Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[C:20]1([C:26]#[CH:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:20]1([C:26]#[C:27][C:2]2[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C#Cc1ccccc1
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: O[C@H](CCc1cccnc1)COc1ccc(C#Cc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 3.6 %

Procedure:
Copper (I) iodide (0.03 g) was added to a mixture of (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (1.05 g, Example 40a), phenylacetylene (0.33 g) and bis(triphenylphosphine)palladium(II) chloride (0.23 g) in triethylamine (10 ml), and the reaction mixture heated to 90° C. with stirring under nitrogen for 4 hours. The reaction mixture was allowed to cool to room temperature and then poured into water (150 ml). The product was extracted with ethyl acetate which was washed with brine and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure and the residue purified by column chromatography over silica eluting with dichloromethane:methanol (19:1) to give the title compound as a white solid (0.040 g).
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9]3[CH2:24][CH2:23][N:22]([C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)[N:13]=2)[CH2:6][CH2:5][O:4][CH2:3]1.[O:31]1[CH2:36]COCC1.C(N(CC)CC)C.C(Cl)(Cl)=O.[F:48][CH:49]([F:52])[CH2:50][NH2:51]>C1(C)C=CC=CC=1>[F:48][CH:49]([F:52])[CH2:50][NH:51][C:36]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([C:12]2[N:13]=[C:8]([N:7]3[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]3[CH3:1])[C:9]3[CH2:24][CH2:23][N:22]([C:25]4[N:26]=[CH:27][CH:28]=[CH:29][N:30]=4)[CH2:21][C:10]=3[N:11]=2)=[CH:15][CH:16]=1)=[O:31]
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2)nc2c1CCN(c1ncccn1)C2
Reactant: NCC(F)F
Reactant: C1COCCO1
Agent: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCC(F)F)cc2)nc2c1CCN(c1ncccn1)C2
Temperature: 50 °C
Reaction time: 72 h

Procedure:
(S)-4-(4-(3-methylmorpholino)-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)aniline (0.0501 g, 0.000124 mol) in dry 1,4-Dioxane (2.00 mL, 0.0256 mol) was added Triethylamine (0.0190 mL, 0.000136 mol) followed by 20% Phosgene in toluene (1:4, Phosgene:Toluene, 0.080 mL). The reaction mixture was heated at 50° C. for 1 hour. The reaction mixture was cooled to room temperature and then added 2,2-difluoroethylamine (0.0604 mL, 0.000876 mol). The reaction mixture was stirred for 3 days. The reaction mixture was concentrated and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.44 (d, J=4.7, 2H), 8.23 (d, J=8.8, 2H), 7.51 (d, J=8.8, 2H), 6.69 (t, J=4.7, 1H), 6.57 (t, J=6.0, 1H), 6.07 (tt, J=56.1, 3.8, 1H), 4.90 (d, J=18.7, 1H), 4.73 (d, J=18.7, 1H), 4.18-4.04 (m, 3H), 3.91-3.78 (m, 2H), 3.70 (dd, J=11.3, 2.5, 1H), 3.65-3.48 (m, 5H), 3.41 (dd, J=17.7, 8.1, 1H), 3.17 (d, J=3.4, 2H), 2.74 (s, 2H), 1.25 (d, J=6.6, 3H). LC/MS-m/z+511.2 (M+H)+
Reaction SMILES: [CH:1]#[C:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[C:10]([O:13][CH:14]([CH3:18])[CH2:15]OC)(=[O:12])[CH3:11]>>[CH:3]1([CH2:2][CH2:1][O:12][CH:10]([O:13][C:14]2[CH:15]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:18]=2)[CH3:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[OH:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1
Reactant: C#Cc1ccc(O)cc1
Reactant: COCC(C)OC(C)=O
Product: C=Cc1ccc(O)cc1
Product: C=Cc1ccc(OC(C)OCCC2CCCCC2)cc1
Temperature: 20 °C
Reaction time: 5 h
Yield: 69.3 %

