Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH:13]=O)=[CH:11][C:10]2[N:9]([CH3:15])[C:8](=[O:16])[CH2:7][CH2:6][C:5]=2[N:4]=1.[C:17]1([C@H:23]2[C@@H:28]([NH2:29])[CH2:27][CH2:26][CH2:25][NH:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][NH:29][C@H:28]1[CH2:27][CH2:26][CH2:25][NH:24][C@H:23]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:9]([CH3:15])[C:8](=[O:16])[CH2:7][CH2:6]2
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Reactant: COc1nc2c(cc1C=O)N(C)C(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COc1nc2c(cc1CN[C@H]1CCCN[C@H]1c1ccccc1)N(C)C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
The 2-methoxy-5-methyl-6-oxo-5,6,7,8-tetrahydro-[1,5]naphthyridine-3-carbaldehyde prepared in step 5 (0.35 g; 1.4 mmol) was dissolved in 20 ml of dichloroethane. To this was added 250 mg (1.1 mmol) of 2-(S)-phenyl-piperidin-3(S)-ylamine and 0.4 ml (2.8 mmol) of triethylamine, and the mixture was stirred for 60 minutes at room temperature. To this mixture was added 0.7 g (3.3 mmol) of sodium triacetoxyborohydride, and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water and stirred at room temperature for 30 minutes. The pH of the mixture was adjusted to 8.5 with Na2CO3. The organic layer was separated from the water layer. An additional 20 ml of water was added to the organic layer. The pH of the mixture was adjusted to 2 with 1N HCl and extracted with ethyl acetate. The pH of the water layer was adjusted to 7.5 with sodium bicarbonate and extracted with ethyl acetate. The pH=7.5 ethyl acetate extracts were combined, dried (Na2SO4), and evaporated to yield 300 mg of 6-methoxy-1-methyl-7-[(2(S)-phenyl-piperidin-3(S)-ylamino)-methyl]-3,4-dihydro-1H-[1,5]naphthyridin-2-one. 1H NMR (CDCl3) δ 7.2–7.4 (m, 5H), 6.85 (s, 1H), 3.90 (s, 1H), 3.85 (s, 3H), 3.60,3.38 (d,d 2H), 3.30 (d, 1H), 3.10 (s, 3H), 3.0 (s, 1H), 2.90 (m, 2H), 2.80 (m, 2H), 2.66 (m, 2H), 2.0–2.2 (m, 3H), 1.9 (m, 1H), 1.6 (m, 1H), 1.45 (m, 1H). Mass spectrum: m/e=381.1 (p+1). TLC: Rf=0.5; (5:1 chloroform/methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]([O:15]C2C=CC=CC=2)=O)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:22][C:23]1[CH:24]=[C:25]([N:29]2[C:33](CN)=[CH:32][C:31]([C:36]([F:39])([F:38])[F:37])=[N:30]2)[CH:26]=[CH:27][CH:28]=1.[CH3:40][N:41](C=O)C>CN(C1C=CN=CC=1)C>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:15])[N:41]([C:33]2[N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=3)[N:30]=[C:31]([C:36]([F:37])([F:38])[F:39])[CH:32]=2)[CH3:40])=[CH:11][C:2]=1[Cl:1]
Reactant: COC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1Cl
Reactant: CN(C)C=O
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Agent: CN(C)c1ccncc1
Product: COC(=O)c1ccc(NC(=O)N(C)c2cc(C(F)(F)F)nn2-c2cccc(Cl)c2)cc1Cl
Temperature: 50 °C

