 mg, 2.2 mmol) to provide 266 (280 mg, 48% yield) as a white solid. LC-MS (M+H=289, obsd.=289).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH:16]([CH3:23])[CH2:17][C:18]([O:20]CC)=O)[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1.[NH3:24]>CO>[CH3:23][CH:16]1[N:4]2[C:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:8]=[CH:7][C:6]=3[N:15]=[C:3]2[CH2:2][NH:24][C:18](=[O:20])[CH2:17]1
Reactant: CCOC(=O)CC(C)n1c(CCl)nc2cnc3ccccc3c21
Reactant: N
Solvent: CO
Product: CC1CC(=O)NCc2nc3cnc4ccccc4c3n21

Procedure:
A solution of ethyl 3-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanoate (8.22 g, 24.8 mmol) in 7 N ammonia in methanol (140 mL) was stirred overnight at room temperature. The volatiles were removed under reduced pressure, and the residue was further dried under high vacuum and purified by automated flash chromatography (eluting with a gradient of dichloromethane/methanol/concentrated ammonium hydroxide in a gradient from 100:0:0 to 50:47.5:2.5) to provide 12-methyl-8,9,11,12-tetrahydro-10H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-10-one as an orange solid. Automated flash chromatography was carried out using a combination of a COMBIFLASH system (an automated high-performance flash purification product available from Teledyne Isco, Inc., Lincoln, Nebr., USA) and a HORIZON HPFC system (an automated high-performance flash purification product available from Biotage, Inc, Charlottesville, Va., USA).
Reaction SMILES: Cl.Cl.[CH2:3]([CH:5]1[C:13]2[C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:11][CH:10]=[N:9][C:8]=2[CH2:7][S:6]1)[CH3:4].[C:20]([O:24][C:25]([NH:27][C@H:28]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(N(CC)CC)C>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][C@@H:28]([NH:27][C:25](=[O:26])[O:24][C:20]([CH3:22])([CH3:21])[CH3:23])[C:29]([N:17]2[CH2:16][CH2:15][N:14]([C:12]3[C:13]4[CH:5]([CH2:3][CH3:4])[S:6][CH2:7][C:8]=4[N:9]=[CH:10][N:11]=3)[CH2:19][CH2:18]2)=[O:30])=[CH:34][CH:35]=1
Reactant: CCC1SCc2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1SCc2ncnc(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.6 %

Procedure:
To a solution of 5-ethyl-4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine dihydrochloride (50 mg, 0.15 mmol) and (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (46 mg, 0.15 mmol) in DCM (10 mL) and triethylamine (1 mL) was added HBTU (59 mg, 0.15 mmol). The mixture was stirred at room temperature for 3 hours. The solvent was removed and the residue was purified by silica gel chromatography, eluting with DCM/ethyl acetate (1:1) to give tert-butyl (R)-3-(4-chlorophenyl)-1-(4-(5-ethyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (50 mg, 60%). 1H NMR (CDCl3, 400 MHz) δ 8.53 (s, 1H), 7.26-7.14 (m, 4H), 5.36 (m, 1H), 4.82 (m, 1H), 4.62 (m, 1H), 4.14 (m, 1H), 3.80-2.90 (m, 8H), 1.94 (m, 1H). 1.68 (m, 1H), 1.54 (m, 1H), 1.42 (s, 9H), 0.94 (m, 3H). MS (APCI+) [M+H]+ 533.
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])[S:15][CH3:16])=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.[CH2:18]([O:25][C:26](ON1C(=O)CCC1=O)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.C(N(CC)CC)C>[C:26]([N:13]([C:11]([C:4]1[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=1)=[O:12])[C:14](=[NH:17])[S:15][CH3:16])([O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:27]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSC(=N)N(C(=O)OCc1ccccc1)C(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
1-(3,5-Diamino-6-chloropyrazinoyl)-2-methyl-pseudothiourea hydroiodide (II, 494 mg, 1.27 mmol) was dissolved in a mixture of anhydrous DMF (10 mL), and triethylamine (3 mL) followed by treatment with N-(benzyloxycarbonyloxy) succinimide (470 mg, 1.7 mmol) dissolved in DMF (3 mL). The reaction mixture was stirred overnight at room temperature. After this time, the reaction mixture was concentrated under reduced pressure and the residue suspended in ethyl acetate (30 mL). Silica gel (25 g) was added to the solution and the solvent was evaporated to leave the silica gel impregnated with the crude product that was purified by flash chromatography on a FlashElute™ system from Elution Solution (P.O. Box 5147, Charlottesville, Va. 22905) using a 90 g silica gel cartridge (eluent: hexanes, ethyl acetate=1:2). The purified N-Cbz-1-(3,5-diamino-6-chloropyrazinoyl)-2-methyl-pseudothiourea (III) was obtained as a pale yellow solid: 416 mg (83% yield); 1H NMR (360 MHz, DMSO-d6) δ 2.33 (s, 3H), 2.61 (s, 3H), 4.99 (s, 2H), 7.39 (m, 10H), 13.7 (s, 1H); API MS m/z=395 [C15H15ClN6O3S+H]+; LC/MS (Method A) >99%, tr=10.1 min.
Reaction SMILES: [OH:1][CH:2]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:3]#[C:4][CH2:5][CH2:6][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].N1C2C(=CC=CC=2)C=CC=1.S([O-])([O-])(=O)=O.[Ba+2].[H][H]>C(OCC)(=O)C>[OH:1][CH:2]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:3]=[CH:4][CH2:5][CH2:6][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCCCCCC(O)C#CCCC(=O)CC(=O)OCC
Reactant: [H][H]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: CCCCCCC(O)C=CCCC(=O)CC(=O)OCC
Yield: 59.6 %

