Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[C:39]=2[CH2:44][O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[C:39]=2[CH2:44][O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1noc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c1COC1CCCCO1
Product: Cc1noc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)c1COC1CCCCO1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J6) and (RS)-3-{3-[3-methyl-4-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-5-yl]-phenyl}-3-oxo-propionic acid tert.-butyl ester (Example K13) according to the general procedure M. Obtained as a red oil (424 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[NH:6]2.Cl[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[O:20][N:19]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[N:6]2[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)[O:20][N:19]=1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: CCCc1cc2c(Cl)c(C#N)ccc2[nH]1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-propyl-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole:
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]2[C@@H:4]([CH2:5][CH2:6][NH:7]2)[N:3]1[S:9]([OH:12])(=[O:11])=[O:10].CC#N.C([O-])(O)=O.[Na+].[NH2:21][CH2:22][CH2:23][NH:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35](ON2C(=O)CCC2=O)=[O:36])=[CH:30][CH:29]=1)=[O:26]>O>[NH2:21][CH2:22][CH2:23][NH:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([N:7]2[CH2:6][CH2:5][C@@H:4]3[C@H:8]2[C:2](=[O:1])[N:3]3[S:9]([OH:12])(=[O:11])=[O:10])=[O:36])=[CH:30][CH:29]=1)=[O:26]
Reactant: NCCNC(=O)Nc1ccc(NC(=O)ON2C(=O)CCC2=O)cc1
Reactant: O=C1[C@H]2NCC[C@H]2N1S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NCCNC(=O)Nc1ccc(NC(=O)N2CC[C@@H]3[C@H]2C(=O)N3S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
(1S,5R)-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulfonic acid (Compound B of Reaction Scheme 2, 2.0 g, 10.41 mmol, 1.0 eq) is dissolved in H2O (12.5 mL). Then CH3CN (100 mL) is added at room temperature to the solution, followed by NaHCO3 (1.57 g, 18.73 mmol, 1.8 eq) and [(2-aminoethyl)amino]-N-{4-[(2,5-dioxoazolidinyloxy)carbonylamino]phenyl}carboxamide (Compound C-1) (6.89 g, 14.57 mmol, 1.4 eq). After stirring overnight at room temperature, the reaction mixture is filtered to afford 3.27 g of the expected (1S,5R)-2-[N-(4-{[(2-aminoethyl)amino]carbonylamino}phenyl)carbamoyl]-7-oxo-2,6-diazabicyclo[3.2.0] heptane-6-sulfonic acid as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]([C:5]1C=[CH:9][C:8]([Br:11])=[CH:7][N:6]=1)=[O:4].BrC1C=[N:16]C(C(O)=O)=NC=1>>[CH3:12][N:2]([CH3:1])[C:3]([C:5]1[N:6]=[CH:7][C:8]([Br:11])=[CH:9][N:16]=1)=[O:4]
Reactant: CN(C)C(=O)c1ccc(Br)cn1
Reactant: O=C(O)c1ncc(Br)cn1
Product: CN(C)C(=O)c1ncc(Br)cn1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 161a, from 5-bromopyrimidine-2-caboxylic acid (1.03 g, 5.074 mmol) to give a yellow oil (308 mg, 26% yield). 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 2 H) 3.17 (s, 3 H) 3.00 (s, 3 H); LCMS for C7H8BrN3O m/z 230.00 and 232.00 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)[CH:5]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH3:27][C:28]1[C:32](B(O)O)=[C:31]([CH3:36])[O:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+].CO>O1CCOCC1.Cl[Pd]Cl.O>[CH3:27][C:28]1[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[N:6]([CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:5]3[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:31]([CH3:36])[O:30][N:29]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: CN1CCC(CN2C(=O)Nc3ccc(Br)cc3C2c2ccccc2)CC1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)N(CC1CCN(C)CC1)C(=O)N2
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a mixture of 6-Bromo-3-[(1-methyl-4-piperidyl)methyl]-4-phenyl-1,4-dihydroquinazolin-2-one (100 mg, 0.24 mmol), 3,5-dimethylisoxazole-4-boronic acid (51 mg, 0.36 mmol), Na2CO3 (77 mg, 0.73 mmol) in dioxane (1.6 ml) with MeOH (0.4 ml) and water (0.2 ml) 1,1′-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (17 mg, 0.02 mmol) is added. The mixture is stirred for 5 h at 80° C., concentrated in vacuo and the product purified by RP HPLC.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.C([O:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)(=O)C.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:25][CH2:24][CH2:23][N:22]([CH2:34][CH2:33][CH2:32][CH2:31][OH:30])[CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=O)OCCCCBr