Procedure:
To a solution of methyl 2-chloro-4-(phenoxycarbonylamino)benzoate (80 mg, 0.26 mmol) in DMF was added DMAP (32 mg, 0.26 mmol) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (74 mg, 0.27 mmol) at room temperature. The reaction mixture was heated to 50° C. overnight. TLC showed complete consumption of starting material. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to give pure example compound E59 (77 mg).
Reaction SMILES: Cl[CH2:2][C:3]([NH2:5])=[O:4].[OH:6][C:7]1[C:12]2[C:13]3[CH2:14][NH:15][CH2:16][CH2:17][C:18]=3[C:19]([CH3:22])([CH3:21])[O:20][C:11]=2[CH:10]=[C:9]([CH:23]([CH3:31])[CH:24]([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:8]=1.C(N(CC)CC)C>CN(C)C=O>[OH:6][C:7]1[C:12]2[C:13]3[CH2:14][N:15]([CH2:2][C:3]([NH2:5])=[O:4])[CH2:16][CH2:17][C:18]=3[C:19]([CH3:21])([CH3:22])[O:20][C:11]=2[CH:10]=[C:9]([CH:23]([CH3:31])[CH:24]([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:8]=1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Reactant: NC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(N)=O)CC1
Reaction time: 17 h

Procedure:
A solution of 1.03 g (0.011 mole) of 2-chloroacetamide in 8 ml of dimethylformamide was added dropwise to a stirred solution of 3.57 g (0.01 mole) of 10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5 H-[1] benzopyrano [4,3-c] pyridine in 12 ml of dimethylformamide and 1.11 g (0.011 mole) of triethylamine. After stirring for 17 hours, the mixture was diluted with 20 ml. of water and extracted with ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was recrystallized from acetonitrile, m.p. 165-168°.
Reaction SMILES: N1C=CC=CC=1.[Si:7]([O:14][C@@H:15]([C@@H:17]1[C@@H:20]([C@@H:21]([CH3:40])[C:22]([C:24]2[S:28][C:27]3=[C:29]([C:32]([C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[O:33])[N:30]=[CH:31][N:26]3[CH:25]=2)=[O:23])[N:19]([CH:41]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=2)=[O:44])O)[C:18]1=[O:56])[CH3:16])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].S(Cl)([Cl:59])=O>O1CCCC1.C(OCC)(=O)C>[Si:7]([O:14][C@@H:15]([C@@H:17]1[C@@H:20]([C@@H:21]([CH3:40])[C:22]([C:24]2[S:28][C:27]3=[C:29]([C:32]([C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[O:33])[N:30]=[CH:31][N:26]3[CH:25]=2)=[O:23])[N:19]([CH:41]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=2)=[O:44])[Cl:59])[C:18]1=[O:56])[CH3:16])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: O=S(Cl)Cl
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(C(O)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1[C@@H](C)C(=O)c1cn2cnc(C(=O)c3cccnc3)c2s1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(C(Cl)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1[C@@H](C)C(=O)c1cn2cnc(C(=O)c3cccnc3)c2s1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Pyridine (0.1 ml) was added to a solution of 0.23 g of the crude product of (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[[(4-nitrobenzyloxy)carbonyl]hydroxymethyl]azetidin-2-one in 2 ml of tetrahydrofuran under an argon atmosphere, and the mixture was cooled to −20° C. Thionyl chloride (0.09 ml) was added thereto, and the mixture was stirred at that temperature for one hr. The reaction mixture was diluted with ethyl acetate, and the diluted reaction mixture was washed with water and saturated brine and was then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation to give a crude product of (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[[(4-nitrobenzyloxy)carbonyl]chloromethyl]azetidin-2-one. Triphenylphosphine (0.26 g) and 0.05 g of potassium iodide were added to a solution of this crude product in 2 ml of dimethylformamide, and the mixture was stirred at 60° C. for one hr. The reaction mixture was diluted with ethyl acetate, and the diluted reaction mixture was washed with water and saturated brine and was then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, and the residue was purified by thin layer chromatography (developed with 10% methanol/ethyl acetate) to give 0.19 g of (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[4-nitrobenzyloxycarbonyl(triphenylphosphoranylidene)methyl]azetidin-2-one.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NC(C(C)C)C(N1C2C(=CC=CC=2)C(C)(C)[C@H]1C(NC1C(F)=CC=CC=1F)=O)=O.[C:54]([O:58][C:59]([N:61](C)[C@@H:62](C)C(O)=O)=[O:60])([CH3:57])([CH3:56])[CH3:55].C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[C:54]([O:58][C:59](=[O:60])[NH:61][CH3:62])([CH3:57])([CH3:56])[CH3:55]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CC(C)C(N)C(=O)N1c2ccccc2C(C)(C)[C@H]1C(=O)Nc1c(F)cccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.2 %

