Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>>[C:18]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)([OH:20])=[O:19]
Reactant: NC(Cc1ccc(C#Cc2ccccc2)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1ccc(C#Cc2ccccc2)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-(4-phenylethynyl-phenyl)-propionic acid to provide the title compound in good yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:12])[N:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:26])[O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:15][CH2:14]1.CCN(CC)CC.CN(C=O)C>O>[Cl:12][C:4]1[N:3]=[C:2]([N:13]2[CH2:14][CH2:15][CH:16]([NH:19][C:20](=[O:26])[O:21][CH2:22][CH:23]([CH3:24])[CH3:25])[CH2:17][CH2:18]2)[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: CC(C)COC(=O)NC1CCNCC1
Reactant: Clc1cc2ccccc2c(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)COC(=O)NC1CCN(c2nc(Cl)cc3ccccc23)CC1
Temperature: 160 °C

Procedure:
A mixture of 1,3-dichloroisoquinoline (0.16 g, 0.78 mmol), isobutyl piperidin-4-ylcarbamate (0.16 g, 0.78 mmol), Et3N (0.11 mL, 0.78 mmol), and DMF (0.5 mL) was sealed in a microwave vessel and heated by microwave irradiation at 160° C. for three minutes. The reaction was cooled to room temperature, diluted with water, and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to yield isobutyl 1-(3-chloroisoquinolin-1-yl)piperidin-4-ylcarbamate. LC/MS: m/z 362.2 (M+H)+ at 3.98 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [N:1]1([CH2:6][CH:7]=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[Br-].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]([CH:40]=[CH:41][C:42]=2[C:43]([O:45][CH3:46])=[O:44])[CH2:20][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[N:1]1([CH2:6][CH:7]=[CH:20][C:19]2[CH:40]=[CH:41][C:42]([C:43]([O:45][CH3:46])=[O:44])=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=3)[CH:18]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(F)cc1
Reactant: O=CCn1ccnc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C=CCn2ccnc2)cc1-c1ccc(F)cc1
Yield: 93 %

Procedure:
A solution of 2-(imidazol-1-yl)acetaldehyde (2.6 g; 0.0 18 mmol), 3-(4-fluorophenyl)-4-methoxycarbonylbenzyl triphenylphosphonium bromide (5.4 g; 0.09 mmol), potassium carbonate (1.38 g; 0.01 mmol) and 18 crown-6 (0.1 g; 0.37 mmol) in THF (150 ml) was stirred under argon atmosphere at ambient temperature overnight. After filtration of the insoluble material and evaporation to dryness, the residue was purified by flash chromatography eluting with a mixture of dichloromethane/ethanol (98/2) to give methyl 4-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate as a mixture of E and Z isomers. Yield: 93%
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]([OH:18])[CH:10]=1.CCN(C(C)C)C(C)C.CN1CCCC1=O>O>[NH2:1][C:2]1[CH:7]=[C:6]([O:18][C:11]2[CH:10]=[CH:9][C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Temperature: 160 °C
Reaction time: 15 h

Procedure:
A mixture of 15.88 g of 2-amino-4-chloropyridine 34.5 g of p-nitrophenol, 52 ml of Hunig's base and 100 ml of 1-methyl-2-pyrrolidinone was stirred at 160° C. for 15 hours. Water was added, extraction was performed with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=1:1) using NH type silica gel to obtain 3.24 g of the target substance as a light yellow solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C:16]([F:28])([F:27])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.[O:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=2)[CH2:31][CH2:30]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C(COC)OC.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:27][C:16]1([F:28])[CH2:15][CH:14]([CH2:13][NH:12][C:10]2[C:9]3[C:4](=[N:5][CH:6]=[CH:7][N:8]=3)[CH:3]=[C:2]([C:38]3[CH:37]=[CH:36][C:35]([N:32]4[CH2:31][CH2:30][O:29][CH2:34][CH2:33]4)=[CH:40][CH:39]=3)[N:11]=2)[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(CNc2nc(Cl)cc3nccnc23)CC(F)(F)C1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(CNc2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)CC(F)(F)C1
Temperature: 160 °C
Reaction time: 1.33 h

