Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][C:14]([CH2:16][CH2:17][C@H:18]([NH:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([N:35](C(OCC2C=CC=CC=2)=O)[CH3:36])=[CH:31][CH:30]=1)=[O:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:15].[N:47]1([NH:53][C:54]([NH:56][C:57]2[C:62]3[C:63](=[O:80])[C:64]4[C:65](=[N:66][NH:67][C:68]=4[C:69]4[CH:79]=[CH:78][C:72]([O:73][CH2:74][C:75](O)=[O:76])=[CH:71][CH:70]=4)[C:61]=3[CH:60]=[CH:59][CH:58]=2)=[O:55])[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:36][NH:35][C:32]1[CH:31]=[CH:30][C:29]([C:27]([NH:26][C@@H:18]([CH2:17][CH2:16][C:14](=[O:15])[NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:75](=[O:76])[CH2:74][O:73][C:72]2[CH:71]=[CH:70][C:69]([C:68]3[NH:67][N:66]=[C:65]4[C:61]5[CH:60]=[CH:59][CH:58]=[C:57]([NH:56][C:54](=[O:55])[NH:53][N:47]6[CH2:48][CH2:49][O:50][CH2:51][CH2:52]6)[C:62]=5[C:63](=[O:80])[C:64]=34)=[CH:79][CH:78]=2)[C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])=[O:28])=[CH:34][CH:33]=1
Reactant: CN(C(=O)OCc1ccccc1)c1ccc(C(=O)N[C@@H](CCC(=O)NCCOCCOCCOCCN)C(=O)OC(C)(C)C)cc1
Reactant: O=C(O)COc1ccc(-c2[nH]nc3c2C(=O)c2c(NC(=O)NN4CCOCC4)cccc2-3)cc1
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: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNc1ccc(C(=O)N[C@@H](CCC(=O)NCCOCCOCCOCCNC(=O)COc2ccc(-c3[nH]nc4c3C(=O)c3c(NC(=O)NN5CCOCC5)cccc3-4)cc2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Compound 12 (0.71 g, 1.4 mmol) and compound 25 (0.57 g, 1.2 mmol) were dissolved in 10 ml DMF and HBTU (0.8 g, 2.1 mmol) was added as a solid followed by DIEA (0.52 ml, 3 mmol). The reaction mixture was stirred at room temperature for 3 days, diluted with EtOAc and the organic phase washed with saturated NaHCO3. The aqueous layer was back extracted with EtOAc twice and the combined organic layers dried over MgSO4, filtered and concentrated to an oil. This oil was purified by flash silica chromatography (2 to 5% MeOH/EtOAc) to give an orange oil (0.50 g, 0.52 mmol, 44%, compound 27).
Reaction SMILES: Br[C:2]1[N:3]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[C:9]=2[N+:18]([O-:20])=[O:19])[CH:4]=[C:5]([CH3:7])[N:6]=1.[CH3:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][O:16][C:10]1[C:9]([N+:18]([O-:20])=[O:19])=[C:8]([N:3]2[CH:4]=[C:5]([CH3:7])[N:6]=[C:2]2[C:23]2[CH:24]=[N:25][CH:26]=[CH:27][C:22]=2[CH3:21])[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=1
Reactant: COc1cc(OC)c([N+](=O)[O-])c(-n2cc(C)nc2Br)c1
Reactant: Cc1ccncc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(OC)c([N+](=O)[O-])c(-n2cc(C)nc2-c2cnccc2C)c1
Yield: 69.5 %