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCCNCC4)n3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCCN(CCCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out as already described starting from 79 mg (0.214 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]-1,4-diazepane and 47 μl (0.321 mmol) of 4-bromobutyl acetate. The protecting group is cleaved off by means of a 1N NaOH solution in methanol. The product is in the form of the hydrochloride.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[C:20]3[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=3[CH:18]=[C:17]([C:26]([O:28][CH3:29])=[O:27])[CH:16]=2)=[CH:10][N:9]=1)=[O:7])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:29][O:28][C:26]([C:17]1[CH:16]=[C:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=2)[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)=[O:27]
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)OC(C)(C)C)nc2)c2c(c1)OC(C)(C)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(Oc2ccc(C(=O)O)nc2)c2c(c1)OC(C)(C)C2

Procedure:
A solution of 5-(6-methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyridine-2-carboxylic acid tert-butyl ester (163a) (260 mg, 0.65 mmol) in 4 mL CH2Cl2 and 2 mL TFA was stirred at room temperature for 2 hr. The mixture was concentrated, dried under vacuum, and taken to the next step as it is.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.[Cl-:6].[CH:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[N:19][O:20][CH2:21][CH2:22][Cl:23])[C:16]([OH:18])=O)[N:14]=1)=[O:8].[NH2:24][CH:25]1[C:45](=[O:46])[N:27]2[C:28]([C:42]([OH:44])=[O:43])=[C:29]([CH2:32][S:33][C:34]3[N:38]([CH2:39][CH:40]=[CH2:41])[N:37]=[N:36][N:35]=3)[CH2:30][S:31][C@H:26]12>C(OCC)(=O)C.O>[CH3:1][N+:2]([CH3:5])=[CH:3][Cl:23].[Cl-:6].[CH:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[N:19][O:20][CH2:21][CH2:22][Cl:23])[C:16]([NH:24][CH:25]2[C:45](=[O:46])[N:27]3[C:28]([C:42]([OH:44])=[O:43])=[C:29]([CH2:32][S:33][C:34]4[N:38]([CH2:39][CH:40]=[CH2:41])[N:37]=[N:36][N:35]=4)[CH2:30][S:31][C@H:26]23)=[O:18])[N:14]=1)=[O:8]
Reactant: CN(C)C=O
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=CNc1nc(C(=NOCCCl)C(=O)O)cs1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCCl)c3csc(NC=O)n3)[C@H]2SC1
Product: C[N+](C)=CCl
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
Vilsmeier reagent was prepared from dry N,N-dimethylformamide (0.3 g.) and phosphory chloride (0.5 g.) in dry ethyl acetate (1.2 ml.) in a usual manner. 2-(2-Formamidothiazol-4-yl)-2-(2-chloroethoxyimino)acetic acid (syn isomer, 0.9 g.) and dry ethyl acetate (10 ml.) were added to the mixture under ice-cooling and then stirred at the same temperature for 30 minutes. [Solution A]Trimethylsilylacetamide (2.9 g.) was added to a solution of 7-amino-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.0 g.) in dry ethyl acetate (20 ml.) and stirred at 40° C. for 30 minutes. To the solution was added the solution A at -10° C. and stirred at -5°to -10° C. for an hour. Water was added to the resultant solution and the organic layer was separated. Water was added to the organic layer and adjusted to pH 7.0 with sodium carbonate. The aqueous layer was separated, washed with ethyl acetate and adjusted to pH 4.5 with 10% hydrochloric acid. The solution was extracted with ethyl acetate. The extract was washed with a sodium chloride saturated aqueous solution, dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diisopropyl ether. The precipitates were collected by filtration, washed with diisopropyl ether and dried to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-chloroethoxyimino)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 0.83 g.).
