Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH:7]([C:9]([O:11]CC)=[O:10])[O:8][C:4]=2[C:3]=1[Cl:16].[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[C:15]([C:24](=[O:25])[C:23]2[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:28][CH:27]=2)=[CH:14][C:5]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:16]
Reactant: CCOC(=O)C1Cc2ccc(Cl)c(Cl)c2O1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2

Procedure:
A solution of ethyl 6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylate (10.0 g.) and p-nitrobenzoyl chloride (14.2 g.) in methylene chloride (40 ml.) was placed on a cold water bath with mechanical agitation and treated with aluminum chloride (15.3 g.) portionwise over 5 minutes. The bath was then heated at 80°-90° C. for 1 hour and removed, and the mixture diluted with 100 ml. of methylene chloride.
Reaction SMILES: CO[C:3]([C:5]1(C)[C:14](=[O:15])[C:13]2[CH:12]=[N:11][CH:10]=[C:9]([Br:16])[C:8]=2[CH2:7][CH2:6]1)=O.Cl>>[Br:16][C:9]1[C:8]2[CH2:7][CH2:6][CH:5]([CH3:3])[C:14](=[O:15])[C:13]=2[CH:12]=[N:11][CH:10]=1
Reactant: COC(=O)C1(C)CCc2c(Br)cncc2C1=O
Agent: Cl
Product: CC1CCc2c(Br)cncc2C1=O
Yield: 90.1 %

Procedure:
(rac)-4-Bromo-7-methyl-8-oxo-5,6,7,8-tetrahydro-isoquinoline-7-carboxylic acid methyl ester (3.3 g, 11.0 mmol) was dissolved in aq. 6 N HCl (28.0 mL, 168 mmol) and heated at reflux for 2.5 h. The acidic solution was concentrated in vacuo, re-suspended in water (ca. 25 mL), cooled in an ice-water bath, and basified with 6 N aq. KOH solution. The aqueous solution was then washed with Et2O (2×) and DCM (3×). The combined organic layers were dried over anhy. Na2SO4, filtered and concentrated in vacuo to afford the title compound (2.38 g, 90% yield) as a brown solid. MS: 240.1 & 242.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](/[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)\O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[N:37]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[O:43][C:42]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[N:44][C:9]=2[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: NC(=O)N1CCCC1
Agent: O=C1CCC(=O)N1Br
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)oc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F

Procedure:
Following a procedure analogous to the procedure described in Intermediate 6 using N-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide (2.0 g, 4.72 mmol, NBS (0.924 g, 5.19 mmol) and 1-pyrrolidinecarboxamide (1.077 g, 9.44 mmol) heated to 90° C. for 24 h the title compound of Step A was obtained as an orange solid (0.980 g). MS-ESI m/z 518 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][CH2:7]2)[CH3:2].OO.S(=O)(=O)(O)[OH:15]>C(O)=O>[CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[O:15])[CH2:7]2)[CH3:2]
Reactant: CCc1cccc2c1C=CC2
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: O=CO
Product: CCc1cccc2c1CC(=O)C2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 59 %

Procedure:
33.9 g (235 mmol) of 4-ethylindene (a2) were slowly added dropwise to a mixture of 141 ml of formic acid (98-100% strength) and 33 ml (340 mmol) of H2O2 (35% strength), while cooling with ice (highly exothermic reaction). The mixture was then stirred at room temperature for a further 2.5 hours. The yellow-orange suspension formed was freed from excess formic acid under a water pump vacuum. 900 ml of 2N sulfuric acid were added to the yellow oil which remained. A total of 3 l of water were distilled over, while topping up with water, the product separating out in the receiver as a yellowish oil. The distillate was neutralized with saturated sodium carbonate solution and extracted with ether. The ether phase was dried over sodium sulfate and evaporated. 22.4 g (59%) of the compound a3 were obtained as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]([C:9]1[N:14]=[C:13]([NH:15]C=O)[CH:12]=[CH:11][N:10]=1)=[N:6][O:7][CH3:8])C.[OH-].[K+].Cl>C(O)C>[NH2:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([C:5](=[N:6][O:7][CH3:8])[C:4]([OH:18])=[O:3])[N:14]=1
Reactant: CCOC(=O)C(=NOC)c1nccc(NC=O)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CON=C(C(=O)O)c1nccc(N)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 1.7 %

