Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:10]([C:14]1[C:19]([OH:20])=[C:18]([CH3:21])[C:17]([CH3:22])=[C:16]([CH2:23]NN(C)C)[CH:15]=1)([CH3:13])([CH3:12])[CH3:11].[CH3:28][O-:29].[Na+].CNC>C1(C)C=CC=CC=1>[C:10]([C:14]1[C:19]([OH:20])=[C:18]([CH3:21])[C:17]([CH3:22])=[C:16]([CH:15]=1)[CH2:23][C:2]([CH2:23][C:16]1[CH:15]=[C:14]([C:10]([CH3:12])([CH3:11])[CH3:13])[C:28]([OH:29])=[C:18]([CH3:19])[C:17]=1[CH3:22])([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1c(CNN(C)C)cc(C(C)(C)C)c(O)c1C
Reactant: C[O-]
Reactant: COC(=O)CC(=O)OC
Agent: CNC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C(Cc1cc(C(C)(C)C)c(O)c(C)c1C)(Cc1cc(C(C)(C)C)c(O)c(C)c1C)C(=O)OC
Temperature: 25 °C

Procedure:
6.6 grams of dimethyl malonate (0.05 moles), 23.5 grams of 6-tert.-butyl-2,3-dimethyl-4-(dimethylaminoaminomethyl)phenol (0.10 moles) and 0.5 grams of sodium methylate were charged to 100 ml of toluene at room temperature and heated at reflux for 41/2 hours, dimethylamine being evolved during this period. The reaction mixture cooled to room temperature was made acid with 3N aqueous hydrochloric, the toluene phase being washed with water, the wash water being separated. The desired product was insoluble in the cooled toluene phase and was isolated as white crystals by filtration. After drying and recrystallization from toluene the product melted at 204° to 207° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][CH:6]=1.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:17]2[C:18]([O:20][C:21](=[O:22])[C:16]=12)=[O:19]>N1C=CC=CC=1>[Cl:1][C:2]1[S:3][C:4]([C:7]([NH:14][C:15]2[C:16]3[C:21](=[O:22])[O:20][C:18](=[O:19])[C:17]=3[CH:23]=[CH:24][CH:25]=2)=[O:9])=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: Nc1cccc2c1C(=O)OC2=O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1cccc2c1C(=O)OC2=O)c1ccc(Cl)s1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To prepare the required acid chloride, 27.77 g of 2-chloro-5-thiophenecarboxylic acid (0.171 mol) are suspended in 50 ml of thionyl chloride (0.685 mol) and stirred at 90° C. for 90 min (after 15 min, a clear solution is formed). The resulting solution is concentrated under reduced pressure, twice subjected to azeotropic distillation with toluene, dissolved in 60 ml of toluene and, over a period of 40 min and at 20° C., added dropwise to a solution of 17.98 g (110.2 mmol) of 3-aminophthalic anhydride in 200 ml of pyridine. The mixture is stirred at RT overnight, the pyridine is evaporated under reduced pressure and the residue is twice stirred with toluene and re-evaporated. 1 l of ethyl acetate and 0.5 l of KH2PO4 buffer (pH=4-5) are added and the mixture is then shaken vigorously and filtered off with suction, and the solids are washed with ethyl acetate, pressed thoroughly dry and dried under reduced pressure over P2O5. The mother liquor is extracted three times with ethyl acetate and evaporated and the residue is stirred with ethyl acetate and filtered off with suction. This gives a total of 19.77 g (58.3% of theory) of the target compound of m.p. 195° C.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:36][C:37]1[C:38](=[O:55])[C:39]([C:49]2[N:53]([CH3:54])[N:52]=[CH:51][CH:50]=2)=[N:40][N:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:42]=1.[N:56]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:59]=[CH:58][C:57]=1[CH2:66][CH2:67]O>C1(C)C=CC=CC=1>[CH3:54][N:53]1[C:49]([C:39]2[C:38](=[O:55])[C:37]([O:36][CH2:67][CH2:66][C:57]3[CH:58]=[CH:59][C:60]4[C:65](=[CH:64][CH:63]=[CH:62][CH:61]=4)[N:56]=3)=[CH:42][N:41]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:40]=2)=[CH:50][CH:51]=[N:52]1
Reactant: Cn1nccc1-c1nn(-c2ccccc2)cc(O)c1=O
Reactant: OCCc1ccc2ccccc2n1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1nccc1-c1nn(-c2ccccc2)cc(OCCc2ccc3ccccc3n2)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.2 %