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=1[CH:10]=[O:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>[Pd]>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=2[CH:10]=[O:11])=[CH:15][CH:14]=1
Reactant: CC1(C)CCC(Cl)=C(C=O)C1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd]
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(C=O)C1

Procedure:
reacting the 2-chloro-5,5-dimethylcyclohex-1-enecarbaldehyde, 4-chlorophenylboronic acid, a first phase transfer catalyst, a fifth base, and a first palladium catalyst to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde and isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:22]1([CH2:28][CH2:29]O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO>ClCCl>[CH2:29]([O:20][C:19](=[O:21])[CH2:18][O:17][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:16][N:15]=1)[CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: OCCc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OCCc1ccccc1
Yield: 73 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 2-phenyl-ethanol (18 mg, 0.15 mmol) as the coupling partner. Chromatography (1:1 methanol:dichloromethane) through SiO2 yielded 49 mg (73%) of the titled compound. ESI-MS m/z 396 (MH+), 394 (M−H−).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([NH:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH2:19][CH3:20].ClC1C=CC=CC=1Cl>O>[CH2:18]([N:21]1[C:1]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]3[C:10]([C:11](=[O:13])[N:25]2[CH2:24][CH2:23][CH2:22]1)=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:19][CH3:20]
Reactant: CCCNCCCN
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: CCCN1CCCN2C(=O)c3ccccc3C12c1ccccc1

Procedure:
22.6 Parts of o-benzoyl-benzoic acid and 11.6 parts of N-propyl-1,3-propanediamine are haeted within 11/2 hours with 50 parts by volume of o-dichlorobenzene until the boiling point of the latter is attained. Almost the theoretical amount of reaction water is azeotropically distilled off. The clear solution is evaporated to dryness in vacuo, the oily residue is dissolved in ethyl acetate and crystallised by the dropwise addition of pentane. In this way, 1-propyl-10b-phenyl-1,3,4,10b-tetrahydro-pyrimido[2,1-a]isoindol-6(2H)-one is obtained of the formula ##STR19## M.P. 135°-137°. 1-Ethyl-10b-phenyl-1,3,4,10b-tetrahydro-pyrimido[2,1-a]isoindol -6(2H)-one is obtained in the same manner from o-benzoyl-benzoic acid and N-ethyl-1,3-propanediamine. M.P. 131°-133°.
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:10]([CH3:12])=[CH2:11])(C)(C)C.[BH4-].[Li+].O.Cl>CCOCC>[C:16]([O:15][C:13]([N:8]([CH2:7][CH2:6][OH:5])[CH2:9][C:10]([CH3:12])=[CH2:11])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: C=C(C)CN(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: C=C(C)CN(CCO)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
A solution of N-(tert-butoxycarbonyl)-N-(2-methylprop-2-enyl)glycine tert-butyl ester (0.26 g, 0.93 mmol) in Et2O (3 mL) was treated with lithium borohydride (0.011 g), then stirred at room temp. overnight. To the resulting mixture was added water (2 mL), then a 1N HCl was added dropwise until gas evolution stopped. The organic phase was washed with a saturated NaHCO3 solution (20 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, gradient from 10% EtOAc/hex to 50% EtOAc/hex) to give N-(tert-butoxycarbonyl)-N-(2-hydroxyethyl)-1-amino-2-methylprop-2-ene (0.113 g, 57%): TLC (10% EtOAc/hex) Rf0.66.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:8][O:9][C:10]=2[C:11]([F:14])([F:13])[F:12])[N:3]=[CH:2]1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[N:8][O:9][C:10]=3[C:11]([F:14])([F:12])[F:13])[N:3]=[CH:2]2)=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: OB(O)c1ccc(F)cc1
Product: Fc1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Yield: 52 %

Procedure:
As described for Example 1j, 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole (100 mg, 0.36 mmol) was converted, using 4-fluorophenylboronic acid instead of phenylboronic acid, to the title compound (70 mg, 52%) which was obtained as a white solid. MS: m/e=374.2 [M+H]+.