Procedure:
Following the general Suzuki coupling procedure, reaction of 2-bromo-1-(3,5-dimethoxy-2-nitrophenyl)-4-methyl-1H-imidazole (1.1 g, 3.2 mmol), 4-methyl-3-pyridylboronic acid (876 mg, 6.4 mmol), K2CO3 (1.32 g, 9.6 mmol) and Pd(PPh3)4 (186 mg, 0.161 mmol) provided 788 mg (69% yield) of the desired product as an off white powder. EIMS 355.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:36])[NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)[CH:17]=[CH:16][C:15]=3[F:37])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[F:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][C:44]=1[C:45]([O:47][CH3:48])=[O:46]>>[F:38][C:39]1[CH:40]=[C:41]([C:2]2[CH:7]=[CH:6][N:5]3[C:8]([C:11](=[O:12])[NH:13][C:14]4[CH:19]=[C:18]([C:20](=[O:36])[NH:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[N:29]5[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]5)[CH:17]=[CH:16][C:15]=4[F:37])=[CH:9][N:10]=[C:4]3[CH:3]=2)[CH:42]=[CH:43][C:44]=1[C:45]([O:47][CH3:48])=[O:46]
Reactant: CN1CCN(c2ccccc2CNC(=O)c2ccc(F)c(NC(=O)c3cnc4cc(Br)ccn34)c2)CC1
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Product: COC(=O)c1ccc(-c2ccn3c(C(=O)Nc4cc(C(=O)NCc5ccccc5N5CCN(C)CC5)ccc4F)cnc3c2)cc1F

Procedure:
The title compound is prepared from 7-Bromo-N-(2-fluoro-5-(2-(4-methylpiperazin-1-yl)benzylcarbamoyl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (Example 1.1 step 1) and 3-fluoro-4-(methoxycarbonyl)phenylboronic acid analogously to Example 1.1 step 2;
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[OH:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)\[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.CCCCCC.O>[C:29]1(/[C:22](=[N:21]/[O:20][CH2:19][C:18]2[CH:35]=[CH:36][C:15]([O:14][CH2:3][C:4]3[CH:13]=[CH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)=[CH:16][CH:17]=2)/[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: COC(=O)CC/C(=N\OCc1ccc(O)cc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CC/C(=N\OCc1ccc(OCc2ccc3ccccc3n2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 69.5 %

Procedure:
A mixture of 2-chloromethylquinoline hydrochloride (488 mg), methyl E-4-(4-hydroxybenzyloxyimino)-4-phenylbutyrate (650 mg), potassium carbonate (1.00 g) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 13 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain methyl E-4-phenyl-4-[4-(2-quinolinylmethoxy)benzyloxyimino]butyrate (655 mg, yield 70%) as a colorless oil from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:16]1([S:22][C:4]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=2[C:6]#[N:7])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Sc1ccccc1
Reactant: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(C(F)(F)F)cc1Sc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
A mixture of 2-nitro4-trifluoromethylbenzonitrile (8.64 g), thiophenol (4.4 g) and potassium carbonate (6.9 g) in acetonitrile was stirred at room temperature for 1 hour then heated at reflux for 9 hours. Thiophenol (0.3 ml) was added and the mixture was stirred and heated at reflux for 1 hour. Water was added and the mixture was extracted with dichloromethane, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was recrystallized from n-hexane to give 2-(phenylsulphenyl)-4-trifluoromethylbenzonitrile (9.5 g) as a white solid, m.p. 51° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1([CH3:13])[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:1][S:2]([N:11]1[CH2:10][CH2:9][NH:8][C:7]([CH3:13])([CH3:6])[CH2:12]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1(C)CN(S(C)(=O)=O)CCN1