Procedure:
Toluene (20 mL) was added to di-tert-butyl diazene-1,2-dicarboxylate (345 mg), triphenylphosphine (459 mg) and the mixture was stirred at room temperature for 10 min. Then, 5-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)-1-phenylpyridazin-4(1H)-one (268 mg), and further, 2-quinolin-2-ylethanol (260 mg) were added, and the mixture was stirred at room temperature for 64 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol). A fraction containing the title compound was again purified by NH silica gel column chromatography (hexane/ethyl acetate) and crystallized from hexane/ethyl acetate to give the title compound (297 mg) as white needles.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)[CH:21]=4)=[CH:19][C:14]3=[N:13][CH:12]=2)[CH:10]=1)[C:5]([NH2:7])=[O:6].[CH3:33][C:34](O)=[O:35].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:34]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]5[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)[CH:21]=4)=[CH:19][C:14]3=[N:13][CH:12]=2)[CH:10]=1)[C:5]([NH2:7])=[O:6])(=[O:35])[CH3:33]
Reactant: NC(=O)c1cc(N)cc(-c2cnc3cc(-c4cccc(CN5CCOCC5)c4)ccn23)c1
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(C(N)=O)cc(-c2cnc3cc(-c4cccc(CN5CCOCC5)c4)ccn23)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.5 %

Procedure:
A mixture of 3-Amino-5-[7-(3-morpholin-4-ylmethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-benzamide (90 mg), AcOH (29 μL, 0.5 mmol), 1-hydroxybenzotriazole (68 mg, 0.5 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (96 mg, 0.5 mmol) in dry DMF (2 ml) was stirred at RT under N2 for 24 h. The mixture was partitioned between CH2Cl2/H2O. The layers were separated and the aqueous layer was loaded on to a SCX cartridge. This was washed with MeOH, then 2M NH3-MeOH. The NH3-MeOH fraction was evaporated and the residue was purified by preparative HPLC to give the title compound (40 mg, solid). 1H NMR (400 MHz, DMSO-d6): 10.26 (1H, s), 8.68 (1H, d), 8.12 (1H, s), 8.07 (2H, brs), 7.99 (1H, s), 7.87 (1H, s), 7.83 (1H, s), 7.81-7.72 (2H, m), 7.54-7.43 (2H, m), 7.43-7.34 (2H, m), 3.66-3.54 (6H, m), 2.47-2.36 (4H, m), 2.11 (3H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:29]([O:31][C:32](=[O:34])[CH3:33])[CH3:30]>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14](=[O:16])[CH2:33][C:32]([O:31][CH2:29][CH3:30])=[O:34])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
In a flask, 3-(Benzyloxycarbonylamino)-3-methylbutanoic acid (14.77 g, 58.8 mmol, prepared as described in Low, Eddy; Nair, Satheesh; Shiau, Timothy; Belisle, Barbara; Debabov, Dmitri; Celeri, Chris; Zuck, Meghan; Najafi, Ron; Georgopapadakou, Nafsika; Jain, Rakesh Bioorganic and Medicinal Chemistry Letters, 2009, 19, 196-198) was dissolved in tetrahydrofuran (200 ml). N,N-dicarbonyldiimidazole (9.54 g, 58.8 mmol) was added to the mixture, and the combined reaction mixture was stirred for about 1 hour at room temperature. In a second flask, lithium bis(trimethylsilyl)amide (1.0 M in tetrahydronfuran, 117 ml, 117 mmol) was cooled to −78° C., and ethylacetate was slowly added. The second flask was stirred for 20 minutes and then added to the first flask, which was also cooled to −78° C. The combined mixture was stirred at −78° C., for 2 hours. The reaction mixture was quenched with saturated, aqueous NaHCO3 solution, and the mixture was extracted with ethylacetate. The ethylacetate layer was concentrated, and purified by column chromatography (0 to 20% ethylacetate in hexanes) to give 10.08 g (53%) of the title compound.
Reaction SMILES: [ClH:1].Cl.[CH3:3][NH:4][C:5]1([CH2:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:7][CH2:6]1.O.[OH-].[Na+].[C:19](=O)([O-])[O-].[Na+].[Na+]>CCOCC.O1CCOCC1>[ClH:1].[CH3:3][N:4]([CH3:19])[C:5]1([CH2:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:7][CH2:6]1
Reactant: O=C([O-])[O-]
Reactant: CNC1(CCc2cccnc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN(C)C1(CCc2cccnc2)CC1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
1.5 g of the compound of Example 30 are dissolved in 10% aqueous sodium carbonate solution; the mixture is then extracted with ether, dried over sodium sulphate and concentrated to dryness. 1.17 ml of formol and 1.43 g of formic acid at 5° C. are then added to the residue obtained, followed by 0.15 ml of water. The mixture is heated at reflux for 5 hours, cooled to 50° C. and then made alkaline by the addition of 4N sodium hydroxide solution. Extraction with ether, followed by evaporation of the aqueous phase allows a residue to be obtained which is taken up in a mixture of 20 ml of ether and 3 ml of dioxane/4N hydrochloric acid. The mixture obtained is diluted with 50 ml of ether and stirred for 20 hours, and is then filtered and dried, allowing the expected product to be isolated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:11][CH:12]2[CH2:16][CH2:15][O:14][CH2:13]2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]([F:22])([F:21])[F:20].C(N(CC)CC)C.[Cl:30][CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33]>CN(C)C=O>[ClH:30].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:11][CH:12]2[CH2:16][CH2:15][O:14][CH2:13]2)[CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33])=[CH:4][C:3]=1[O:17][CH2:18][C:19]([F:20])([F:21])[F:22]
Reactant: Fc1ccc(CCNCC2CCOC2)cc1OCC(F)(F)F
Reactant: CN(C)C(=O)CCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN(CCc1ccc(F)c(OCC(F)(F)F)c1)CC1CCOC1
Product: Cl
Yield: 64.3 %