Reaction SMILES: [ClH:1].O1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:8][NH:9][C:10]([C:12]1[N:13]=[C:14]([N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]2COC2C=NC=CC=2)[S:15][CH:16]=1)=[O:11]>CO>[ClH:1].[ClH:1].[CH3:8][NH:9][C:10]([C:12]1[N:13]=[C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]2[CH2:7][CH2:6][O:5][C:4]2[CH:3]=[N:9][CH:10]=[CH:12][CH:16]=2)[S:15][CH:16]=1)=[O:11]
Reactant: CNC(=O)c1csc(N2CCN(C(=O)OC(C)(C)C)CC2COc2cccnc2)n1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: CNC(=O)c1csc(N2CCNCC2CCOc2cccnc2)n1
Reaction time: 1 h
Yield: 97 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(4-(methylcarbamoyl)thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (35 mg, 0.081 mmol) in MeOH (1 mL). After stirring for 1 h, the reaction mixture was concentrated under reduced pressure, yielding 31.9 mg (97%) of the title compound. LC-MS: RT=1.37 min, (M+H)+=334.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.Cl.Cl[CH2:21][C:22]1[C:23]([NH:35][CH2:36][CH3:37])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[C:27]([F:34])[CH:26]=2.[Li+].[OH-]>C1COCC1>[CH2:36]([NH:35][C:23]1[C:22]([CH2:21][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=2[OH:18])=[CH:31][C:30]2[C:25](=[CH:26][C:27]([F:34])=[C:28]([O:32][CH3:33])[CH:29]=2)[N:24]=1)[CH3:37]
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: CCNc1nc2cc(F)c(OC)cc2cc1CCl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1nc(O)c(Cc2cc3cc(OC)c(F)cc3nc2NCC)c2cc(OC)c(OC)cc12
Temperature: 155 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (184 mg, 0.744 mmol) in THF (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-N-ethyl-7-fluoro-6-methoxyquinolin-2-amine hydrochloride SMA 44096 (227 mg, 0.744 mmol) at RT followed by a 2 N aq. LiOH solution (0.75 mL, 1.50 mmol) and the mixture was stirred at 155° C. for 1.5 h under microwave irradiation. The microwave vial was then cooled in an ice bath and the solid was filtered, washed with cold THF (20 mL) and taken up in CH2Cl2:MeOH=9:1 (50 mL). The organic solution was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) followed by a second purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) gave 83 mg of 4-((2-(ethylamino)-7-fluoro-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (5 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.0 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((2-(ethylamino)-7-fluoro-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 70 as a yellow solid (96 mg, 23% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[N:6]([CH3:12])[N:5]=1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[CH:26]=[C:27]([CH:44]=[CH:45][C:46]=1[F:47])[O:28][C:29]1[CH:30]=[CH:31][C:32]2[N:33]([CH:35]=[C:36]([NH:38][C:39]([CH:41]3[CH2:43][CH2:42]3)=[O:40])[N:37]=2)[N:34]=1>CN(C)C=O.CN1CCCC1=O>[CH:41]1([C:39]([NH:38][C:36]2[N:37]=[C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[CH:44]=[CH:45][C:46]([F:47])=[C:25]([NH:24][C:9]([C:7]5[N:6]([CH3:12])[N:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:8]=5)=[O:11])[CH:26]=4)=[N:34][N:33]3[CH:35]=2)=[O:40])[CH2:42][CH2:43]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: CCOc1cc(C(=O)O)n(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)n(C)n1
Yield: 38.4 %

Procedure:
Using 3-ethoxy-1-methyl-1H-pyrazole-5-carboxylic acid (170 mg, 1.0 mmol), N,N-dimethylformamide (2 drops), tetrahydrofuran (15 mL), oxalyl chloride (0.172 mL, 2.0 mmol), N-methylpyrrolidone (5 mL) and N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (164 mg, 0.50 mmol), and in the same manner as in Example 173, the title compound (92 mg, yield 38%) was obtained.