Procedure:
In 320 g of propylene glycol monomethyl ether acetate (PGMEA) was dissolved 70 g of poly(p-hydroxystyrene) (VP-8000, manufactured by Nippon Soda Co., Ltd.) with heating and the solution was subjected to dehydration by distillation under a reduce pressure and cooled to 20° C. To the solution were added 0.35 g of pyridinium p-toluenesulfonate and 22.4 g of 2-cyclohexylethanol. Then, 17.5 g of tert-butyl vinyl ether was gradually added to the solution, followed by reacting at 20° C. for 5 hours. To the reaction mixture were added 0.28 g of triethylamine and 320 ml of ethyl acetate and the mixture was washed three times with each 150 ml of distilled water. The solvent was distilled off to concentrate, the resulting oily substance was dissolved in 100 ml of acetone and the solution was gradually poured into 2 liters of distilled water. The powder thus-deposited was collected by filtration and dried to obtain 54 g of the desired compound. The Mw of the resin was 12,000 and the molecular weight distribution (Mw/Mn) thereof was 1.1.
Reaction SMILES: [CH2:1]([O:4][NH:5][C@@H:6]1[CH:11]=[C:10]([CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH:9]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[NH:8][CH2:7]1)[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.Cl[C:41](Cl)([O:43]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:4][N:5]1[C:41](=[O:43])[N:8]2[CH2:7][C@H:6]1[CH:11]=[C:10]([CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:19])[CH3:20])([CH3:16])[CH3:17])[C@H:9]2[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[CH:2]=[CH2:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCON[C@@H]1C=C(CCO[Si](C)(C)C(C)(C)C)C(CO[Si](C)(C)C(C)(C)C)NC1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCON1C(=O)N2C[C@H]1C=C(CCO[Si](C)(C)C(C)(C)C)[C@H]2CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 260 %

Procedure:
To a solution of O-allyl-N-((3R)-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3,6-tetrahydropyridin-3-yl)hydroxylamine (Intermediate 284, 3.95 g, 8.65 mmol) and diisopropylethyl amine (6.02 mL, 34.58 mmol) in acetonitrile (600 mL) at 0° C. was added triphosgene (0.871 g, 2.94 mmol) as a solution in acetonitrile (26 mL). The triphosgene solution was added at a rate of 4 mL/hour. Once addition was complete the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and 1:1 brine:water. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-30% ethyl acetate/hexanes) afforded the title compound as a yellow oil (3.69 g, 88%). This reaction was run in two separate 1 L flasks due to the large volume and combined for work up and purification.
Reaction SMILES: N[C@@H]1C(=O)N2C(C(OCC3C=CC=CC=3)=O)=C(OS(C(F)(F)F)(=O)=O)CC[C@H]12.C(N(CC)CC)C.C1(C([NH:55][C:56]2[S:57][CH:58]=[C:59]([C:61](=[N:92][O:93][CH3:94])[C:62]([NH:64][C@@H:65]3[C:90](=[O:91])[N:67]4[C:68]([C:80]([O:82]CC5C=CC=CC=5)=[O:81])=[C:69]([O:72][S:73]([C:76]([F:79])([F:78])[F:77])(=[O:75])=[O:74])[CH2:70][CH2:71][C@H:66]34)=[O:63])[N:60]=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)=O>C(#N)C>[NH2:55][C:56]1[S:57][CH:58]=[C:59]([C:61](=[N:92][O:93][CH3:94])[C:62]([NH:64][C@@H:65]2[C:90](=[O:91])[N:67]3[C:68]([C:80]([OH:82])=[O:81])=[C:69]([O:72][S:73]([C:76]([F:78])([F:77])[F:79])(=[O:74])=[O:75])[CH2:70][CH2:71][C@H:66]23)=[O:63])[N:60]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccccc3)=C(OS(=O)(=O)C(F)(F)F)CC[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: N[C@@H]1C(=O)N2C(C(=O)OCc3ccccc3)=C(OS(=O)(=O)C(F)(F)F)CC[C@H]12
Solvent: O=CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(OS(=O)(=O)C(F)(F)F)CC[C@H]12)c1csc(N)n1