Procedure:
A mixture of tert-butyl 5-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)-3,3-difluoropiperidine-1-carboxylate (206 mg, 0.5 mmol), 4-morpholinophenylboronic acid (207 mg, 1.0 mmol), tri(cyclohexyl)phosphine (56 mg, 0.2 mmol), Pd2(dba)3 (91 mg, 0.1 mmol) and Cs2CO3 (325 mg, 2.0 mmol) in dimethoxyethane/H2O was sealed in a microwave reaction tube and stirred at 160° C. for 80 minutes in a microwave reactor. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by chromatography to give the title compound. MS (m/z): 541 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30](Cl)=[O:31]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:27]([O:26][CH3:25])[CH:28]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1OC
Yield: 71 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 3,4-dimethoxybenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 71%. Melting point: 171-173° C. (Ethyl acetate-hexane).
Reaction SMILES: CN(C=O)C.[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]1[NH:15][C:16](=[O:37])/[C:17](=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]2)=[C:25]([O:35][CH3:36])[CH:24]=1)/[CH2:18][CH2:19][CH2:20]Cl.[H-].[Na+]>O>[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]1[N:15]1[CH2:20][CH2:19][CH2:18]/[C:17](=[CH:22]\[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]3)=[C:25]([O:35][CH3:36])[CH:24]=2)/[C:16]1=[O:37]
Reactant: COc1cc(/C=C(\CCCCl)C(=O)NC2Cc3ccccc3C2)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(/C=C2\CCCN(C3Cc4ccccc4C3)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a DMF (50 mL) solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid indan-2-ylamide (6.9 g), sodium hydride (40% mineral oil content, 740 mg) was added at room temperature, and the reaction solution was agitated at room temperature for 1 hour and 30 minutes. The reaction solution was poured into iced water after the reaction ended, and the deposited solids were separated by filtering. 4.9 g of the title compound was obtained by recrystallizing the obtained solid from a mixed solvent of ethyl acetate, ethanol, and hexane. The physical properties of the compound are as follows.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:18]([F:21])([F:20])[F:19])=[C:12]([CH:17]=2)[C:13]([O:15]C)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:18]([F:19])([F:20])[F:21])=[C:12]([CH:17]=2)[C:13]([OH:15])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(Oc2ccccc2)ccc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(Oc2ccccc2)ccc1C(F)(F)F
Reaction time: 8 h
Yield: 112.6 %

Procedure:
To a solution of methyl 5-(phenyloxy)-2-(trifluoromethyl)benzoate (0.504 g, 1.70 mmol) in ethanol (20 ml), was added 2 M aqueous sodium hydroxide (2.0 ml, 4 mmol). The solution was stirred and left to stand overnight. The solvent was evaporated in vacuo. The residue was dissolved in water and diluted with aqueous 2 M HCl. The mixture extracted with chloroform and the phases separated using a hydrophobic frit. The solvent was removed in vacuo to give a colourless oil (0.540 g). The residue was dissolved in chloroform and dried (Na2SO4), filtered and the solvent removed in vacuo to give the title compound as a colourless oil (0.519 g); LCMS: (System 4) (M-H)−=281, tRET=2.84 min.
Reaction SMILES: C([C@H]1[O:9][C@:8]([CH2:11][NH:12]C(=O)OC)([CH3:10])[C:7](=[O:17])[O:6]1)(C)(C)C.[ClH:18]>O>[ClH:18].[NH2:12][CH2:11][C@@:8]([OH:9])([CH3:10])[C:7]([OH:17])=[O:6]
Reactant: COC(=O)NC[C@]1(C)O[C@H](C(C)(C)C)OC1=O
Agent: Cl
Solvent: O
Product: C[C@](O)(CN)C(=O)O
Temperature: 115 °C

