Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[N:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10](O)[C:5]=2[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:3]1.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][N:7]=[C:6]2[N:2]([CH3:1])[N:3]=[C:4]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:5]=12
Reactant: Cn1nc(N2CCCC2)c2c(O)c(-c3ccccc3)nnc21
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1nc(N2CCCC2)c2c(Cl)c(-c3ccccc3)nnc21
Temperature: 60 °C

Procedure:
A suspension of 1-methyl-5-phenyl-3-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-c]pyridazin-4-ol (117 mg) in POCl3 (1.9 mL) was heated to 60° C. for 2.5 h. The mixture was concentrated in vacuo and the residue was partitioned between CH2Cl2 and sat. aq. NaHCO3 solution. The layers were separated and the aqueous was extracted with CH2Cl2, the combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel to give the title compound (81 mg).
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]2[N:8]([CH:14]3[CH2:16][CH2:15]3)[CH2:9][NH:10][S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=1)([OH:3])=[O:2].[C:19]1(O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1.O>CN(C=O)C>[CH:14]1([N:8]2[C:7]3[CH:17]=[CH:18][C:4]([C:1]([O:3][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:2])=[CH:5][C:6]=3[S:11](=[O:13])(=[O:12])[NH:10][CH2:9]2)[CH2:15][CH2:16]1
Reactant: Oc1ccccc1
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)NCN2C1CC1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: O=C(Oc1ccccc1)c1ccc2c(c1)S(=O)(=O)NCN2C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-carbonyldiimidazole (0.6 g) is added to a solution of the compound of Example 78 (3.5 mmol) in DMF (7 mL). After stirring for 1 hour at ambient temperature, phenol (0.5 g) and DBU (0.5 mL) are added. After stirring for 2 hours at ambient temperature, water (40 mL) is added and the mixture is extracted three times with ethyl acetate (30 mL). The organic phases are combined, dried over anhydrous MgSO4 and filtered. The filtrate is evaporated to dryness and the residue is re-dissolved in methanol (5 mL). Water (50 mL) is added to the solution and the precipitate obtained is collected by filtration, washed with water and dried to yield the title product in the form of a white solid.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:15][CH2:14][CH2:13][C@@H:12]([O:16]CC2C=CC=CC=2)[C@@H:11]1[C:24]1[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[C].[Pd].C(O)C>[C:1]([O:9][C@H:10]1[CH2:15][CH2:14][CH2:13][C@@H:12]([OH:16])[C@@H:11]1[C:24]1[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1nccc1[C@@H]1[C@@H](OC(=O)c2ccccc2)CCC[C@H]1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Cn1nccc1[C@H]1[C@H](O)CCC[C@@H]1OC(=O)c1ccccc1
Yield: 43.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 106b by using the (1S*,2S*,3R*)-3-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl benzoate (1.81 g, 4.64 mmol) prepared in Example 117a, palladium carbon (5%; 1.80 g) and ethanol (20 mL), to yield the title compound (600 mg, 43%) as a colorless oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([OH:15])=O)[CH2:8][CH2:7]1)=[O:5].[NH2:16][C@@H:17]([CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19]>>[CH2:37]([O:36][CH2:35][C@H:17]([NH:16][C:13](=[O:15])[CH2:12][N:9]1[CH2:8][CH2:7][CH:6]([C:4]([O:3][CH3:2])=[O:5])[CH2:11][CH2:10]1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COC(=O)C1CCN(CC(=O)O)CC1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: COC(=O)C1CCN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)CC1
Yield: 50.3 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(methoxycarbonyl)piperidin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 238, (S)-methyl 1-(2-(3-(benzyloxy)-1-(4-(4-fluorophenoxy)phenylamino)-1-oxopropan-2-ylamino)-2-oxoethyl)piperidine-4-carboxylate (22.7 mg, 50.3%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 7.95 (d, 1H), 7.60 (d, 2H), 7.29 (m, 5H), 7.21 (t, 2H), 7.04-6.98 (m, 4H), 4.69 (m, 1H), 4.52 (s, 2H), 3.77 (m, 1H), 3.70 (m, 1H), 3.61 (s, 3H), 2.96 (s, 2H), 2.80 (m, 2H), 2.32 (m, 1H), 2.12 (t, 2H), 1.79 (m, 2H), 1.60 (m, 2H). MS (EI) for C31H34FN3O6. found 564.6 (MH+).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:23]4[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH:28]=4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.C([SiH](CC)CC)C>[Pd]>[F:30][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([CH:23]4[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: CN1CC=C(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)CC1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Product: CN1CCC(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)CC1