Procedure:
syn-2-(2-Triphenylmethylthiazol-4-yl)-2-methoxyiminoacetyl chloride is reacted in acetonitrile with benzyl 7β-amino-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylate in the presence of triethylamine and the acylation product, benzyl 7β-[2-(2-triphenylmethylaminothiazol-4-yl)-2-methoxyiminoacetylamino]-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylate is treated with formic acid to remove the triphenylmethyl group and with aluminum chloride in anisole to remove the benzyl ester group to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([C:8](=[C:14]([C:16](=[O:52])[N:17]([CH:27]([CH3:51])[CH:28]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:29][C:30]1[O:31][C:32]([C:35](=[O:43])[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:33][CH:34]=1)[CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:15])[CH2:9][C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>O1CCCC1.O>[C:1]([O:5][C:6]([C:8](=[C:14]([C:16](=[O:52])[N:17]([CH:27]([CH3:51])[CH:28]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:29][C:30]1[O:31][C:32]([C:35](=[O:43])[NH:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:33][CH:34]=1)[CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:15])[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CC(C(=O)OC(C)(C)C)=C(O)C(=O)N(C/C=C/c1ccccc1)C(C)C(Cc1ccc(C(=O)Nc2ccccc2)o1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(Cc1ccc(C(=O)Nc2ccccc2)o1)C(=O)OC(C)(C)C)N(C/C=C/c1ccccc1)C(=O)C(O)=C(CC(=O)O)C(=O)OC(C)(C)C
Yield: 66 %

Procedure:
68 mg of methyl 3-(tert-butoxycarbonyl)-4-[N-[(1RS,2RS)-2-(tert-butoxycarbonyl)-1-methyl-3-{5-(phenylcarbamoyl)-2-furyl}propyl]-N-{(E)-3-phenyl-2-propenyl}carbamoyl]-4-hydroxy-3-butenoate was dissolved in a mixture of 3 ml of tetrahydrofuran and 1 ml of water and stirred together with 1 ml of 1N aqueous sodium hydroxide at room temperature for 40 hours. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [chloroform/methanol=20/1→10/1] to give 44 mg (yield: 66%) of the title compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH:9]([OH:11])[CH3:10].[Cl:12][CH2:13][C:14](Cl)=[O:15]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:14](=[O:15])[CH2:13][Cl:12])=[C:3]([CH:9]([OH:11])[CH3:10])[CH:4]=1
Reactant: O=C(Cl)CCl
Reactant: CC(O)c1cc(Br)ccc1N
Product: CC(O)c1cc(Br)ccc1NC(=O)CCl

Procedure:
Prepared by from 1-(2-amino-5-bromo-phenyl)-ethanol and chloroacetyl chloride generally according to the procedure described in Example 1. 1H-NMR (DMSO-d6) δ 10.11 (s, 1H), 7.64 (d, J=8.63 Hz, 1H), 7.57 (d, J=2.31 Hz, 1H), 7.44 (dd, J=2.34, 8.57 Hz, 1H), 5.77 (d, J=3.88 Hz, 1H), 4.93-4.89 (m, 1H), 4.35, (s, 2H), 1.31 (d, J=6.45 Hz, 3H); MS (ES) m/z 290/292/294 ([M−H]−, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[H-].[Na+].[H][H].F[C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([CH3:25])[N:16]=1>CS(C)=O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH:4][C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:18]=[C:17]([CH3:25])[N:16]=1
Reactant: Nc1c(Cl)cccc1Cl
Reactant: [H][H]
Reactant: Cc1cc(C(F)(F)F)cc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C(F)(F)F)cc(Nc2c(Cl)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.8 %

