Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12](Br)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)CCC>>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2snc(C)c2c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Product: CCCCOC(=O)c1nc(-c2ccccn2)c2snc(C)c2c1O

Procedure:
The title compound was synthesized in analogy Example 3 from 7-bromo-4-hydroxy-3-methyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester and 2-(tributylstannyl)pyridine: MS (m/z) 344.2 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10]O.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:13][CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: OCc1cc2ccccc2o1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cc2ccccc2o1
Temperature: 25 °C

Procedure:
To benzofuran-2-yl-methanol (4.3 g, 29.0 mmol, 1 eq., Example 140, Step 1), dichloromethane (200 mL) was added and the solution was cooled using an ice-ethanol bath. Then carbon tetrabromide (10.6 g, 31.9 mmol, 1.1 eq.) and 1,3-bis(diphenylphosphino)-propane (6.6 g, 16.0 mmol, 0.55 eq.) were added under argon, and the reaction was allowed to slowly warm to room temperature for 2.5 hours. After work-up and flash column chromatography, 2-bromomethyl-benzofuran was obtained in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.9 (s, 2 H) 7.0 (dd, J=5.3, 0.5 Hz, 1 H) 7.3 (dd, 1 H) 7.4 (m, 1 H) 7.6 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[C:21]([O-])([O-])(OCC)[CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:21]([CH3:22])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: CCOC(C)([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 6 h

Procedure:
To a solution of 2.84 parts of 7-chloro-2-hydrazino-5-phenyl-3-H-1,4-benzodiazepine in 50 parts by volume of chloroform are added 10 parts of ethyl orthoacetate and 4 parts of p-toluenesulfonic acid. The solution is left standing at room temperature for 6 hours and heated for a while on a water-bath to complete the reaction. The mixture is washed with saturated aqueous sodium bicarbonate, then with water and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue is treated in a similar manner to Example 18 to give 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-a][1,4] benzodiazepine as colorless needles. Melting point: 224° C to 225° C.
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][C@@H:7]([C@@H:9]1[C@@H:12]([C@H:13]([C:15]([S:17][CH3:18])=[S:16])[CH3:14])[NH:11][C:10]1=[O:19])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH:22][CH:23](O)[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25]>C1(C)C=CC=CC=1>[CH2:27]([O:26][C:24]([C@H:23]([N:11]1[C@H:12]([C@H:13]([C:15]([S:17][CH3:18])=[S:16])[CH3:14])[C@@H:9]([C@H:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:20])[CH3:21])[CH3:8])[C:10]1=[O:19])[OH:22])=[O:25])[CH:28]=[CH2:29]
Reactant: C=CCOC(=O)C(O)O
Reactant: CSC(=S)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Solvent: Cc1ccccc1
Product: C=CCOC(=O)[C@@H](O)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](C)C(=S)SC
Yield: 97.1 %

Procedure:
To a solution of (3S,4S)-3-[(1R)-1-(tertbutyldimethylsilyloxy)ethyl]-4-[(1R)-1-{(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine (700 mg) in toluene (7 ml) was added allyl dihydroxyacetate (560 mg), and the mixture was heated under reflux for 3 hours. The solution was washed with water, dried, and evaporated under reduced pressure to give a mixture (903 mg) of (3S,4S)-1-[(1R)-1-(allyloxycarbonyl)-1-hydroxymethyl]-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-{(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine and (3S,4S)-1-[(1S)-1-(allyloxycarbonyl)-1-hydroxymethyl]-3[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-{(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]2[C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][CH:25]=[CH:24]3)=[CH:6][CH:5]=1.[CH3:30]I>C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]2[C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([CH3:30])[CH:25]=[CH:24]3)=[CH:6][CH:5]=1
Reactant: CI
Reactant: O=c1c2ccccc2nc(-c2ccc3[nH]ccc3c2)n1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc2cc(-c3nc4ccccc4c(=O)n3-c3ccc(Cl)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
NaH (60% in oil) (0.006 g, 0.14 mmol) was added to a 0° C. solution of 3-(4-chlorophenyl)-2-(1H-indol-5-yl)quinazolin-4(3H)-one (0.14 mmol) in THF (5 mL). After stirring for 15 min, MeI (0.01 mL, 0.16 mmol) was added, and the reaction was warmed to room temperature for 1 hour. After quenching with H2O, diluting with EtOAc, washing with brine, drying with Na2SO4, and filtering, the mixture was concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 10% to 70% EtOAc in heptane, afforded the title compound as a white solid (65%). 1H-NMR (300 MHz, DMSO-d6): δ8.18 (d, J=6.8 Hz, 1H), 7.87-7.90 (m, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.66 (s, 1H), 7.57-7.59 (m, 1H), 7.21-7.47 (m, 6H), 7.12 (d, J=7.0 Hz, 1H), 6.4 (d, J=2.9 Hz, 1H), 3.74 (s, 3H). MS (APCI) m/z: 386 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:35])[NH:10][C@H:11]([C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30](Br)=[C:29]([CH3:34])[CH:28]=2)[N:26]=1)=[O:16])[CH:12]([CH3:14])[CH3:13].[CH3:36][C:37]1[CH:38]=[C:39]([NH2:52])[CH:40]=[CH:41][C:42]=1B1OC(C)(C)C(C)(C)O1.C1(C)C=CC=CC=1.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>[CH3:7][O:8][C:9](=[O:35])[NH:10][C@H:11]([C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:42]3[CH:41]=[CH:40][C:39]([NH2:52])=[CH:38][C:37]=3[CH3:36])=[C:29]([CH3:34])[CH:28]=2)[N:26]=1)=[O:16])[CH:12]([CH3:14])[CH3:13]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(Br)c(C)c2)c[nH]1)C(C)C
Reactant: Cc1cc(N)ccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(N)cc3C)c(C)c2)c[nH]1)C(C)C
Temperature: 100 °C