Procedure:
The title compound was synthesized according to the procedure described in example 126 using 6-chloro-2-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, palladium on carbon and triethylsilane. 1H NMR (400 MHz, DMSO-d6) δ 8.80 (t, J=5.81 Hz, 1H), 8.05 (d, J=8.72 Hz, 1H), 7.98 (d, J=9.01 Hz, 1H), 7.78 (d, J=9.01 Hz, 1H), 7.61 (d, J=8.71 Hz, 1H), 3.27 (t, J=6.21 Hz, 4H), 3.04 (s, 1H), 2.69 (s, 2H), 2.58 (s, 3H), 2.03 (s, 6H), 1.74-1.86 (m, 5H), 1.22-1.33 (m, 2H). m/z: 436.0 [M+H]+
Reaction SMILES: [N+:1]([C:4]1[C:17]2[O:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:18])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[C:17]2[O:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:18])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=c1c2ccccc2oc2c([N+](=O)[O-])cccc12
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc2c(=O)c3ccccc3oc12
Yield: 88.6 %

Procedure:
A mixture of 4-nitroxanthen-9-one 2k (4.5 g, 18.7 mmol) and 10% palladium on carbon (200 mg) in ethanol (70 mL) was hydrogenated (hydrogen pressure: 55 psi) for 16 h. The catalyst was removed via filtration and the solvent was evaporated to yield 3.5 g (89%) of title compound 4-aminoxanthen-9-one 3k.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[C:7]1(=O)[O:12][C:10](=[O:11])[CH:9]2[CH2:13][CH2:14][CH2:15][CH2:16][CH:8]12>C(O)C>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][N:1]1[C:10](=[O:11])[CH:9]2[CH2:13][CH2:14][CH2:15][CH2:16][CH:8]2[C:7]1=[O:12]
Reactant: O=C1OC(=O)C2CCCCC12
Reactant: NCC(O)CO
Solvent: CCO
Product: O=C1C2CCCCC2C(=O)N1CC(O)CO
Yield: 81 %

Procedure:
A 500-ml, two necked flask was equipped with a magnetic stirring bar, heating mantle and condenser. The flask was charged with 46 g of 3-amino-1,2-propanediol (0.50 mol.) and 300 ml of ethanol. Next, 77 g of hexahydrophthalic anhydride (0.50 mol.) was slowly added to the flask after which the reaction was refluxed for 12 hours. The imide formation was confirmed by IR. The ethanol was removed by a rotoevaporator to yield 92 g (81%) of the N-(2,3-dihydroxypropyl)hexahydrophthalimide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:13]N(C=O)C.C(Cl)(=O)C.CO>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5]([O:7][CH3:13])=[O:6]
Reactant: CN(C)C=O
Reactant: COc1cc(Br)cc(C(=O)O)c1
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: COC(=O)c1cc(Br)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of crude 3-bromo-5-methoxybenzoic acid (40% purity, 0.8 g, 1.4 mmol) in CH2Cl2 (50 mL) at 0° C. were added DMF (0.1 mL) and acetyl chloride (0.2 mL, 3 mmol). The mixture was slowly warmed to rt and stirred overnight. Then the mixture was cooled to 0° C. and methanol (2 mL) was slowly added. The mixture was stirred at rt for 3 h and then washed with aq. Na2CO3 solution, brine, dried (Na2SO4), and concentrated. The residue was purified via flash chromatography to afford the desired product as a white solid. 1H NMR (CDCl3, 400 MHz): 7.76 (t, J=1.6 Hz, 1H), 7.49 (t, J=1.3 Hz, 1H), 7.24 (t, J=2.2 Hz, 1H), 3.92 (s, 3H), 3.84 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.C(O)(=O)C.[C:13]1(C)[CH:18]=CC=C[CH:14]=1>>[N:1]1[C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=2[CH:18]=[CH:13][CH:14]=1
Reactant: NC1=CC(=O)CCC1
Reactant: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C1CCCc2ncccc21