Procedure:
To a solution of ethyl 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (30.8 g) in ethanol (308 ml) was added 1 N alcoholic solution (550 ml) of potassium hydroxide and the mixture was stirred for 3.5 hours at ambient temperature. The reaction mixture was cooled in an ice bath and adjusted to pH3 with concentrated hydrochloric acid (53 ml). The resultant solid was filtered and washed with ethanol (60 ml), water (100 ml), acetone (100 ml) to give a crude product (28.8 g). This product (1 g) was recrystallized from water (10 ml) to give a purified product of 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid (dihydrate, syn isomer) (0.4 g), mp. 178°-183° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:17]2[C:25]3[C:20](=[C:21]([N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)([CH2:15][CH3:16])[C:9]#[C:10][C:11]([O:13]C)=[O:12])=[CH:4][CH:3]=1.O.[Li+].[OH-]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:17]2[C:25]3[C:20](=[C:21]([N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:36])[CH3:37])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)([CH2:15][CH3:16])[C:9]#[C:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CCC(C#CC(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(C#CC(=O)O)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound from step A (100 mg, 0.17 mmol, enantiomer A) in MeOH (5 mL) was added H2O (1 mL), LiOH (72 mg, 1.7 mmol). The mixture was stirred at RT overnight. After removing the organic solvent, the residue was dissolved with H2O (5 mL) and adjusted to pH=4 with 1M HCl, then extracted with ethyl acetate, and washed with brine (20 mL), dried over dry sodium sulfate, then filtered. The solvent was evaporated to give the title compound. LC/MS m/z=583.0 [M+Na]+.
Reaction SMILES: C([O:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)(=O)C.[OH-].[K+]>C(O)C.O>[C:14]1([C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:12]=2[CH2:13][CH:5]([OH:4])[CH2:6]3)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)OC1Cc2cccc(-c3ccccc3)c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OC1Cc2cccc(-c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.3 %

Procedure:
A mixture of 1.22 g (0.0048 mole) of 4-phenyl-2-indanyl acetate, prepared as described above, and 0.39 g (0.007 mole) of potassium hydroxide in 10 ml of absolute ethanol and 5 ml of water was stirred at room temperature for approximately 18 hours. The reaction mixture was concentrated, and water was added to the residue, forming a precipitate. The precipitate was collected on a filter paper and dried to give 0.79 g of (+)-4-phenyl-2-indanol, mp 87°-92° C., EE 50%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[N:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][C:22]=1[CH3:30])=[C:19]=[S:20]>O1CCCC1>[C:25]([C:24]1[CH:28]=[CH:29][C:21]([NH:18][C:19]([NH:1][C:2]2[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=2[Cl:12])[C:5]([O:7][CH3:8])=[O:6])=[S:20])=[C:22]([CH3:30])[CH:23]=1)(=[O:26])[NH2:27]
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Reactant: Cc1cc(C(N)=O)ccc1N=C=S
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ccc(C(N)=O)cc2C)c1NCCCO
Temperature: 60 °C
Reaction time: 48 h
Yield: 57.6 %

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (2.09 g, 8.08 mmol) and 4-isothiocyanato-3-methylbenzamide (2.33 g, 12.1 mmol) in tetrahydrofuran (20 mL) was stirred at 60° C. for 2 days. The mixture was concentrated in vacuo, and the residue was washed with ethyl acetate to give methyl 3-{[(4-carbamoyl-2-methylphenyl)carbamothioyl]amino}-4-chloro-2-[(3-hydroxypropyl)amino]benzoate as a colorless powder (2.10 g).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]3[N:18]=[N:17][NH:16][N:15]=3)=[CH:12][C:11]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:10]([Cl:23])[CH:9]=2)[S:4][CH:5]=1.[C:24]([O:28][CH2:29]Cl)(=[O:27])[CH2:25][CH3:26].C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[Cl:23][C:10]1[CH:9]=[C:8]([NH:7][CH2:6][C:3]2[S:4][CH:5]=[CH:1][CH:2]=2)[C:13]([C:14]2[N:15]([CH2:29][O:28][C:24]([CH2:25][CH3:26])=[O:27])[N:16]=[N:17][N:18]=2)=[CH:12][C:11]=1[S:19]([NH2:22])(=[O:21])=[O:20]
Reactant: CCC(=O)OCCl
Reactant: NS(=O)(=O)c1cc(-c2nn[nH]n2)c(NCc2cccs2)cc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)OCn1nnnc1-c1cc(S(N)(=O)=O)c(Cl)cc1NCc1cccs1