Procedure:
Methyl ((2S,4S)-2-tert-butyl-4-methyl-5-oxo-1,3-dioxolan-4-yl)methylcarbamate (310 mg, 1.27 mmol) (Huang et al. (2006) Tetrahedron: Asymmetry 17(22):3152-3157) was suspended in 6 N HCl (12.7 mL) in a sealed tube. The resulting mixture was heated at 110-120° C. for 16 hours and then cooled to room temperature. The reaction crude was diluted with H2O (12 mL) and then extracted twice with EtOAc. The aqueous layer was concentrated to give the title compound in 187 mg, which was used directly in the subsequent step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([Cl:9])=[C:6](N)[CH:7]=1.Cl.N([O-])=O.[Na+].[F:16][B-](F)(F)F.[H+]>O>[Br:1][C:2]1[CH:7]=[C:6]([F:16])[C:5]([Cl:9])=[CH:4][C:3]=1[CH3:10]
Reactant: F[B-](F)(F)F
Reactant: Cc1cc(Cl)c(N)cc1Br
Agent: Cl
Agent: O=N[O-]
Agent: [H+]
Solvent: O
Product: Cc1cc(Cl)c(F)cc1Br
Temperature: 80 °C

Procedure:
1.25 mol of 5-bromo-2-chloro-4-methyl-phenylamine are added to 750 ml of concentrated aqueous HCl and the mixture is stirred at 80° C. until formation of a homogenous suspension, then the mixture is cooled to 0° C. and a solution of 1.38 mmol of sodium nitrite in 330 ml of water is added dropwise over 1 hour. The mixture is stirred for an additional 20 minutes and then a solution of 700 ml of fluoroboric acid (prepared by dissolving 264 g of boric acid in 744 ml of 40% aqueous hydrofluoric acid) is added. After 30 minutes of stirring, the separated fluoroborate is filtered off, washed successively with small amounts of fluoroboric acid solution, ethanol and water, and dried in vacuo. Thermal decomposition of the fluoroborate is carried out in a flask at 130-170° C. The distillate is partitioned between water and diethyl ether. The organic phase is washed successively with 10% aqueous NaOH, 3N aqueous HCl and water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (SiO2 60 F) to afford the title compound which is identified based on the Rf value.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si](C(C)(C)C)(C)C)[CH2:10][C@H:9]1[C:21](=[O:30])[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+].C(N(CC)CC)C.[CH3:58][S:59](Cl)(=[O:61])=[O:60]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:59]([CH3:58])(=[O:61])=[O:60])[CH2:10][C@H:9]1[C:21](=[O:30])[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)CC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To a solution of (2S,4R)-N-tert-butoxycarbonyl-2-(2-tert-butoxycarbonyl-1-oxoethyl)-4-tert-butyldimethylsiloxypyrrolidine (3.39 g, 7.64 mmol) in tetrahydrofuran (35 ml) was added a 1M tetrabutylammonium fluoride--tetrahydrofuran solution (8.41 ml, 8.41 mmol). This solution was stirred at room temperature for 8 h. Saturated aqueous ammonium chloride was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was dissolved in methylene chloride (50 ml), and triethylamine (3.22 ml, 22.9 mmol) and methanesulfonyl chloride (1.18 ml, 15.3 mmol) were successively dropwise added thereto at 0° C. The mixture was stirred at the same temperature for 2 h. Then, saturated aqueous ammonium chloride was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (heptane-ethyl acetate=1:1) to obtain the title compound (2.33 g, yield: 74.8%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].C([O:9][CH:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C:12](=[CH:13][C:14](=[O:37])[C@@H:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=O)C>C1COCC1>[CH2:3]([C:14]1([OH:37])[CH:13]=[C:12]2[C@:32]([CH3:35])([CH2:33][CH2:34][CH:10]([OH:9])[CH2:11]2)[C@@H:31]2[C@@H:15]1[C@H:16]1[C@:28]([CH3:36])([CH2:29][CH2:30]2)[C@@H:19]([C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:25])[CH3:26])[CH2:18][CH2:17]1)[CH:2]=[CH2:1]
Reactant: CC(=O)OC1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC1(O)C=C2CC(O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]21