Procedure:
A mixture of 57.93 g of 3-amino-2-cyclohexene-1-one, 76.8 g of 3-(dimethylamino)acrotein, 62.5 ml of glacial acetic acid and 270 ml of toluene is refluxed under argon for 16 hours and concentrated under vacuum to dryness. Toluene (200 ml) is added and the solvent removed under vacuum. To the residue is added one liter of dichloromethane and then 200 ml of saturated NaHCO3 slowly added and solid NaHCO3 added to bring the pH to 8. The mixture is filtered and the CH2Cl2 layer separated. The CH2Cl2 layer is passed through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residual black oil is extracted with hot hexane and the hexane decanted. This process is repeated until no more product extracted into the hexane. The hexane extracts are combined and the solvent removed to give 17.3 g of product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=S)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].C(O)(=O)C.O1CCOCC1.[NH:35]([C:37]1[N:42]=[C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)[N:40]=[C:39]([NH2:49])[N:38]=1)[NH2:36]>O>[CH2:10]([C:9]1[N:35]([C:37]2[N:42]=[C:41]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)[N:40]=[C:39]([NH2:49])[N:38]=2)[N:36]=[C:6]([C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:8]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cc1ccccc1)NC(=S)c1ccc(Cl)cc1
Reactant: NNc1nc(N)nc(-c2ccccn2)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc(-c2ccccn2)nc(-n2nc(-c3ccc(Cl)cc3)nc2Cc2ccccc2)n1
Temperature: 90 °C
Reaction time: 15 h
Yield: 60 %