Procedure:
A mixture of 85 mg (0.26 mmol) of [2-[4-fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl]-(tetrahydrofuran-3-ylmethyl)amine, 0.06 ml of triethylamine and 48 mg (0.39 mmol) of 2-chloro-N,N-dimethyl-acetamide in 3 ml of dimethylformamide was heated for 1 hour to 120° C. with microwaves. The solvent was removed under vacuum. The crude product was purified by flash chromatography (dichloromethane/methanol/NH3 100:3:0.3 v:v:v). The product was dissolved in anhydrous hydrochloric acid in ethyl acetate, the solvent was removed under reduced pressure and the product was triturated with diethyl ether. 74 mg (65% yield) of the title compound were isolated as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][N:13]=[C:12]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[C:31]([OH:32])=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][NH:27]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][N:13]=[C:12]2[O:32][C:31]1[C:23]([F:22])=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[CH:25]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2[nH]ccc2c1F
Reactant: COc1cc2ncnc(Cl)c2cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3ccc4[nH]ccc4c3F)c2cc1OCc1ccccc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
A mixture of 6-benzyloxy-4-chloro-7-methoxyquinazoline (0.88 g, 2.9 mmol), (EP1153920 production examples 28-30), 4-fluoro-5-hydroxyindole (0.53 g, 3.5 mmol) and potassium carbonate (0.607 g, 4.39 mmol) in DMF (18 ml) was stirred at 95° C. for 2 hours. After cooling, the mixture was filtered and the volatiles were removed under vacuum. The residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride and ethyl acetate to give 6-benzyloxy-4-(4-fluoroindol-5-yloxy)-7-methoxyquinazoline (0.8 g, 67%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@@H:5]([C:7]([O:9]CC)=O)[CH2:4][CH2:3]1.[BH4-].[Na+].Cl.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>O1CCCC1.CO>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:9][CH2:7][C@H:5]2[CH2:4][CH2:3][C:2](=[O:1])[NH:6]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: CCOC(=O)[C@H]1CCC(=O)N1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCC(=O)N2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.4 %