Procedure:
Following the analogous general Grignard procedure of Example 2, allyl magnesium bromide was reacted with Compound 1 in dry THF to yield the titled product 11. Proton NMR confirmed the assigned structure.
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[CH:15]=3)[CH:9]=2)[CH:4]=[CH:3]1.[Cl:29][C:30]1[C:37]([F:38])=[CH:36][CH:35]=[C:34]([Cl:39])[C:31]=1[CH:32]=O>CCCCCCC>[Cl:29][C:30]1[C:37]([F:38])=[CH:36][CH:35]=[C:34]([Cl:39])[C:31]=1/[CH:32]=[N:1]/[N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[CH:15]=3)[CH:9]=2)[CH:4]=[CH:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(N)c4c3)cn2)CC1
Reactant: O=Cc1c(Cl)ccc(F)c1Cl
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(/N=C/c5c(Cl)ccc(F)c5Cl)c4c3)cn2)CC1
Temperature: 120 °C
Yield: 86.9 %

Procedure:
A mixture of tert-butyl 4-[4-(1-amino-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (100 mg, 0.26 mmol) and 2,6-dichloro-3-fluorobenzaldehyde (50 mg, 0.26 mmol) in heptane (2.0 mL) was heated in a sealed tube at 120° C. for 15 min. The product was purified by column chromatography (ethyl acetate) to give the desired intermediate as an off-white solid (126 mg, yield 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:40])[CH:5]=[C:6]([Cl:39])[C:7]=1[CH2:8][C@@H:9]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[C:26]([O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)[CH:25]=1)[O:10][C:11](=[O:23])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1.[H-].[Na+].I[CH3:44]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:40])[CH:5]=[C:6]([Cl:39])[C:7]=1[CH2:8][C@@H:9]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[C:26]([O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)[CH:25]=1)[O:10][C:11](=[O:23])[N:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)[CH3:44]
Reactant: COc1ccc(NC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(N(C)C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
To a stirred solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,4-dimethoxyphenylcarbamoyloxy)ethyl)pyridine 1-oxide (127.5 mg, 0.21 mmol) in anhydrous THF (4 ml) and cooled at 0° C., sodium hydride (10.21 mg, 0.255 mmol) and iodomethane (0.016 ml, 0.255 mmol) were sequentially added. The cold bath was removed and the mixture was stirred at RT for 2 hours. Then the reaction was quenched with iced water and extracted with EtOAc. The combined organic layer were washed with brine, dried over Na2SO4 and evaporated. Purification of the resulting crude by flash chromatography on silica gel (DCM:MeOH 100:2) afforded the desired product as a white solid (95 mg, 0.155 mmol, 72.8% yield, [α]D=+21.41, c 0.569, DCM)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:10](O)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.ClC(OCC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:10][OH:11])[CH2:6][CH2:7][CH2:8][CH2:9]1)=[O:4]
Reactant: COC(=O)C1(C(=O)O)CCCC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C1(CO)CCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 47.1 %