Procedure:
A solution of 10 g of the product of Step A in 50 ml of ethyl acetate containing 1 ml of quinoline was added to a suspension of 1 g of 50% palladized barium sulfate in 50 ml of ethyl acetate and the mixture was stirred in a hydrogen atmosphere until absorption ceased. The catalyst was removed by filtration and the filtrate was washed with dilute hydrochloric acid and water, dried over magnesium sulfate and evaporated. The residue was chromatographed over silica and was eluted with an 8-2 mixture of methylene chloride-ethyl acetate to obtain 6 g of ethyl 8-hydroxy-3-oxo-6-tetradecenoate in the form of a pale yellow oil with a refractive index of nD23 = 1.4602.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][CH3:38])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][N:35]([CH2:36][CH2:37][CH3:38])[C:1](=[O:5])[CH2:2][OH:3])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: O=C(O)CO
Reactant: CCCNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CCCN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(=O)CO
Yield: 26 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(propylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 7, preparation of starting materials) to give the title compound in 26% yield; NMR spectrum (DMSO-d6) 0.84 (t, 3H), 1.53-1.65 (m, 2H), 3.26 (t, 2H), 3.95 (t, 2H), 4.14 (d, 2H), 4.38 (t, 1H), 4.47 (t, 2H), 4.53-4.58 (m, 1H), 5.36 (s, 1H), 7.24 (d, 1H), 7.31 (d, 1H), 7.39-7.44 (m, 2H), 7.63-7.67 (m, 2H), 7.76-7.81 (m, 1H), 7.92-7.96 (m, 1H), 8.05 (s, 1H), 8.51 (s, 1H), 8.66 (d, 1H), 9.87 (s, 1H); Mass spectrum MH+ 522.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.[Cl:16][C:17]1[CH:25]=[C:24]([C:26]#[C:27][CH2:28][O:29][CH3:30])[C:20]2[O:21][CH2:22][O:23][C:19]=2[C:18]=1[NH2:31].Cl[C:33]1[C:42]2[C:37](=[CH:38][C:39]([O:50][CH2:51][CH2:52][CH2:53][N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)=[CH:40][C:41]=2[O:43][CH:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[N:36]=[CH:35][N:34]=1>CN(C=O)C>[Cl:16][C:17]1[CH:25]=[C:24]([C:26]#[C:27][CH2:28][O:29][CH3:30])[C:20]2[O:21][CH2:22][O:23][C:19]=2[C:18]=1[NH:31][C:33]1[C:42]2[C:37](=[CH:38][C:39]([O:50][CH2:51][CH2:52][CH2:53][N:54]3[CH2:55][CH2:56][O:57][CH2:58][CH2:59]3)=[CH:40][C:41]=2[O:43][CH:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)[N:36]=[CH:35][N:34]=1
Reactant: Clc1ncnc2cc(OCCCN3CCOCC3)cc(OC3CCOCC3)c12
Reactant: COCC#Cc1cc(Cl)c(N)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCOCC4)cc(OC4CCOCC4)c23)c2c1OCO2
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 36.2 %