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:50])[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[S:11]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]([S:38]([C:41]1[C:46]([CH3:47])=[CH:45][C:44]([CH3:48])=[CH:43][C:42]=1[CH3:49])(=[O:40])=[O:39])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][S:26]([C:29]1[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=1[CH3:37])(=[O:28])=[O:27])(=[O:13])=[O:12].I[CH2:52][CH2:53][CH3:54].[CH3:55][CH2:56]CCCC.CCOC(C)=O>CN(C=O)C>[C:5]1([CH3:10])[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([CH3:50])[C:4]=1[S:11]([N:14]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]([S:38]([C:41]1[C:42]([CH3:49])=[CH:43][C:44]([CH3:48])=[CH:45][C:46]=1[CH3:47])(=[O:39])=[O:40])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]([S:26]([C:29]1[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=1[CH3:37])(=[O:27])=[O:28])[CH2:55][CH3:56])[CH2:52][CH2:53][CH3:54])(=[O:13])=[O:12]
Reactant: Cc1cc(C)c(S(=O)(=O)NCCCCCN(CCCCNS(=O)(=O)c2c(C)cc(C)cc2C)S(=O)(=O)c2c(C)cc(C)cc2C)c(C)c1
Reactant: CCCI
Reactant: CCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCN(CCCCN(CCCCCN(CC)S(=O)(=O)c1c(C)cc(C)cc1C)S(=O)(=O)c1c(C)cc(C)cc1C)S(=O)(=O)c1c(C)cc(C)cc1C
Yield: 80 %

Procedure:
NaH (60%, 0.273 g, 6.84 mmol), 33 (2.24 g, 3.11 mmol), and 1-iodopropane (0.67 mL, 6.9 mmol) in DMF (30 mL) were combined and worked up by the method of 43. Column chromatography (3:1 hexane/EtOAc) provided 2.01 g (80%) of 54 as an oil: NMR δ 0.71-0.78 (m, 6 H), 1.01-1.11 (m, 2 H), 1.34-1.48 (m, 12 H), 2.29 (s, 6 H), 2.57-2.58 (2 s, 18 H), 2.98-3.13 (m, 12 H), 6.92 (s, 6 H). Anal. (C42H65N3O6S3.H2O) C, H, N.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>CC(C)=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:2][C:3]([C:5]2([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6]2)=[O:4])=[CH:22][CH:21]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CCOC(=O)C1(C(=O)CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C(=O)COc2ccc(Cl)cc2)CC1
Yield: 69 %

Procedure:
47.2 g (0.2 mol) of ethyl 1-(bromoacetyl)-cyclopropanecarboxylate are added to a suspension of b 28 g (0.2 mol) of potassium carbonate and 26 g (0.2 mol) of 4-chlorophenol in 300 ml of acetone and the mixture is heated under reflux for 6 hours. Inorganic salts are then filtered off, the filtrate is concentrated under reduced pressure and the residue is distilled in vacuo. 39 g (69% of theory) of ethyl 1-(4-chlorophenoxyacetyl)-cyclopropanecarboxylate are obtained. B.P. 148°-150° C./0.45 mbar.
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[C:11]1(/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:15][C:14]([C:17](O)=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[C:11]1(/[CH:20]=[CH:21]/[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:12]=[CH:13][C:14]([C:17]([N:7]2[CH2:8][CH2:9][C:10]3[O:2][CH:3]=[CH:4][C:5]=3[CH2:6]2)=[O:18])=[CH:15][CH:16]=1
Reactant: c1cc2c(o1)CCNC2
Reactant: O=C(O)c1ccc(/C=C/c2ccccc2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(/C=C/c2ccccc2)cc1)N1CCc2occc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.269 g (1.2 mmol) of (E)-4-stilbenecarboxylic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was recrystallized from hexane-methanol to yield the desired product.