Procedure:
Potassium carbonate (224 mg, 1.619 mmol) was added to a mixture of ((S)-1-{(S)-2-[4-(4-bromo-3-methyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (150 mg, 0.324 mmol) and 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (90.6 mg, 0.389 mmol) in toluene (0.6 mL, 6 mmol) and water (0.3 mL, 20 mmol). The reaction mixture was degassed and flushed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (44.9 mg, 0.039 mmol) was added under nitrogen and then the reaction mixture was capped and heated at 100° C. overnight, cooled to RT and partitioned between ethyl acetate (10 mL) and water (2 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give a brownish oil, which was purified by silica gel chromatography (12 g silica gel, 0-100% EtOAc/hexanes). Desired fractions were combined and concentrated to give the title compound as a light yellowish foam (135 mg, 85% yield). (m/z): [M+H]+ calcd for C28H35N5O3 490.27 found 490.6.
Reaction SMILES: C([O:8][C:9]([C:11]1([C:20]#[N:21])[CH2:13][C:12]1([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[O:10])C1C=CC=CC=1>CO.Cl.[Pt](=O)=O>[NH2:21][CH2:20][C:11]1([C:9]([OH:10])=[O:8])[CH2:13][C:12]1([CH2:14][CH2:15][CH3:16])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC1(CCC)CC1(C#N)C(=O)OCc1ccccc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: CCCC1(CCC)CC1(CN)C(=O)O
Reaction time: 21 h
Yield: 25.2 %

Procedure:
To a solution of 1-cyano-2,2-dipropyl-cyclopropanecarboxylic acid benzyl ester (0.35 g, 1.79 mmol) in 16 mL MeOH—HCl was added platinum dioxide (PtO2) (0.035 g). The mixture was hydrogenated in a Parr shaker at 48 psi for 21 hours. The mixture was filtered and concentrated. Flash chromatography of the residue on silica gel (0.25:1.25:3.5 conc. ammonium hydroxide (NH4OH) (aq):MeOH:CH2Cl2), followed by ion-exchange chromatography on a DOWEX-50WX8-100 resin provided 0.09 g (18%) of 1-aminomethyl-2,2-dipropyl-cyclopropanecarboxylic acid as a colorless solid, mp 255–257° C.: 1H NMR (CD3OD) δ 3.26 (d, J=12.9 Hz, 1H), 3.03 (d, J=12.9 Hz, 1H), 1.69 (m, 1H), 1.56 (m, 2H), 1.28–1.50 (m, 4H), 1.26 (d, J=4.4 Hz, 1H), 1.17 (m, 1H), 0.93 (t, J=7.3 Hz, 3H), 0.85 (t, J=7.3 Hz, 3H), 0.54 (d, J=4.6 Hz, 1H). LRMS: m/z 198.1 (M−1). Anal. Calcd for C11H21NO2: C, 66.29; H, 10.62; N, 7.03. Found: C, 66.39; H, 10.79; N, 7.05.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([F:43])[C:29]=1[Sn](CCCC)(CCCC)CCCC>>[F:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([F:43])[C:29]=1[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(F)cncc1F
Reactant: Fc1ccc(-c2nncc(-c3ccc(F)c(Br)c3)n2)c(F)c1
Product: Fc1ccc(-c2nncc(-c3ccc(F)c(-c4c(F)cncc4F)c3)n2)c(F)c1