Procedure:
In similar manner to Example 12, azosemide can be reacted with chloromethyl propionate, triethylamine and sodium iodide in DMF to yield 2-chloro-5-[1-(ethylcarbonyloxymethyl)-1H-tetrazol-5-yl]-4-[(2-thienylmethyl)amino]benzenesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])O[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[C:3](=[O:14])[N:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)C(c2ccccc2)=C1Cl
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C(Cl)=C(c2ccccc2)C(=O)N1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.13 g (15 mmol) of 3-chloro-4-phenylfuran-2,5-dione and 2.44 g (15 mmol) of 4-fluorophenylhydrazine hydrochloride were initially charged in 50 ml of methylene chloride, and the mixture was, at room temperature, admixed dropwise with stirring with 1.52 g (15 mmol) of triethylamine and stirred at room temperature overnight. A further 50 ml of methylene chloride were added, and the mixture was washed three times with in each case 80 ml of water, dried over sodium sulfate and concentrated under reduced pressure. Yield: 3.9 g of a crystalline solid, m.p. 115-117° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([N+:18]([O-:20])=[O:19])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1.O.O.O.O.[C:31]1([CH3:40])[CH:36]=[CH:35][C:34]([S:37]([O-:39])=[O:38])=[CH:33][CH:32]=1.[Na+]>C(O)C>[CH2:11]([O:10][C:8]([C:7]1[C:2]([S:37]([C:34]2[CH:35]=[CH:36][C:31]([CH3:40])=[CH:32][CH:33]=2)(=[O:39])=[O:38])=[N:3][C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:5]([N+:18]([O-:20])=[O:19])[C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])[CH3:12]
Reactant: CCOC(=O)c1c(Cl)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(S(=O)(=O)c2ccc(C)cc2)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Yield: 57.9 %

Procedure:
A mixture of 0.379 g of 2-chloro-3,4- diethoxycarbonyl-5-nitro-6-phenylpyridine, 0.5 g of sodium p-toluenesulfinate tetrahydrate and 15 ml of ethanol was heated under reflux for 3 hours. After concentration, the concentrate was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. After the solvent was distilled off, the residue was subjected to silica gel column chromatography with n-hexane/ethyl acetate (4:1) as the eluent. The eluate was concentrated to give crystals. The obtained crystals were recrystallized from the same solvent, to give 0.289 g of the title compound as colorless needles.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][CH2:8][N:7]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[C:6]=2[CH:23]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([N:7]2[CH2:8][CH2:9][C:10]3=[N:14][N:13]=[C:12]([CH3:15])[N:11]3[C:5]3[CH:4]=[CH:3][C:2]([C:32]4[CH:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=4)=[CH:23][C:6]2=3)=[CH:17][CH:18]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(Cl)cc1)CC2
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nnc2n1-c1ccc(-c3ccc(N)nc3)cc1N(c1ccc(Cl)cc1)CC2
Yield: 28.9 %

Procedure:
A solution of 8-bromo-6-(4-chlorophenyl)-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (30 mg, 0.08 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (35 mg, 0.16 mmol), Tetrakis(triphenylphosphine)palladium(0) (10 mg) and Cs2CO3 (60 mg, 0.16 mmol) in dioxane (5 mL) and water (1 mL) was heated at 120° C. under microwave for 20 min. The reaction mixture was concentrated to give the crude product, which was purified by prep-TLC (DCM:MeOH=12:1) to afford 5-(6-(4-chlorophenyl)-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)pyridin-2-amine (9.3 mg, yield 29%).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH:3]([C:5]1[NH:13][C:8]2=[CH:9][N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)[OH:4]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][CH:2]([CH3:14])[C:3]([C:5]1[NH:13][C:8]2=[CH:9][N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)=[O:4]
Reactant: CC(C)C(O)c1cc2ccncc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)C(=O)c1cc2ccncc2[nH]1
Reaction time: 14 h
Yield: 87.2 %