Procedure:
A solution of 52.8 g of methanesulphonyl chloride in 100 ml of toluene is added dropwise to a mixture of 52.6 g of 2,2-dimethylpiperazine, 69.9 g of potassium carbonate and 150 ml of toluene, the internal temperature rising to about 55° C. After a stirring time of 3 hours, the insoluble fraction is filtered off with suction and the toluene solution is evaporated in vacuo. The oil which remains gradually solidifies and is recrystallised from isopropanol for purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([CH3:18])[N:11]=[C:12]([CH3:17])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].ClCCl.C(N(CC)CC)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([CH3:18])[N:11]=[C:12]([CH3:17])[CH:13]=2)[N:8]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c(C)nc(C)cc2c1=O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cn(C(=O)OCc2ccccc2)c2c(C)nc(C)cc2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
6,8-Dimethyl-4-oxo-1,4-dihydro-[1,7]naphthyridine-3-carboxylic acid ethyl ester (0.2 g, 0.628 mmol), prepared in step (ii), and dichloromethane (10 mL) were added to a 50 mL round bottom flask. This mixture was cooled to 0° C. and stirred, and triethylamine (0.19 g, 1.88 mmol) was then added to the mixture dropwise. Stirring of the reaction mixture was continued at the same temperature for another 0.5 h, after which time benzyl chloroformate (0.16 g, 0.943 mmol) was added to the mixture. The temperature was allowed to increase to RT, and stirring was continued at this temperature for 2 h. Water was added to the reaction mixture and the mixture was extracted with dichloromethane (2×25 mL). The combined organic phase was washed with brine, dried over sodium sulfate, and the organic solvent was evaporated to provide a residue. This residue was purified by column chromatography over 100-200 mesh silica gel, used 5% MeOH and chloroform as eluent, to provide the compound as a yellow solid (0.1 g, 42%).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][CH2:24][CH2:23]2>C(OCC)C>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc2c(c1)CCC2
Solvent: CCOCC
Product: O=C(Nc1ccc2c(c1)CCC2)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and 5-aminoindan (Aldrich) according to the method described in Example 1c. Melting Point: 106-109° C. (diethylether)
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7]([CH2:10][CH2:11][C:12]3[CH:40]=[CH:39][N:15]4[C:16](=[O:38])[C:17](/[CH:29]=[CH:30]/[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[C:18]([N:20]5[CH2:25][CH2:24][CH2:23][CH:22]([O:26]C=O)[CH2:21]5)[N:19]=[C:14]4[CH:13]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C[O-].[Na+].C(Cl)(Cl)Cl>CO.[Cl-].[Na+].O>[CH:1]1([C:5]2[N:6]=[C:7]([CH2:10][CH2:11][C:12]3[CH:40]=[CH:39][N:15]4[C:16](=[O:38])[C:17](/[CH:29]=[CH:30]/[C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])=[C:18]([N:20]5[CH2:25][CH2:24][CH2:23][CH:22]([OH:26])[CH2:21]5)[N:19]=[C:14]4[CH:13]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)/C=C/c1c(N2CCCC(OC=O)C2)nc2cc(CCc3nc(C4CCC4)cs3)ccn2c1=O
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1c(N2CCCC(O)C2)nc2cc(CCc3nc(C4CCC4)cs3)ccn2c1=O
Reaction time: 0.75 h
Yield: 84.3 %

Procedure:
tert-Butyl (E)-3-[8-[2-(4-cyclobutyl-1,3-thiazol-2-yl)ethyl]-2-(3-formyloxy-piperidino)-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl]-2-propenoate (95 mg, 0.168 mmol) dissolved in methanol (4 ml) was added with sodium methoxide (4 mg, 0.074 mmol) under ice cooling and stirred for 45 minutes under ice cooling. Then the reaction solution was further added with sodium methoxide (4 mg), and after 5 minutes, further added with sodium methoxide (10 mg). After the reaction solution was stirred for 15 minutes, the reaction was stopped with saturated brine and added with chloroform for extraction. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (chloroform:methanol=20:1) to obtain 76 mg (84%) of the title compound as yellow crystals in a mixture with triphenylphosphine oxide.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.IC(C)C>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH:37]([CH3:41])[CH3:38])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CC(C)I
Product: COC(=O)C(c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3)C(C)C
Yield: 53.5 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5 mmol), LHMDS 1N in THF (0.75 mL; 0.75 mmol), 2-iodopropane (0.100 mL; 1 mmol) in DMF (2.5 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.109 g (54%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:16]=2[N:17]=[C:18]([C:20]2[O:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[O:24]1[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:16]=3[N:17]=2)=[CH:21][CH:22]=[N:23]1
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1C
Reactant: NCCc1ccc2c(c1)OCO2
Product: Cc1sc2nc(-c3ccno3)nc(NCCc3ccc4c(c3)OCO4)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-methylenedioxyphenethylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](CS([O-])(=O)=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CC(O)(C)C>[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(F)cc1
Reactant: COc1cc(CS(=O)(=O)[O-])cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COc1cc(Nc2ccc(F)cc2)cc(OC)c1OC
Temperature: 110 °C
Yield: 86.6 %