Procedure:
5-(3-Bromo-4-fluorophenyl)-3-(2,4-difluorophenyl)-[1,2,4]triazine was coupled to 3,5-difluoro-4-tributylstannylpyridine using the method of Example 6 to give 5-[3-(3,5-difluoropyridin-4-yl)-4-fluorophenyl]-3-(2,4-difluorophenyl)-[1,2,4]triazine, crystallised from hot 2-propanol as a pale yellow solid: δH (500 MHz, d6-DMSO) 7.35 (1H, m), 7.52 (1H, m), 7.79 (1H, t, J 8.9 Hz), 8.34 (1H, m), 8.71 (2H, m), 8.79 (2H, s), 10.13 (1H, s); m/z (ES+) 401.
Reaction SMILES: [NH2:1][CH2:2][C@@:3]1([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:9][C@H:8]2[C@@H:4]1[CH:5]=[C:6]([CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:7]2>Cl.C(OCC)(=O)C>[NH2:1][CH2:2][C@@:3]1([CH2:15][C:16]([OH:18])=[O:17])[CH2:9][C@H:8]2[C@@H:4]1[CH:5]=[C:6]([CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:7]2
Reactant: CC(C)(C)OC(=O)C[C@]1(CN)C[C@@H]2CC(C3CCCC3)=C[C@@H]21
Agent: Cl
Solvent: CCOC(C)=O
Product: NC[C@@]1(CC(=O)O)C[C@@H]2CC(C3CCCC3)=C[C@@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.2 %

Procedure:
Tert-butyl(±)-[(1S,5R,6R)-6-aminomethyl-3-cyclopentylbicyclo[3.2.0]hept-3-en-6-yl]acetate (2.00 g, 6.5 mmol) was dissolved in a 4 N hydrochloric acid-ethyl acetate solution (30 mL), and the solution was stirred at room temperature for 2 hours. Then, the solvent was distilled off under reduced pressure. The residue was suspended by the addition of dichloromethane. To the suspension, triethylamine was then added dropwise, and the resulting powder was collected by filtration. The obtained powder was washed with dichloromethane to obtain the compound of interest as a white powder (0.70 g, 43%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O.C[O:15][C:16](=[O:19])[CH2:17][NH2:18].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][C:11]([NH:18][CH2:17][C:16]([OH:19])=[O:15])=[O:13]
Reactant: O=C(O)CCCNc1ccccn1
Reactant: COC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Product: O=C(O)CNC(=O)CCCNc1ccccn1

Procedure:
0.364 g of [4-(pyridin-2-ylamino)butyrylamino]acetic acid [obtained from peptide coupling of 4-(pyridin-2-ylamino)butyric acid with glycine methyl ester in the presence of HOBT/TBTU and subsequent hydrolysis of the methyl ester, in each case under standard conditions] is dissolved in 30 ml of DMF, and 0.3 g of methyl 3-amino-3-(4-trifluoromethoxyphenyl)propionate is added, and the mixture is cooled to −30°. Addition of 0.321 g of TBTU and 0.045 g of HOBT is followed by neutralization with 0.22 ml of N-methylmorpholine (NMM). The reaction mixture is stirred at room temperature for 2 days. After removal of the solvent by distillation, the residue is taken up in ethyl acetate, washed with NaHCO3 and saturated NaCl solution and further worked up as usual. Methyl 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-trifluoromethoxyphenyl)propionate is obtained, FAB-MS (M+H)+ 497.
Reaction SMILES: [CH2:1]([N:8](C)[CH:9]1[CH2:13][O:12][CH:11]2[CH:14]([O:17]CC3C=CC=CC=3)[CH2:15][O:16][CH:10]12)C1C=CC=CC=1.Cl>CCO.[Pd]>[CH3:1][NH:8][CH:9]1[CH:10]2[O:16][CH2:15][CH:14]([OH:17])[CH:11]2[O:12][CH2:13]1
Reactant: CN(Cc1ccccc1)C1COC2C(OCc3ccccc3)COC21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNC1COC2C(O)COC12
Temperature: 60 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of N-benzyl-6-(benzyloxy)-N-methylhexahydrofuro[3,2-b]furan-3-amine (5.10 g, 15 mmol) in EtOH (40 mL) were added Pd/C (10% wt, 1.0 g) and concentrated HCl (36.5%, 2 mL) in a autoclave under 5 MPa H2. The reaction mixture was stirred at 60° C. overnight and filtered. The filtrate was concentrated in vacuo to give the title compound as yellow oil (2.12 g, 88.6%).
Reaction SMILES: [C:1](O)(=[O:4])[CH:2]=[CH2:3].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[F:22][C:23]1[CH:36]=[CH:35][C:26]([O:27][CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>ClCCl.O>[C:1]([N:32]1[CH2:31][CH2:30][CH:29]([CH2:28][O:27][C:26]2[CH:25]=[CH:24][C:23]([F:22])=[CH:36][CH:35]=2)[CH2:34][CH2:33]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: Fc1ccc(OCC2CCNCC2)cc1
Reactant: C=CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)N1CCC(COc2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 27.8 %