Procedure:
To a mixture of (R)-ethyl 5-oxopyrrolidin-2-carboxylate (Aldrich, 3 g, 19 mmol) and sodium borohydride (1.89 g, 50 mmol) in tetrahydrofuran (30 mL) at 50° C. was added dropwise for 30 min methanol (10 mL). The reaction was then continued for an additional 15 min and cooled to room temperature. The mixture was treated with 1N HCl to pH=3 and concentrated under reduced pressure. The residue was triturated with anhydrous methanol and the solid was filtered off and washed with methanol. The filtrate and washings were combined and concentrated under reduced pressure. The concentrate was then triturated with anhydrous tetrahydrofuran and filtered. The filtrate was concentrated under reduced pressure and the concentrate was dissolved in anhydrous CH2Cl2 (20 mL). p-Toluenesulfonyl chloride (3.64 g, 19 mmol) was added, the mixture was cooled to 0° C. and triethylamine (2.66 mL, 19 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The mixture was then washed with water, brine, dried with anhydrous MgSO4 and concentrated under reduced pressure. The residue was chromatographed (SiO2, ethyl acetate-ethanol 9:1) to afford 3.5 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 1.62 (m 1H), 2.06 (m, 3H), 2.42 (s, 3H), 3.71 (m, 1H), 3.87 (dd, J=10 Hz, 4 Hz, 1H), 3.97 (dd, J=10 Hz, 4 Hz, 1H), 7.49 (d, J=9 Hz, 2H), 7.75 (broad s, 1H), 7.82 (d, J=9 Hz, 2H); MS (DCI/NH3) m/z 270 (M+H)+, 287 (M+NH4)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.ClC(OCC)=O.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40]([NH:42][C:43]2[CH:47]=[C:46]([C:48]([CH3:51])([CH3:50])[CH3:49])[O:45][N:44]=2)=[O:41])=[CH:35][CH:34]=1>C(Cl)Cl>[C:48]([C:46]1[O:45][N:44]=[C:43]([NH:42][C:40](=[O:41])[NH:39][C:36]2[CH:35]=[CH:34][C:33]([NH:32][C:14](=[O:16])[C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:13][N:12]=3)=[CH:38][CH:37]=2)[CH:47]=1)([CH3:51])([CH3:49])[CH3:50]
Reactant: CN1CCN(c2ccc(C(=O)O)nc2)CC1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(N)cc2)no1
Agent: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.6 %

Procedure:
To a stirred solution of 5-(4-methylpiperazin-1-yl)picolinic acid (185 mg, 0.46 mmol) in 5 mL of DCM was added DIEA (82 μL, 0.46 mmol) and ethyl chloroformate (45 μL, 0.46 mmol). The resulting mixture was stirred at rt for 15 min, sonicated for 10 min. 1-(4-Aminophenyl)-3-(5-tert-butylisoxazol-3-yl)urea (128 mg, 0.46 mmol) was added. The resulting mixture was refluxed for 30 min. LC-MS indicated the reaction mostly done. Solvent was then removed under reduced pressure and residue was purified on reverse phase HPLC to give N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-5-(4-methylpiperazin-1-yl)picolinamide (65 mg, 29%) as a white foamy solid. LC-MS (ESI) m/z 478 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.48 (s, 1H), 8.79 (s, 1H), 8.36 (d, J=2.45 Hz, 1H), 7.96 (d, J=8.85 Hz, 1H), 7.80 (d, J=8.85 Hz, 2H), 7.47 (dd, J=2.64, 8.85 Hz, 1H), 7.41 (d, J=9.04 Hz, 2H), 6.50 (s, 1H), 3.35 (br. s., 8H), 2.26 (s, 3H), 1.30 (s, 9H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:71]1[CH2:76][CH2:75][CH:74]([N:77]2[CH2:82][CH2:81][O:80][CH2:79][CH2:78]2)[CH2:73][CH2:72]1>CN1C(=O)CCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:10]=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:27][C:28]4[CH:29]=[CH:30][C:31]([C:32]([N:71]5[CH2:76][CH2:75][CH:74]([N:77]6[CH2:82][CH2:81][O:80][CH2:79][CH2:78]6)[CH2:73][CH2:72]5)=[O:34])=[CH:35][CH:36]=4)=[O:37])=[CH:23][CH:24]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: C1CC(N2CCOCC2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(C(=O)N2CCC(N3CCOCC3)CC2)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 61.6 %

Procedure:
To the stirred solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 1 mL of NMP was reacted according to example 68 with 4-(piperidin-4-yl)morpholine (67 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (40.1 mg, 62% yield); MS (ESI) m/z=658.7
Reaction SMILES: O[C:2]1([CH3:14])[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=2[O:5][CH2:4][CH2:3]1.P(Cl)(Cl)(Cl)=O.O>N1C=CC=CC=1>[CH3:13][O:12][C:10]1[CH:9]=[CH:8][C:7]2[C:2]([CH3:14])=[CH:3][CH2:4][O:5][C:6]=2[CH:11]=1
Reactant: COc1ccc2c(c1)OCCC2(C)O
Solvent: O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)OCC=C2C