Procedure:
To a solution of cyclopentane-1,1-dicarboxylic acid methyl ester (1.00 g, 5.81 mmol) and triethylamine (808 uL, 5.81 mmol) in THF (15 mL) is added isobutyl chloroformate (750 uL, 5.81 mmol) at 0° C. The mixture is stirred at 0° C. for 20 minutes. The mixture is filtrated, and the filtrate is added to a suspension of NaBH4 (242 mg) in THF (15 mL) at 0° C. The mixture is stirred at 0° C. for 3 hours and at room temperature for 12 hours. To the mixture, H2O is added and the mixture is extracted with EtOAc. The organic layer is dried over MgSO4, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give 1-hydroxymethyl-cyclopentanecarboxylic acid methyl ester (433 mg, 47%); TLC (hexane/EtOAc, 1:1) Rf 0.43.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])=[N:6][CH:7]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:33]=2)=[CH:7][N:6]=1)(=[O:12])=[O:11]
Reactant: CC(C)CN(Cc1ccc(Br)cn1)S(=O)(=O)c1ccccc1Cl
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)cn1)S(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 1, step 3, N-(5-bromo-pyridin-2-ylmethyl)-2-chloro-N-isobutyl-benzenesulfonamide was reacted with (3-methylsulfonylphenyl)-boronic acid, Na2CO3 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct in dioxane/water to give 2-chloro-N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-pyridin-2-ylmethyl]-benzenesulfonamide as a colorless solid. MS: 493.0 ([M+H]+)
Reaction SMILES: [CH2:1]([N+:3]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([CH3:24])([CH2:16][CH2:17][CH2:18][CH2:19][S:20]([OH:23])(=[O:22])=[O:21])[C:4]=1[CH3:25])[CH3:2].Cl.[C:27]1([N:33]=[CH:34][CH2:35][CH:36]=NC2C=CC=CC=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)(=O)C>[NH:33](/[CH:34]=[CH:35]/[CH:36]=[CH:25]/[C:4]1[C:5]([CH3:24])([CH2:16][CH2:17][CH2:18][CH2:19][S:20]([OH:23])(=[O:22])=[O:21])[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([S:12]([O-:15])(=[O:13])=[O:14])[CH:7]=2)[N+:3]=1[CH2:1][CH3:2])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C(CC=Nc1ccccc1)=Nc1ccccc1
Reactant: CC[N+]1=C(C)C(C)(CCCCS(=O)(=O)O)c2cc(S(=O)(=O)[O-])ccc21
Agent: Cl
Solvent: CC(=O)O
Product: CC[N+]1=C(/C=C/C=C/Nc2ccccc2)C(C)(CCCCS(=O)(=O)O)c2cc(S(=O)(=O)[O-])ccc21

Procedure:
1-Ethyl-2,3-dimethyl-3-(4-sulphobutyl)-3H-indolium-5-sulphonate, crude (1.1 g), malonaldehyde bis(phenylimine) HCl (0.5 g) and acetic acid (20 ml) were heated under nitrogen at 130° C. for 8 hrs to give a dark orange-red solution. The solvent was then evaporated under vacuum; the residue was partitioned in a water/dichloromethane/methanol mixture. UV/Vis is analysis (ethanol) confirmed the presence of the product in the upper, aqueous layer (λmax=524 nm) while the malonaldehyde starting material was present only in the lower, organic layer (λmax=384 nm). The aqueous layer was evaporated under vacuum and purified by HPLC (water/0.1% TFA and acetonitrile/0.1% TFA eluants). Fractions containing the product were pooled and evaporated, with final drying under high vacuum over phosphorus pentoxide to give the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[C:18]([C:25]#[C:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:13]1[C:22]2[C:17](=[C:18]([C:25]#[C:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1
Reactant: COc1ccc2c(Cl)nncc2c1C#Cc1ccccc1
Reactant: Cc1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C#Cc1ccccc1
Reaction time: 1 h
Yield: 60.2 %

Procedure:
A solution under N2 of 3,5-dichloro-4-methyl-pyridine (0.768 g, 4.74 mmoles) in dry DMF (10 ml) was added under stirring at room temperature with 60% NaH (189.6 mg, 4.74 mmoles) and the mixture was stirred for 1 hour, then dropwise added with 1-chloro-6-methoxy-5-phenylethynyl-phthalazine (700 mg, 2.37 mmoles), prepared as described in example 61, in dry DMF (20 ml). After 3 hours the mixture was poured into water, extracted with ethyl acetate, washed with water, anhydrified over Na2SO4 and brought to dryness. The residue was flash chromatographed (eluent: petrolatum/ethyl acetate 3:7). The separated product was taken up in ethyl ether and crystallised from 30 ml of ethyl acetate/CH2Cl2 to give 600 mg of the title compound (yield: 60%). m.p.: 217-219° C.