Procedure:
To a solution of N-(4-chloro-thiobenzoyl)-2-phenyl-acetamide (0.536 g, 1.85 mmol) and sodium acetate (ca. 0.25 g) in 1:1 acetic acid/1,4-dioxane (30 mL) was added 4-hydrazino-6-pyridin-2-yl-[1,3,5]triazin-2-ylamine (0.376 g, 1.85 mmol). The solution was heated to 90° C. and stirred for 15 hours. The reaction mixture was allowed to cool to room temperature, and water (100 mL) was added. The precipitate was removed by filtration, triturated with hot ethanol (300 mL), and dried to provide 0.489 g (60%) of the product as a white solid: 1H NMR (DMSO-d6) δ 8.78 (d, J=4.3 Hz, 1H), 8.32 (d, J=6.1 Hz, 2H), 8.22 (d, J=7.8 Hz, 1H), 8.06 (d, J=8.5 Hz, 2H), 7.96 (dt, J=J=1.5, 7.8 Hz, 1H), 7.62-7.57 (m, 3H), 7.36-7.26 (m, 2H), 7.24-7.22 (m, 2H), 7.19-7.16 (m, 1H), 4.90 (s, 2H) ppm.
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[CH2:9]([O:12][C:13](=[O:45])[CH:14]([CH2:32][CH2:33][N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44])[NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:10]=[CH2:11]>CN(C)C=O>[CH2:9]([O:12][C:13](=[O:45])[CH:14]([CH2:32][CH2:33][N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44])[N:15]([CH3:3])[S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:23][CH:24]=1)(=[O:17])=[O:18])[CH:10]=[CH2:11]
Reactant: O=C([O-])[O-]
Reactant: C=CCOC(=O)C(CCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCOC(=O)C(CCN1C(=O)c2ccccc2C1=O)N(C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
Methyl iodide (0.83 g, 5.8 mmol) and potassium carbonate (5.34 g, 38.4 mmol) were added to a solution of (±)-N-(4-phenoxybenzenesulfonyl)-2-(2-phthalimidoethyl)glycine allyl ester (2.00 g, 3.8 mmol), the product of (2) above, in N,N-dimethylformamide (20 ml). This mixture was stirred at room temperature for 1 hour. The insoluble material was removed by filtration. The filtrate was extracted with ethyl acetate and the organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=3/1 as the eluant to afford the desired compound (1.90 g, yield 93%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:4][N:5](C(OC(C)(C)C)=O)[C@H:6]1[CH2:11][N:10](C(OC(C)(C)C)=O)[C@H:9]([C:19](=[O:21])[NH2:20])[CH:8]=[C:7]1[CH2:22][O:23][CH3:24])[CH:2]=[CH2:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:4][NH:5][C@H:6]1[CH2:11][NH:10][C@H:9]([C:19]([NH2:20])=[O:21])[CH:8]=[C:7]1[CH2:22][O:23][CH3:24])[CH:2]=[CH2:3]
Reactant: C=CCON(C(=O)OC(C)(C)C)[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1COC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCON[C@H]1CN[C@H](C(N)=O)C=C1COC
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
(2S,5R)-tert-butyl 5-(allyloxy(tert-butoxycarbonyl)amino)-2-carbamoyl-4-(methoxymethyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 73, 3.07 g, 6.95 mmol) was dissolved in 20 mL DCM. Then 5.36 mL TFA was added dropwise at 0° C. The mixture was stirred at rt for 3 h. The solvent was removed in vacuo and co-evaporated twice with 5 mL MeOH. The residue was dissolved in MeOH (10 mL) and ammonium hydroxide (30% in water) was added until it was basic. The mixture was rotovapored at rt and the residue was freeze-dried over night to give a solid. It was dissolved in DCM and purified on silica gel eluting with 0-100% MeOH/DCM to give a off-white solid (1.12 g, 66.8%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]=[C:6]([NH2:11])[C:7]([F:10])([F:9])[F:8])[CH3:2].[C:13](Cl)(=[O:16])[CH:14]=[CH2:15].Cl>C1(C)C=CC=CC=1.CCCCCCC>[CH2:1]([O:3][C:4]([C:5]1[CH2:15][CH2:14][C:13](=[O:16])[NH:11][C:6]=1[C:7]([F:10])([F:8])[F:9])=[O:12])[CH3:2]
Reactant: CCOC(=O)C=C(N)C(F)(F)F
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(C(F)(F)F)NC(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.8 %

Procedure:
To 3-amino-4,4,4-trifluoro-2-butenoic acid ethyl ester (529 mL, 3.47 mol) was added acryloylchloride (600 mL, 6.95 mol) dropwise over a period of 15 min. The suspension was stirred at RT for 1 h. The temperature was slowly raised with stirring to 80° C. (HCl gas evolution) and maintained at 80° C. for 5 h. Stirring continued overnight at 40° C. The mixture was cooled, diluted with toluene (2 L) and n-heptane (2 L) to precipitate the product and stirred for another 15 min at room temperature. The product was isoloated by filtration, the filter cake was washed with toluene/n-heptane (1:2; 4×100 mL) and dried in vacuo at 40° C. for 5 h. This procedure yielded the title compound (286 g, 35%) as a white solid, MS (ISP) 236.1 (M−H)−. Concentration of the mother liquor and addition of toluene/n-heptane (1:10) yielded a second crop of 29.8 g.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][C:18]([CH3:24])([CH3:23])[CH2:17][C:16]3([CH3:26])[CH3:25])=[CH:7][CH:6]=1.[OH-].[Na+]>CO>[CH3:23][C:18]1([CH3:24])[CH2:17][C:16]([CH3:25])([CH3:26])[C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:27])=[O:2])=[CH:10][CH:9]=3)[CH:14]=2)[O:19]1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CC(C)(C)c2cc(C#Cc3ccc(CC(=O)O)cc3)ccc2O1
Temperature: 55 °C
Yield: 75.1 %