Procedure:
HATU (45 mg, 118 μmol, Eq: 1.48) was added to a solution of (S)-1-(2-amino-3-methylbutanoyl)-N-(2,6-difluorophenyl)-3,3-dimethylindoline-2-carboxamide (32 mg, 79.7 μmol, Eq: 1.00), (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (20 mg, 98.4 μmol, Eq: 1.23) and diisopropylethylamine (50 μl, 286 μmol, Eq: 3.59) in DMF (1 mL) and the resulting yellow solution was stirred at rt for 1 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with 0.1 M aqueous NaOH, 0.1 M aqueous HCl and brine and then concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 50% EtOAc in hexanes) to give ((S)-1-{(S)-1-[(R)-2-(2,6-difluoro-phenylcarbamoyl)-3,3-dimethyl-2,3-dihydro-indole-1-carbonyl]-2-methyl-propylcarbamoyl})-ethyl)-methyl-carbamic acid tert-butyl ester (higher Rf, 15 mg) and ((S)-1-{(S)-1-[(S)-2-(2,6-difluoro-phenylcarbamoyl)-3,3-dimethyl-2,3-dihydro-indole-1-carbonyl]-2-methyl-propylcarbamoyl})-ethyl)-methyl-carbamic acid tert-butyl ester (lower Rf, 15 mg) along with some mixed fractions.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([O-:7])=[O:6].Br[C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[F:20].Cl.CO[C:24](C)(C)[CH3:25]>O.O1CCOCC1>[F:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH:4]([C:5]([O:7][CH2:24][CH3:25])=[O:6])[C:3]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: COC(C)(C)C
Reactant: Fc1cccc(F)c1Br
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1c(F)cccc1F

Procedure:
Into a mixture of 8.00 g of sodium hydride (60% in oil) and 100 ml of 1,4-dioxane, 32.0 g of ethyl malonate were added dropwise at 60° C. , further 14.6 g of cuprous bromide and 19.3 g of 1-bromo-2,6-difluorobenzene were added subsequently, and then refluxed for 16 hours under heating. To the reaction mixture, conc. hydrochloric acid was added under ice-cooling, and then tert-butyl methyl ether and water were added. The separated organic layer was washed with dil. hydrochloric acid and water subsequently, dried over sodium sulfate and concentrated. The residue was distilled under reduced pressure to give 16.5 g of diethyl (2,6-difluorophenyl)malonate. b.p. 107–109° C. (0.14 mmHg)
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[O:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([Si](C)(C)C)([F:22])[F:21].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[CH:1]([N:14]1[CH2:17][C:16]([C:20]([F:22])([F:21])[F:19])([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 46.32 %

Procedure:
1-Benzhydrylazetidin-3-one (5.0 g, 1.0 eq.) was dissolved in THF (50 mL). Trifluoromethyl trimethylsilane was added at 5-10° C. The reaction mixture was stirred at 10° C. for 10 min. Tetrabutyl ammonium fluoride was then added. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by chromatography (6% ethyl acetate-hexane) to give 3 g of 1-benzhydryl-3-(trifluoromethyl)azetidin-3-ol (Yield: 46.32%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>COCCOC.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.O>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(Br)cc1)C(C)C
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
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: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)C(C)C
Temperature: 25 °C
Yield: 81 %