Procedure:
4.0 g (0.025 mol) of 2,6-dichloroaniline in 20 ml of dimethyl sulfoxide are added dropwise at 15°-20° C. to 1.2 g (0.05 mol) of sodium hydride in 20 ml of dimethyl sulfoxide. After hydrogen has ceased to evolve, 4.5 g (0.025 mol) of 2-fluoro-4-trifluoromethyl-6-methylpyridine in 10 ml of dimethyl sulfoxide are added dropwise, whereupon the temperature rises to 30° C. The reaction mixture is stirred for 2 hours at room temperature and then ice-water is added. After extraction with diethyl ether, the ether phase is dried over sodium sulfate and concentrated by evaporation. The residue is chromatographed over silica gel with ethyl acetate/hexane (1:3), affording 4.4 g (54.8%) of the title compound of formula ##STR28## in the form of crystals which melt at 108° C. (compound 2.033).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([Cl:16])[C:5]([NH:8][NH:9]C(=O)C(F)(F)F)=[N:6][CH:7]=1.Cl.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>O>[Br:1][C:2]1[N:3]=[C:4]([Cl:16])[C:5]([NH:8][NH2:9])=[N:6][CH:7]=1
Reactant: O=C(NNc1ncc(Br)nc1Cl)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NNc1ncc(Br)nc1Cl
Temperature: 80 °C
Yield: 59 %

Procedure:
A 250 mL round bottom flask was charged with N′-(5-bromo-3-chloropyrazin-2-yl)-2,2,2-trifluoroacetohydrazide (2.97 g, 9.4 mmol), concentrated HCl (6 mL) and ethanol (60 mL). The resulting mixture was heated at 80° C. for 4 h. The reaction mixture was then allowed to cool to room temperature and neutralized with Na2CO3. It was then diluted with water and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 20% EtOAc in petroleum ether, to afford 1.24 g (59%) of the product as a yellow solid.
Reaction SMILES: [NH2:1][PH:2](=[O:4])[OH:3].BrCC(O[CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=O>CC(=O)CC>[NH2:1][PH:2](=[O:3])[O:4][CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: N[PH](=O)O
Reactant: CC(C)(C)CCOC(=O)CBr
Solvent: CCC(C)=O
Product: CC(C)(C)CCO[PH](N)=O

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene (2.15 g), α-amino-(n-propyl)methylphosphinic acid (1.63 g), K2CO3 (1.64 g) and DMSO (10 ml) is stirred at RT for one week and then poured into water and extracted with ether. The aqueous solution is acidified with dilute HCl and extracted with ether. The combined extracts are dried and evaporated to dryness to give the aminophosphinic acid (XVI; R is NO2, R1 is Me, R2 is H, R6 is Et, R5 is H, Y is Cl, Z is CF3). The aminophosphinic acid is reacted with neohexyl bromoacetate in 2-butanone under reflux to give neohexyl aminophosphinate (Compound 1, Table H).
Reaction SMILES: C([O:8]C([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](C(CO)CCO)[CH:18]=2)[NH:13][C:12]=1C)=O)C1C=CC=CC=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].CCCCCC.C(OCC)(=[O:47])C>C1COCC1>[S:35]([OH:37])(=[O:47])(=[O:36])[CH3:34].[S:35]([OH:37])(=[O:8])(=[O:36])[CH3:34].[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12]1
Reactant: CCOC(C)=O
Reactant: CS(=O)(=O)Cl
Reactant: Cc1[nH]c2ccc(C(CO)CCO)cc2c1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CS(=O)(=O)O
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5-(3-Hydroxy-1-hydroxymethyl-propyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.180 g, 0.547 mmol, 1 eq) was suspended in dry THF (5 mL) under Ar. Triethylamine (0.307 mL, 2.2 mmol, 4 eq) was added followed by the addition of methanesulfonyl chloride (0.088 mL, 0.1.09 mmol, 2.0 eq). The reaction mixture was stirred at room temperature. The reaction was followed by TLC (CH2Cl2/MeOH 9/1). After 4 hours, the reaction was quenched with brine and extracted with ethyl acetate (3×). The combined organic extracts were washed with brine and dried over Na2SO4. After removing the solvent, the crude residue was collected. 0.272 g of the indole-bis-mesylate was obtained as a colorless oil. This was carried on crude to the next step.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].Br.[NH2:50][C:51]1[S:52][C:53]([Br:56])=[CH:54][N:55]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Br:56][C:53]1[S:52][C:51]([NH:50][C:40](=[O:42])[C@@H:39]([C:31]2[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([Cl:28])[CH:30]=2)[CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[N:55][CH:54]=1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1ncc(Br)s1
Agent: Br
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(Br)s2)cc1Cl
Temperature: 0 °C
Yield: 50.5 %