Procedure:
Following general procedure A, a mixture of 3,4,5-trimethoxyphenylmethanesulfonate (131 mg, 0.5 mmol), 4-fluoroaniline (57 μL, 0.6 mmol), K2CO3 (97 mg, 0.7 mmol), 10 (4 mg, 1 mol %), 1 (2.5 mg, 1 mol %), and t-BuOH (6 mL) was heated to 110° C. for 16 h. The crude product was purified via the Biotage SP4 (silica-packed 25+M; 5-40% EtOAc/hexanes) to provide the title compound as a yellow oil (120 mg, 87%). 1H NMR (300 MHz, CDCl3) δ: 6.99 (m, 4H), 6.22 (s, 2H), 5.57 (s, 1H), 3.80 (s, 3H), 3.78 (s, 6H) ppm. 13C NMR (75 MHz, CDCl3) δ: 159.7, 156.5, 154.1, 140.5, 139.6, 132.5, 120.4, 120.3, 116.4, 116.1, 95.2, 61.3, 56.2 ppm. IR (neat, cm−1): 3360, 2937, 1597, 1499, 1454, 1216, 1129, 1007, 785. Anal. Calcd. for C15H16FNO3: C, 64.97; H, 5.82. Found: C, 65.24; H, 6.00.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)[CH:22]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH:28]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2cccnc2)c1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2cccnc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 3-(pyridin-3-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions I): tR=1.19 min.; [M+H]+: 417.16 g/mol.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.Br[C:31]1[CH:32]=[N:33][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:35][CH:36]=1>C1COCC1.ClCCl.[Cl-].[Zn+2].[Cl-].[Pd]>[C:37]1([C:34]2[N:33]=[CH:32][C:31]([C:2]3[N:3]=[CH:4][N:5]([C:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:6]=3)=[CH:36][N:35]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Brc1cnc(-c2ccccc2)nc1
Agent: [Pd]
Agent: CC[Mg]Br
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: c1ccc(-c2ncc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)cn2)cc1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-Iodo-1-trityl-1H-imidazole (Synthonix, 2.0 g, 4.58 mmol) in THF (50 mL) at room temperature was added ethylmagnesium bromide (Aldrich, 1.0 M solution in THF, 5.5 mL, 5.50 mmol) under dry conditions. After stirring for 90 minutes, zinc chloride (Aldrich, 0.749. g, 5.50 mmol) was added to the reaction mixture. After stirring for an additional 90 minutes, tetrakis(triphenyl)phosphine)palladium (Strem, 0.529 g, 0.46 mmol) and 5-bromo-2-phenylpyrimidine (as prepared in Example 1, step A, 1.29 g, 5.50 mmol) were added to the reaction mixture. The reaction mixture was heated in a 70° C. oil bath overnight. Upon cooling, the reaction was diluted with dichloromethane and washed with 0.5 M EDTA buffer (at pH ˜9) (2×250 mL) followed by brine (150 mL). The organics were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica column chromatography using an 80 g Silicycle® column (elution with 10-30% ethyl acetate in hexane) which afforded the desired intermediate, 2-phenyl-5-(1-trityl-1H-imidazol-4-yl)pyrimidine, as a white solid (1.38 g, 65%). Rf 0.87 with 95:5 v/v dichloromethane-methanol; 1H-NMR (400 MHz; DMSO-d6) δ 9.29 (s, 2H), 8.42 (m, 2H), 7.92 (d, 1H), 7.62 (d, 1H), 7.56-7.43 (m, 13H), 7.24-7.22 (m, 6H); MS (ESI−) m/z 463.0 (M−1); H-PGDS FPBA IC50: >20 μM.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18]1([CH2:21][CH2:22][CH3:23])[O:20][CH2:19]1.B(F)(F)F.CCOCC>C(OCC)C>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1])([CH2:21][CH2:22][CH3:23])[CH2:19][OH:20]
Reactant: CCCC1(c2ccc(Cl)cc2Cl)CO1
Reactant: OCc1ccccc1F
Agent: FB(F)F
Solvent: CCOCC
Product: CCCC(CO)(OCc1ccccc1F)c1ccc(Cl)cc1Cl
Yield: 9 %