Procedure:
A solution of [4-(2,2,4,4-tetramethyl-chroman-6-yl-ethynyl) phenyl] acetic acid methyl ester (Compound 27, 0.047 g, 0.13 mmol) in 5 mL of methanol was treated with 1M sodium hydroxide solution (2 mL) and heated at 55° C. for 2 h. The volatiles were distilled off in vacuo and the residue was acidified with 10% hydrochloric acid and extracted with ethyl acetate (×2). The combined organic phase was washed with brine (×1), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was purified by preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase to afford the title compound (0.034 g, 82%). 1H NMR (300 MHz, CDCl3): δ 7.49-7.45 (m, 3H), 7.26-7.22 (m, 3H), 6.75 (d, 1H, J=8.2 Hz), 3.65 (s, 2H), 1.84 (s, 2H), 1.36 (s, 6H), 1.35 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][SH:16])=[CH:13][CH:12]=1.[Na]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:15]([S:16][CH:15](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: SCc1ccc(Cl)cc1
Agent: [Na]
Product: Cc1ccc(/C=C\C(SC(/C=C\c2ccc(C)cc2)c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1

Procedure:
A solution of 4-methylphenylacetylene (0.02 mol) and 4-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to Procedure 2 to form (Z)-4-methylstyryl 4-chlorobenzylsulfide. The title compound was obtained in 74% yield following oxidation. 1HNMR (CDC13) δ2.46 (3H, s), 4.64 (2H, s), 6.75 (1H, d, JH,H=12.21), 7.18-7.57 (9H aromatic+1H ethylenic).
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=O)[C:8](=[O:14])[NH:9]2)[CH:2]([CH3:4])[CH3:3].[CH:16]1[C:21]([NH:22][NH2:23])=[CH:20][CH:19]=[C:18]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:17]=1.Cl>>[CH2:1]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[N:23][NH:22][C:21]1[CH:20]=[CH:19][C:18]([S:24]([NH2:27])(=[O:25])=[O:26])=[CH:17][CH:16]=1)[C:8](=[O:14])[NH:9]2)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1cccc2c1C(=O)C(=O)N2
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: CC(C)Cc1cccc2c1C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Yield: 65 %

Procedure:
Condensation of 4-isobutyl-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G gave the title compound in 65% yield: 1H NMR (DMSO-d6): δ 0.96 (d, J=6.4 Hz, 6H), 2.05 (m, 1H), 2.87 (d, J=7.0 Hz, 2H), 6.79 (d, J=7.6 Hz, 1H), 6.85 (d, J=7.6 Hz, 1H), 7.20 (t, J=7.6 Hz, 1H), 7.26 (s, 2H), 7.51 (d, J=8.5 Hz, 2H), 7.81 (d, J=8.5 Hz, 2H), 11.13 (s, 1H), 13.03 (s, 1H); APCI-MS m/z 371 (M−1)−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:9][C:10]2[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([CH3:23])[CH:11]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)#[CH:25].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1CCCCC1.C(NC(C)C)(C)C>O1CCCC1.[Cu]I>[Br:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([CH3:23])[CH:11]=2)[CH:3]=[C:2]([C:25]#[C:24][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:7]=1
Reactant: C#Cc1ccccn1
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(Br)c2)cc1C
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1CCCCC1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2cc(Br)cc(C#Cc3ccccn3)c2)cc1C
Temperature: 40 °C
Reaction time: 8 h