Procedure:
To a solution of acrylic acid (34 μL, 0.49 mmol) in dichloromethane (2.4 mL) cooled at 0° C. was added 4-methylmorpholine (134 μL, 1.22 mol) and isobutyl chloroformate (74 μL, 0.57 mmol). The solution was stirred 15 minutes at 0° C. and then 4-[(4-fluorophenoxy)methyl]piperidine hydrochloride (100 mg, 0.41 mmol) was added. The mixture was stirred at room temperature overnight, diluted with water (7 mL) and extracted twice with DCM (2×5 mL). The combined organic phases were washed with water, dried over sodium sulphate and concentrated in vacuo. The residue obtained was purified by preparative TLC (eluent: dichloromethane/MeOH 95/5) to give the title compound (30 mg, 28%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([NH:6][C:7]2[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[CH:17]=[CH:16][C:8]=2[C:9]([O:11]C(C)(C)C)=[O:10])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]2[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[CH:17]=[CH:16][C:8]=2[C:9]([OH:11])=[O:10])=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)c1ccc(/C=C/c2cccc(O)c2)cc1Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(/C=C/c2cccc(O)c2)cc1Nc1ccc(F)cc1

Procedure:
Trifluoroacetic acid 10 mL solution of the obtained tert-butyl 2-(4-fluoroanilino)-4-((E)-2-(3-hydroxyphenyl)vinyl)benzoate was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 40-90% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-(4-fluoroanilino)-4-((E)-2-(3-hydroxyphenyl)vinyl)benzoic acid 27 mg of pale yellow solid.
Reaction SMILES: CS[C:3]([S:8][CH3:9])=[CH:4][N+:5]([O-:7])=[O:6].[NH2:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[O:19][C:18]([CH2:20][N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=1.[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>O1CCOCC1>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[CH3:22][N:21]([CH3:23])[CH2:20][C:18]1[O:19][C:15]([CH2:14][S:13][CH2:12][CH2:11][NH:10][C:3]([S:8][CH3:9])=[CH:4][N+:5]([O-:7])=[O:6])=[CH:16][CH:17]=1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Agent: O=C(O)C(=O)O
Solvent: C1COCCO1
Product: CSC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Yield: 99.4 %

Procedure:
A solution of 1,1-bis(methylthio)-2-nitroethene (19.8 g) and 5-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl-2-furanmethanamine (6.42 g) in dry dioxan (120 ml) was heated at 80° C. for 6 hours. Oxalic acid (3.8 g) in dry dioxan (40 ml) was added and the crystalline solid which separated was filtered, washed with dioxan and dried to give the title compound (12.55 g) m.p. 140°-143° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]2)[CH2:9]1)=O)(C)(C)C.[ClH:22]>C(OCC)(=O)C>[ClH:22].[CH3:21][S:18]([N:15]1[CH2:14][CH2:13][C:10]2([CH2:9][NH:8][CH2:12][CH2:11]2)[CH2:17][CH2:16]1)(=[O:19])=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(S(C)(=O)=O)CC2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCC2(CCNC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 8-methanesulfonyl-2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (1.32 g) in ethyl acetate (10 ml), a 1 M ethyl acetate solution of HCl (20 ml). After stirring for 2 h at room temperature, solvent is evaporated down to give 8-methanesulfonyl-2,8-diaza-spiro[4.5]decane hydrochloride as a solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:28][N:29](C)C(=O)C>[Zn].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.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].O>[C:28]([C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:22])=[O:23])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1)#[N:29]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)nc23)c1F
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(C#N)nc23)c1F
Temperature: 120 °C
Yield: 41.6 %