Procedure:
A solution of sodium bis(trimethylsilyl)amide (1.28 ml) in tetrahydrofuran (1.0M, 1.28 mmol) was added to a suspension of 5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-amine (0.153 g) and 4-chloro-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinazoline (0.260 g) in DMF (4 ml) that had been cooled to −10° C. and the mixture was stirred for 90 minutes. A further portion of sodium bis(trimethylsilyl)amide (0.64 ml) in tetrahydrofuran (1.0M, 0.64 mmol) was added and the reaction was allowed to warm to room temperature and then stirred for a further 2 hours. The reaction mixture was quenched into water and saturated ammonium chloride solution was added. This was then extracted into dichloromethane and the organic portion was then washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of dichloromethane and methanol as eluent. The product material gathered after chromatography as a foam was triturated with diethyl ether giving an off-white solid. This was then re-dissolved into dichloromethane and then evaporated under reduced pressure. The resulting solid was triturated with diethyl ether and air-dried. There was thus obtained the title compound (0.141 g) as a white solid; NMR Spectrum: (CDCl3) 2.00 (m, 4H), 2.23 (m, 2H), 2.48 (m, 4H), 2.54 (t, 2H), 3.46 (s, 3H), 3.63 (dq, 2H), 3.73 (t, 4H), 4.02 (dt, 2H), 4.16 (t, 2H), 4.35 (s, 2H), 4.76 (tt, 1H), 6.11 (s, 2H), 6.51 (d, 1H), 6.85 (d, 1H), 7.06 (s, 1H), 8.52 (s, 1H), 9.26 (s, 1H); Mass Spectrum: M+H+ 611/613.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].Br[CH2:11][CH2:12][CH2:13][Cl:14].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:14][CH2:13][CH2:12][CH2:11][N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: ClCCCBr
Reactant: CC1(C)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)NC(=O)N(CCCCl)C1=O

Procedure:
A mixture of 5,5-dimethylhydantoin (5.25 g), 1-bromo-3-chloropropane (8.5 mL), and Cs2CO3 (20.78 g) in 40 mL DMF was allowed to react overnight. The reaction was poured into 125 mL H2O, extracted with ether, and the combined extracts dried over MgSO4. The crude extract was filtered, then reduced in vacuo to yield a clear oil. The residue was chromatographed (50% EtOAc in hexanes) to yield 3-(3-chloropropyl)-5,5-dimethylimidazolidinedione as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:56]1[CH2:61][CH2:60][S:59](=[O:63])(=[O:62])[CH2:58][CH2:57]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:19]([N:56]4[CH2:61][CH2:60][S:59](=[O:63])(=[O:62])[CH2:58][CH2:57]4)=[O:21])=[CH:22][CH:23]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S1(=O)CCNCC1
Reactant: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)N2CCS(=O)(=O)CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (69 mg, 0.2 mmol) in DMF (300 μL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.0 mmol) and thiomorpholine-S,S-dioxide (0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (80 mg, 87%) which was obtained as a white solid. MS: m/e=462.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([C:11]2[C:12]([CH3:18])=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C1C=CC=CN=1)C.[Cl:28][C:29]1[CH:30]=[C:31]([S:36](Cl)(=[O:38])=[O:37])[CH:32]=[CH:33][C:34]=1[Cl:35]>N1C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[C:31]([S:36]([NH:1][C:2]2[C:3]([C:9]([C:11]3[C:12]([CH3:18])=[N:13][CH:14]=[CH:15][C:16]=3[CH3:17])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=2)(=[O:37])=[O:38])[CH:32]=[CH:33][C:34]=1[Cl:35]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Cc1ccnc(C)c1C(=O)c1ncc(Cl)cc1N
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: Cc1ccnc(C)c1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 23.9 %

Procedure:
To a solution of (3-Amino-5-chloro-pyridin-2-yl)-(2,4-dimethyl-pyridin-3-yl)-methanone (43 mg, 0.16 mmol) and 10 mg of dimethylaminopyridine in 1.0 ml of pyridine was added 3,4-dichlorobenzenesulfonylchloride (70 mg, 0.28 mmol). The mixture was stirred at 80° C. for 3 hours, cooled to room temperature and concentrated. The residue was directly purified by flash column (50% ethyl acetate in hexane) or preparative HPLC (20-80% acetonitrile in water) to afford 18 mg of title compound as an off-white solid. MS: (M+H)/z=470.4.