Procedure:
2-Methyl-1-(1H-pyrrolo[2,3-c]pyridin-2-yl)-1-propanol (Example 78) (75 mg, 0.39 mmol) was dissolved in methylene chloride (10 mL). Manganese dioxide (343 mg, 3.94 mmol) was added and the reaction mixture was stirred for ca. 14 h. The reaction mixture was filtered through diatomaceous earth and the filter cake was washed several times with hot methanol. The filtrate was concentrated to give a white solid. Drying under vacuum produced 2-methyl-1-(1H-pyrrolo[2,3-c]pyridin-2-yl)-1-propanone (64 mg, 88%) as a white solid: mp 224-228° C.; 1H NMR (500 MHz, CD3OD) δ1.26 (6H, d, J=7.0 Hz), 3.45-3.62 (1H, m), 7.37 (1H, s), 7.72-7.74 (1H, m), 8.14 (1H, d, J=6.0 Hz), 8.82 (1H, s); ESI MS m/z 189 [C11H12N2O+H]+; HPLC (Method A) 95.4% (AUC), tR=13.7 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]S(C(F)(F)F)(=O)=O)[C:5]([F:16])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.O[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[F:16][C:5]1[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[N:3][C:2]([NH2:1])=[N:7][C:6]=1[O:8][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: OCc1ccccn1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c(F)c(-c2ccco2)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Nc1nc(OCc2ccccn2)c(F)c(-c2ccco2)n1
Temperature: 50 °C
Yield: 9.6 %

Procedure:
To a stirred solution of 260 mg (0.80 mmol) trifluoromethanesulfonic acid 2-amino-5-fluoro-6-furan-2-yl-pyrimidin-4-yl ester in 15 ml DME were added 0.27 ml (2.80 mmol) 2-(hydroxymethyl)pyridine and 0.12 ml (0.80 mmol) DBU and the mixture heated at 50° C. for 2 hour. The reaction mixture was then concentrated in vacuo. Chromatography (ethyl acetate) followed by trituration in dichloromethane/ether/hexane afforded 22 mg (10%) 5-fluoro-4-furan-2-yl-6-(pyridin-2-ylmethoxy)-pyrimidin-2-ylamine as a white crystalline solid. EI-MS m/e (%): 286 (M+, 100), 107 (52).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[C:10]([C:19]([NH:21][CH:22]3[CH2:24][CH2:23]3)=[O:20])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>CS(C)=O.[Cu]I>[CH:22]1([NH:21][C:19]([C:10]2[C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[N:14][C:13]=3[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:26]#[C:25][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:3]=3)[N:9]=2)=[O:20])[CH2:24][CH2:23]1
Reactant: C#Cc1cccnc1
Reactant: O=C(NC1CC1)c1nn(-c2cccc(Br)c2)c2ncccc2c1=O
Agent: [Cu]I
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(NC1CC1)c1nn(-c2cccc(C#Cc3cccnc3)c2)c2ncccc2c1=O
Yield: 18.9 %

Procedure:
To 1-(3-Bromophenyl)-N-cyclopropyl-4-oxo-1,4-dihydropyridino[2,3-c]pyridazine-3-formamide (1 g, 2.6 mmol) in 50 mL DMSO was successively added 3-ethynyl-pyridine (0.34 g, 3.3 mmol), bistriphenylphosphine palladium dichloride (0.53 g, 0.76 mmol), CuI (0.14 g, 0.74 mmol), triethylamine (0.63 g, 6.25 mmol), reacted in a microwave reactor at 100° C. for 90 min. After reaction was complete, extraction was performed with H2O/DCM, and organic phase was purified by preparation chromatography column to obtain product 0.2 g.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[O:28])[O:26][C:25]([CH3:30])([CH3:29])[O:24][C:23]=4[CH:31]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][N:18]([C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[O:28])[O:26][C:25]([CH3:29])([CH3:30])[O:24][C:23]=4[CH:31]=3)[C:40]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:41])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)C3CCCCC3)c3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1