Procedure:
The carbinol of step (a) (73.3 g) was stirred with phosphorus oxychloride (19.3 g; 11.6 ml) in dry pyridine (380 ml) for 20 hours under nitrogen. The reaction mixture was poured into water, extracted with ether and the ethereal extracts were washed with dilute acid, then sodium bicarbonate solution, then water and dried. Evaporation of the solvent left 58 g of residue (87.2%). MS evidence was correct for the required compound. NMR suggested that the product was in fact a mixture of isomeric alkenes.
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.C(N(CC)CC)C.[NH2:20][C:21]1[CH:48]=[CH:47][C:24]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][C:34]3[CH:35]=[C:36]([CH:44]=[CH:45][CH:46]=3)[C:37]([NH:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:29][CH2:28]2)=[O:26])=[C:23]([Cl:49])[C:22]=1[F:50].[CH:51]1([CH2:54][NH2:55])[CH2:53][CH2:52]1>ClCCl>[C:40]([NH:39][C:37](=[O:38])[C:36]1[CH:44]=[CH:45][CH:46]=[C:34]([CH2:33][N:30]2[CH2:29][CH2:28][N:27]([C:25](=[O:26])[C:24]3[CH:47]=[CH:48][C:21]([NH:20][C:1]([NH:55][CH2:54][CH:51]4[CH2:53][CH2:52]4)=[O:12])=[C:22]([F:50])[C:23]=3[Cl:49])[CH2:32][CH2:31]2)[CH:35]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCC1CC1
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3Cl)CC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)NCC4CC4)c(F)c3Cl)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 193.5 %

Procedure:
To a stirred solution of bis(trichloromethyl) carbonate (0.076 mmol, 22.60 mg) in dichloromethane (3 mL) was added triethylamine (40 mL) and 3-((4-(4-amino-2-chloro-3-fluorobenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (0.206 mmol, 92 mg) in dichloromethane (3 mL). The reaction mixture was heated to reflux for 2 hours. After this time the reaction was allowed to cool to room temperature and cyclopropylmethylamine (35 μl, 0.412 mmol) and triethylamine (35 μl) were added. After 30 minutes stirring, the volatiles were removed under reduced pressure and the crude residue was purified by silica chromatography (eluting with 5% methanol in dichloromethane) to yield the title compound (80 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8][CH:9]([CH3:13])CNC)[CH:5]=[N:6][CH:7]=1.O=[C:15](O)[C@@H]([C@H]([C@H]([C@@H](C(O)=O)O)O)O)O.[OH2:28].O=C(O)[C@@H]([C@H]([C@H]([C@@H](C(O)=O)O)O)O)O.BrC1C=C(SC(C)CNC)C=NC=1.BrC1C=C(SC(C)CNC)C=NC=1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH:13]([OH:28])[CH3:15])[CH:5]=[N:6][CH:7]=1
Reactant: O
Reactant: CNCC(C)Sc1cncc(Br)c1
Reactant: O=C(O)[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CCO
Product: CC(O)CSc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A hot solution of the mixture of (2-(5-bromo(3-pyridylthio))isopropyl)methylamine and (2-(5-bromo(3-pyridylthio))propyl)methylamine (1.01 g, 3.867 mmol) in ethanol (15 mL) was treated in one portion with galactaric acid (0.406 g, 1.937 mmol). Water (3 mL) was added drop-wise, while warming the solution to reflux. To remove some white, insoluble solids, the warm solution was filtered through a glass wool plug, washing the filter plug with a warm solution of ethanol-water (4:1, v/v) (5 mL). The filtrate was diluted with ethanol (22.5 mL). The mixture was allowed to cool to ambient temperature and was allowed to stand for 16 h. The resulting solids were filtered, washed with ethanol (2×5 mL), and vacuum dried at 45° C. to give 0.512 g (36.1%) of light-beige, crystalline flakes, mp 146.5-149.5° C. Analysis indicated a 57:41 mixture of (2-(5-bromo(3-pyridylthio))-isopropyl)methylamine hemigalactarate and (2-(5-bromo(3-pyridylthio))propyl)methylamine hemigalactarate. The compound exhibits a Ki of 5500 nM.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:2]1.[C:15]([O-])([O-])=O.[K+].[K+].IC.O>CC#N>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:2]1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: [K+]
Solvent: CI
Solvent: CC#N
Solvent: O
Product: COC(=O)CCc1c[nH]c2ccccc12
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a stirring solution of 3-(1H-indol-3-yl)propanoic acid (0.3 g) in MeCN (9 mL) was added K2CO3 (0.33 g) at ambient temperature followed by addition of iodomethane (0.15 mL). After 3 hours, water was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified by column chromatography (n-hexane:EtOAc=3:1) to give methyl 3-(1H-indol-3-yl)propanoate (0.32 g).