Procedure:
A solution of triphenylphosphine (595 mg, 2.27 mmol) in methylene chloride (20 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (457 mg, 2.57 mmol). The reaction mixture was stirred at 0° C. until it became homogeneous. The resulting light purple reaction mixture was then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (500 mg, 1.51 mmol). The reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-amino-5-bromothiazole monohydrobromide (589 mg, 2.27 mmol) and pyridine (0.37 mL, 4.53 mmol), and then the reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 55/45 hexanes/ethyl acetate) afforded N-(5-bromo-thiazol-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (375 mg, 51%) as a light green foam: [α]23589=−110.3° (c=0.068, chloroform); EI-HRMS m/e calcd for C18H20ClBrN2O3S2 (M+) 489.9787, found 489.9792.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[CH2:13]([Mg]Cl)[CH2:14][CH3:15]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:11])[CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CCC[Mg]Cl
Product: CCCC(O)c1ccc(C(=O)OC)cc1

Procedure:
This compound is made from 4-formyl-benzoic acid methyl ester and n-propylmagnesium chloride following the general method exemplified in Preparation 1.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]1.Cl>C(O)CCC.O1CCOCC1>[C:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1nc(-c2ccccc2)c2ccccc2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCO
Product: c1ccc(-c2nc(NC3CCNCC3)nc3ccccc23)cc1
Yield: 117.1 %

Procedure:
A solution of 2-chloro-4-phenylquinazoline (1.38 g, 5.75 mmol), and tert-butyl 4-aminopiperidine-1-carboxylate (2.81 g, 14.1 mmol) was heated at reflux in n-butanol (20 mL) for 4 h. After removal of the n-butanol on a rotary evaporator, dichloromethane (100 mL) was added and the suspension was sonicated for 30 min and filtered. The solution was then concentrated on a rotary evaporator to give a brown residue. This residue was purified by column chromatography on silica gel (95:5 hexanes/ethyl acetate) to yield a green oil that was treated with 4M HCl in 1,4-dioxane (100 mL) at 100° C. for 1 h. The solvent was removed on a rotary evaporator to give 4-phenyl-N-(piperidine-4-yl)quinazolin-2-amine (2.05 g, 90%) as a dark yellow solid.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1.[CH:31]1([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH2:33][CH2:32]1>>[CH:31]1([C:34]2[CH:40]=[CH:39][C:37]([N:38]3[CH2:13][CH2:12][C:6]4([CH2:7][CH2:8][N:9]([S:23]([C:20]5[CH:21]=[CH:22][C:17]([F:16])=[CH:18][C:19]=5[C:27]([F:30])([F:29])[F:28])(=[O:25])=[O:24])[CH2:10][CH2:11]4)[C:4]3=[O:5])=[CH:36][CH:35]=2)[CH2:33][CH2:32]1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: Nc1ccc(C2CC2)cc1
Product: O=C1N(c2ccc(C3CC3)cc2)CCC12CCN(S(=O)(=O)c1ccc(F)cc1C(F)(F)F)CC2