Procedure:
In a vial containing propane-1-sulfonic acid [3-(2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl)-2,4-difluoro-phenyl]-amide (P-0002, 0.075 g, 0.16 mmol), N,N-dimethylacetamide (0.147 mL, 1.58 mmol) was added. The solution was degassed by bubbling with argon. Zinc powder (0.99 mg, 0.015 mmol), 1,1′-bis(diphenylphosphino)ferrocene (2.87 mg, 0.00518 mmol), zinc cyanide (11.2 mg, 0.0959 mmol), and Tris(dibenzylideneacetone)dipalladium (0) (02.7 mg, 0.0026 mmol) were added at room temperature under argon. The mixture was heated at 120° C., for 1 hour and 50 minutes and cooled to room temperature. Then, 2 mL of water was added and the reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with a gradient from 1 to 3% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum to give the desired compound (P-0006, 27 mg). MS (ESI)[M+H+]+=406.0.
Reaction SMILES: [N:1]1([S:7]([C:10]2[C:18]3[C:13](=[C:14]([N+:19]([O-])=O)[CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[C:22]([NH2:24])=[O:23])(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11]([C:22]([NH2:24])=[O:23])=[C:10]2[S:7]([N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1)(=[O:9])=[O:8]
Reactant: NC(=O)c1[nH]c2c([N+](=O)[O-])cccc2c1S(=O)(=O)N1CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1[nH]c2c(N)cccc2c1S(=O)(=O)N1CCOCC1
Reaction time: 2 h

Procedure:
To a solution of 3-(morpholin-4-ylsulfonyl)-7-nitro-1H-indole-2-carboxamide (708 mg, 2.00 mmol) in 30 mL of methanol was added 10% palladium on carbon (200 mg), and the reaction was equipped with a balloon of hydrogen gas. After 2 hours, the reaction was filtered through celite, the filter pad was rinsed with ethyl acetate, and the resulting solution was concentrated in vacuo to provide the titled compound as a yellow solid. A portion of this was taken up in dichloromethane, treated with excess ethereal HCl, and concentrated in vacuo to give an off-white solid, used for biological testing. HRMS (ES) exact mass calculated for C13H17N4O4S (M+H+): 325.0965. Found 325.0971.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl.C(O[CH:14](O)[C:15]([CH3:17])=[CH2:16])(=O)C.CC(=C)C(O)O>O1CCOCC1.O>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[N:6]=[CH:16][C:15]([CH3:17])=[CH:14]2
Reactant: Nc1ccc(Cl)cc1
Reactant: C=C(C)C(O)OC(C)=O
Agent: C=C(C)C(O)O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cnc2ccc(Cl)cc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
To a solution of 4-chloroaniline (9.59 g, 75.2 mmol) in dioxane (112 mL) was added a 6 M aqueous solution of HCl (180 mL). The reaction mixture was heated to 100° C. and a solution of 2-methyl-2-propene-1,1-diol acetate (15.5 g, 90.3 mmol) in dioxane (20 mL) was added dropwise during 1 h under an argon atmosphere. The reaction mixture was stirred for 2 h at 120° C. after which an aliquot was taken and analyzed by HPLC. Since some starting material was still left, the reaction mixture was cooled down to 100° C. and another portion of 2-methyl-2-propene-1,1-diol actetate (5.2 g, 30 mmol) was added during 1 h. After heating for 2 h at 120° C., the reaction mixture was cooled down again to 100° C. and a final portion of 2-methyl-2-propene-1,1-diol actetate (5.2 g, 30 mmol) was added during 1 h at 100° C. Heating was continued for 30 min. at 120° C. After cooling to ambient temperature the reaction mixture was diluted with water (100 mL) and extracted with 2-methoxy-2-methylpropane (2×200 mL). The combined organic phases were extracted with a 4 M HCl solution (100 mL). The combined aqueous phases were basified to pH 9 with a 4 M NaOH solution and extracted with TBME (3×200 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated at reduced pressure to afford a brown oil. The crude product was purified by flash column chromatography (silica gel, cyclohexane/EtOAc 95:5) to afford 6-chloro-3-methylquinoline as a pale brown crystalline solid (6.32 g, 35.6 mmol, 47%). 1H NMR (400 MHz, CDCl3, 298 K): δ=8.78 (d, J=2.2 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.86 (bs, 1H), 7.75 (d, J=2.2 Hz, 1H), 7.60 (dd, J=8.8 Hz, 2.2 Hz, 1H), 2.55 (s, 3H). MS (ES+): 178 (M(C10H835ClN)+H)+.