Procedure:
The titled compound was prepared following the procedure M using 7-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one and cyclohexanecarbonyl chloride as an orange oil (52%). 1H NMR (CDCl3, 300 MHz) δ 7.92 (d, J=8.3 Hz, 1H), 7.41 (m, 4H), 7.14 (m, 4H), 6.77 (m, 0.5H), 6.75 (m, 0.5H), 6.57 (m, 1H), 4.87 (s, 2H), 2.60 (t, J=7.5 Hz, 2H), 2.2 (m, 1H), 1.71 (s, 6H), 1.69-1.52 (m, 8H), 1.39-0.97 (m, 6H), 0.91 (t, J=7.3 Hz, 3H). M+ (ESI): 550.1. HPLC, Rt: 6.35 min (Purity: 97.5%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11]Br)[CH:5]=1.[C:14]([O-:17])(=[O:16])[CH3:15].[K+].O>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][O:17][C:14](=[O:16])[CH3:15])[CH:5]=1
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1cc(C)cc(CBr)c1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(C)cc(COC(C)=O)c1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
In a 5 liter flask were combined 507 g (2.09 mole) of methyl-3-bromomethyl-5-methylbenzoate with 615 g (6.3 mole) of potassium acetate in 2850 ml of glacial acetic acid and refluxed for 3 hours. The contents of the flask were then cooled down to room temperature and divided in 3 equal portions for work up. Each portion was poured into 2 liter of water and extracted with ethyl ether (3×300 ml). The combined organic layers were washed with water (3×600 ml) and then with 2% aqueous sodium hydroxide (5×200 ml) and then dried over sodium sulfate. The solvent was then eliminated in the rotavap to give 420.8 g (90% yield) of crude product, used as such in the next step.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C@@H:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C@H:21]([C@@H:10]2[C@@H:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=3)[CH2:12][NH:8][CH2:9]2)[CH3:22])=[N:25][CH:26]=1
Reactant: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CNC[C@@H]1c1ccc(F)c(F)c1
Temperature: 100 °C
Yield: 64.3 %

Procedure:
To a solution of 2-{(S)-1-[(3R,4S)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-chloro-pyridine 917 mg (2.13 mmol) dissolved in toluene (20 mL) were added 0.69 mL (6.39 mmol) of 1-chloroethyl chloroformate and 1.09 mL (6.39 mL) of Hunig's base. The reaction mixture was heated at 100° C. for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (20 mL). The reaction mixture was heated at 85° C. for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 464 mg (64%) of the title compound as a light yellow oil. ES-MS m/e: 339.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[O:6][C@@H:7]([C@:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1)[C:8]([OH:10])=[O:9].[CH2:32]1COCC1.Cl[Si](C)(C)C.CI>CC(=O)OCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[O:6][C@@H:7]([C@:11]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][N:12]1[CH3:32])[C:8]([OH:10])=[O:9]
Reactant: COc1cc(OC)cc(O[C@H](C(=O)O)[C@@]2(c3ccccc3)NCCc3ccccc32)c1
Reactant: C1CCOC1
Agent: C[Si](C)(C)Cl
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1cc(OC)cc(O[C@H](C(=O)O)[C@]2(c3ccccc3)c3ccccc3CCN2C)c1
Temperature: 55 °C
Reaction time: 16 h
Yield: 67.2 %

Procedure:
To a suspension of (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (200 mg, 0.477 mmol, Example 1) in THF (5 ml) Hünig's base (327 μl, 1.91 mmol) followed by chlorotrimethylsilane (72 μl, 0.572 mmol) is added. The mixture is stirred at 55° C. for 3 h before methyliodide (30 μl, 0.477 mmol) is added. Stirring at 55° C. is continued for another 16 h. The mixture is diluted with EA and extracted with water. The aqueous phase is acidified with 2 N HCl and extracted with EA. The EA-phase is dried over Na2SO4 and evaporated. The crude product is purified by prep. HPLC on Rp-C18-silica gel to give (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-2-methyl-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (139 mg) as a white powder. LC-MS2: tR=4.03 min, [M+1]+=434.34, [M−1]−=432.32.