Procedure:
Light brown solid. MS (ESI): 497.15 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 4-fluoro-2-trifluoromethyl-benzenesulfonyl chloride and 4-cyclopropyl-aniline.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([NH:19][C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:18]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[CH:18]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: COc1ccc(C(=O)Nc2cc(N)ccc2C)cc1OC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccc(CCl)cc3)ccc2C)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
4-(Chloromethyl)benzoyl chloride (0.73 g) was added dropwise to a stirred mixture of N-(5-amino-2-methylphenyl)-3,4-dimethoxybenzamide (1 g), triethylamine (0.98 ml) and methylene chloride (80 ml) and the mixture was stirred at ambient temperature for 16 hours. A 1N hydrochloric acid solution (10 ml) was added and the resultant solution was stirred at ambient temperature for 1 hour. The resultant white solid was filtered off, washed with water and with diethyl ether, dried under vacuum at 40° C. to give the title compound (1.35 g); NMR Spectrum: (DMSOd6) 2.18 (s, 3H), 3.82 (s, 6H), 4.82 (s, 2H), 7.06 (d, 1H), 7.21 (d, 1H), 7.58 (m, 5H), 7.81 (s, 1H), 7.94 (d, 2H), 9.76 (s, 1H), 10.23 (s, 1H); Mass Spectrum: M+H+ 439.
Reaction SMILES: [CH3:1][N:2]([CH3:46])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:45])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:29]=[C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[C:27]4[C:22](=[CH:23][C:24]([C:36]5[O:40][C:39]([C:41]([O:43]C)=[O:42])=[CH:38][CH:37]=5)=[CH:25][CH:26]=4)[N:21]=3)=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)=[O:4].O.[OH-].[Li+]>CO.C1COCC1.O>[CH3:1][N:2]([CH3:46])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:45])[NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[N:29]=[C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[C:27]4[C:22](=[CH:23][C:24]([C:36]5[O:40][C:39]([C:41]([OH:43])=[O:42])=[CH:38][CH:37]=5)=[CH:25][CH:26]=4)[N:21]=3)=[CH:18][CH:19]=2)=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2ccc3c(N4CCOCC4)nc(-c4ccc(NC(=O)Nc5ccc(C(=O)N(C)C)cc5)cc4)nc3c2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)c4ccc(-c5ccc(C(=O)O)o5)cc4n3)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.8 %

Procedure:
To a 100 mL round bottom flask, methyl 5-(2-(4-(3-(4-(dimethylcarbamoyl)phenyl)ureido)phenyl)-4-morpholino-quinazolin-7-yl)furan-2-carboxylate (0.1 g, 0.00016 mol) in MeOH (2 mL), THF (2 mL) and water (2 mL) was added. Subsequently, lithium hydroxide monohydrate (0.034 g, 0.0008 mol) was added and stirred at 25° C. for 12 h. The volatiles were evaporated under reduced pressure, the residue redissolved in water and acidified with 2 N HCl to obtain a pH of 5.0. The volatiles were evaporated under reduced pressure and the residue was stirred with water and filtered. The obtained solid was washed with MeOH to yield the title compound [0.06 g, 61%]. 1H NMR (300 MHz, DMSO-d6): δ 12.12 (s, 1H), 8.57 (s, 1H), 8.54 (s, 1H), 8.25 (s, 1H), 8.05 (d, J=9.0 Hz, 2H), 7.97 (d, J=7.5 Hz, 2H), 7.87 (d, J=8.4 Hz, 1H), 7.79 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.28 (s, 2H), 7.04 (s, 1H), 3.85 (s, 8H), 2.98 (s, 6H). LC-MS (ESI): Calculated mass: 606.2; Observed mass: 607.2 (RT: 0.63 min).