Procedure:
In nitrogen atmosphere, ethyl [4-(3,5-dibromophenylsulfanyl)-2-methylphenoxy]-acetate (460 mg, 1 mmol; prepared as described in example 1) and 2-ethynylpyridine (110 μL, 1.1 mmol) were dissolved in anhydrous tetrahydrofuran (7 mL). 0.15 M Solution of tri-tert-butylphosphine in cyclohexane (0.6 mL, 0.06 mmol) was added via syringe. Copper(I) iodide (3.8 mg, 0.02 mmol), dichloro(bisbenzonitrile)palladium (11 mg, 0.03 mmol) and diisopropylamine (155 μL, 1.1 mmol) were added. Traces of the air were removed and mixture was stirred under nitrogen at 40° C. overnight. The mixture was diluted with ethyl acetate (10 mL) and filtered through a short path of silica gel. The filtrate was concentrated and purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 90:10-85:15) yielding ethyl [4-[3-bromo-5-[(pyridin-2-yl)ethynyl]phenylsulfanyl]-2-methylphenoxy]acetate beside of 144 mg (30%) of unchanged starting dibromo derivative.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][CH2:9][N:10]([CH2:14][CH2:15][OH:16])[C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1)#[N:2].C([Li])CCC.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][N:10]([CH2:14][CH2:15][O:16][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[C:11]([NH2:13])=[O:12])=[CH:17][CH:18]=1)#[N:2]
Reactant: N#Cc1ccc(OCCN(CCO)C(N)=O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCCN(CCOc2ccc(C#N)cc2)C(N)=O)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of intermediate 1-[2-(4-cyanophenoxy)ethyl]-1-(2-hydroxy-ethyl)urea (4.7 g, 0.0188 mol; see step (i) above) in dry THF (150 mL) was added n-butyllithium (18.89 mL, 1.1 M) at −78° C. The reaction mixture was stirred at −78° C. for 1 h, after which a solution of freshly crystallised p-toluenesulfonyl chloride (4.3 g, 0.023 mol) in THF (50 mL) was added dropwise. The reaction mixture was then stirred at −78° C. for a further 30 min, before being warmed to −30° C., and stirred for 2 h more. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, concentrated and the residue was recrystallised in ethyl acetate/hexane to yield the title compound as an off-white solid. Yield: 3.5 g.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH:18]3[CH2:20][CH2:19]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1Br.[C:22]([C:25]1[CH:26]=[CH:27][C:28](B(O)O)=[N:29][CH:30]=1)(=[O:24])[NH2:23]>>[NH2:1][C:2]1[C:3]([C:28]2[CH:27]=[CH:26][C:25]([C:22]([NH2:23])=[O:24])=[CH:30][N:29]=2)=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14](=[O:16])(=[O:15])[NH:17][CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: NC(=O)c1ccc(B(O)O)nc1
Reactant: Nc1ncc(-c2ccc(S(=O)(=O)NC3CC3)cc2)cc1Br
Product: NC(=O)c1ccc(-c2cc(-c3ccc(S(=O)(=O)NC4CC4)cc3)cnc2N)nc1
Yield: 28.1 %

Procedure:
General method B was applied to 4-(6-amino-5-bromopyridin-3-yl)-N-cyclopropylbenzenesulfonamide (112 mg, 0.304 mmol) and 5-carbamoylpyridin-2-ylboronic acid (75 mg, 0.453 mmol) to provide 2′-amino-5′-(4-(N-cyclopropylsulfamoyl)phenyl)-[2,3′-bipyridine]-5-carboxamide as a white solid (35 mg, 28% yield) after purification by reverse phase preparatory HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.07-9.16 (m, 1H), 8.53 (d, J=2.3 Hz, 1H), 8.47 (d, J=2.3 Hz, 1H), 8.32 (dd, J=14.1, 10.8 Hz, 2H), 8.21 (br. s., 1H), 8.01 (d, J=8.5 Hz, 2H), 7.91 (d, J=2.5 Hz, 1H), 7.85 (d, J=8.3 Hz, 2H), 7.79 (br. s., 2H), 7.61 (br. s., 1H), 2.06-2.18 (m, 1H), 0.34-0.55 (m, 4H); MS (EI) m/z: 410 [M+H]+.