Procedure:
A mixture of 11.6 g (92 mmoles) of 2-fluorobenzyl alcohol and 21.9 g (92 mmoles) of 2-(2,4-dichlorophenyl)-1,2-epoxypentane is added dropwise at 0°-2° C. to a solution of 2.0 ml (16.5 mmoles) of boron trifluoride ethyl etherate in 10 ml of diethyl ether. The solution is allowed to react further overnight at +7° C. and is worked up as in Example I by extraction and column chromatography. 2.95 g of the pure product are obtained in the form of a colourless oil. 100 MHz-1H-NMR (CDCl3): δ=6.8-7.7 ppm (m, 7H aromatic); 4.5 ppm (s, 2H, ##STR27## 3.9-4.4 ppm (m, 2H, --CH2OH); 1.7-2.3 ppm (m, 3H, --CH2CH2CH3 and OH); 0.7-1.4 ppm (m, 5H, --CH2CH3).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:19])(=[O:18])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].[CH3:20][O:21][CH2:22]Br>ClCCl.C(N(CC)C(C)C)(C)C>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:19])(=[O:18])[N:11]([CH2:20][O:21][CH3:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4]
Reactant: COCBr
Reactant: COC(=O)c1sccc1S(=O)(=O)Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCN(c1ccccc1)S(=O)(=O)c1ccsc1C(=O)OC
Temperature: 0 °C

Procedure:
The Sulfonamide of Step One, 3-phenylsulfamoylthiophene-2-carboxylic acid methyl ester, was dissolved in dry dichloromethane and N,N-diisopropyl ethylamine. The resulting mixture was chilled to 0° C. prior to the addition of bromomethyl methyl ether. The reaction mixture was stirred over night at room temperature. The mixture was partitioned between dichloromethane and aqueous HCl (2N). The organic layer will then be washed one time with saturated sodium chloride solution and dried over sodium sulfate, followed by concentration to dryness under reduced pressure to give the desired product, 3-(N-methoxymethyl-N-phenylsulfamoyl)thiophene-2-carboxylic acid methyl ester (3 g, quantitative).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Mg+2:11].OBr.S(=O)(=O)([O-])N.[Al+3].S(=O)(=O)([O-])N.S(=O)(=O)([O-])N>O>[NH2:1][CH2:2][CH2:3][C:4]([O-:6])=[O:5].[Mg+2:11].[NH2:1][CH2:2][CH2:3][C:4]([O-:6])=[O:5]
Reactant: NCCC(=O)O
Agent: NS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: OBr
Solvent: O
Product: NCCC(=O)[O-]
Temperature: 75 °C

Procedure:
Magnesium β-alaninate was prepared by reacting 4.86 grams of β-alanine with 2.5 grams of basic magnesium carbonate (26.3% Mg) in 25 grams of water. The mixture was heated at 75° C. with agitation for one half hour. The hot solution was added to 100 grams of zirconyl hydroxybromide solution (17.5% Zr). To the resultant solution was added 14.2 grams of 2/3 basic aluminum sulfamate, Al(OH)2 (OSO2NH2) (9.19% Al, see U.S. Pat. No. 2,765,213 by S. M. Beekman) with agitation. The solution was evaporated at 60° C. under a vacuum of 252 m of Hg. The product contained 1.8% Al, 30.9% Zr, 0.53 Mg, 5.91% β-alanine and 5.3% sulfamates.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CS(C)=O.C(O)(C(F)(F)F)=O.CCOC(C)=O>[C:16]1([NH:15][C:2]2[N:7]=[N:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: Oc1ccc(-c2ccc(Nc3ccccc3)nn2)cc1
Temperature: 80 °C

Procedure:
To a solution of 4-(6-chloro-pyridazin-3-yl)-phenol (Step 2, 1 g, 4.84 mmol) and aniline (1.35 g, 14.52 mmol) in 20 mL of DMSO was added 5 drops of TFA. The reaction was heated to 80° C. for 16 h. The solution was cooled to RT and diluted with 100 mL of EtOAc. The organic phase was washed with 40 mL of water, 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (50% EtOAc/hexane to EtOAc) to give the title compound as a white solid. MS (ESI pos. ion) m/z: 264.2(M+H). Calc'd Exact Mass for C16H13N3O: 263.29.