Procedure:
A mixture of 0.175 g (0.5 mmol) of methyl N-[(4-bromophenyl)sulfonyl]-L-valinate, 0.25 g (1.5 mmol) of 4-nitrophenylboronic acid, 0.087 g of tetrakis(triphenylphosphine)palladium and 8 mL of saturated sodium bicarbonate in 8 mL of ethylene glycol dimethyl ether were refluxed for 2 h, then cooled to room temperature. To the reaction was added 50 mL of ethyl acetate and 40 mL of water. The water layer was extracted with ethyl acetate. The combined ethyl acetate layers was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexane:ethyl acetate (2:1) to provide 0.159 g of methyl N-[(4′-nitro-1,1′-biphenyl-4-yl)sulfonyl]-L-valinate as a yellow solid. Yield 81%. m.p. 144-146° C.; MS: 391.0(M−H)−.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)=[C:2]=[S:3].[NH2:14][CH:15]([C:19]#[N:20])[C:16]([NH2:18])=[O:17]>CCOC(C)=O>[NH2:20][C:19]1[S:3][C:2]([NH:1][C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[CH:7]3)=[N:14][C:15]=1[C:16]([NH2:18])=[O:17]
Reactant: S=C=Nc1ccc2ncccc2c1
Reactant: N#CC(N)C(N)=O
Solvent: CCOC(C)=O
Product: NC(=O)c1nc(Nc2ccc3ncccc3c2)sc1N
Yield: 65.4 %

Procedure:
A mixture of 6-isothiocyanatoquinoline (0.50 g, 2.7 mmol) and 2-amino-cyanoacetamide (0.26g, 2.68 mmol) in EtOAc (20 mL) was refluxed for 90 min. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluted with 2% MeOH in DCM to give 0.50 g (65% yield) of the titled compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:23][C:24](N(OC)C)=[O:25])=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([C@@H:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:23][C:24]([C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[O:25])=[CH:20][CH:21]=1
Reactant: CON(C)C(=O)C[C@@H](c1ccc(Br)cc1)c1ccccc1C
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)C[C@@H](c2ccc(Br)cc2)c2ccccc2C)cn1

Procedure:
In analogy to example 151, step 1, 5-bromo-2-methoxypyridine was reacted first with n-butyllithium and later with (S)-3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 142, step 1) to give the title compound as a colourless oil, MS (ESI+): m/z=410.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16]CC(C)(C)C(O)=O)=[CH:14][N:15]=1.BrCC1C=CC([F:44])=CC=1Cl.C([O:48][C:49](=[O:60])[C:50](SC1SC(N)=NC=1)([CH3:52])[CH3:51])C>>[Cl:1][C:2]1[CH:35]=[C:34]([F:44])[CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16][C:50]([CH3:52])([CH3:51])[C:49]([OH:48])=[O:60])=[CH:14][N:15]=1
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: Fc1ccc(CBr)c(Cl)c1
Product: CC(C)(Sc1cnc(NC(=O)N(CCOCc2ccc(F)cc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using 1-bromomethyl-2-chloro-4-fluoro-benzene and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [Br:1][CH2:2][C@H:3]1[CH2:7][C:6]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:5]=2[O:4]1.[Br:13]Br>C(O)(=O)C.CO>[Br:13][C:11]1[C:5]2[O:4][C@@H:3]([CH2:2][Br:1])[CH2:7][C:6]=2[CH:8]=[C:9]([F:12])[CH:10]=1
Reactant: BrBr
Reactant: Fc1ccc2c(c1)C[C@H](CBr)O2
Solvent: CO
Solvent: CC(=O)O
Product: Fc1cc(Br)c2c(c1)C[C@H](CBr)O2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (R)-2-bromomethyl-5-fluoro-2,3-dihydro-benzofuran (3.20 g, 14 mmol) in acetic acid was added bromine (2.2 ml, 42 mmol) and the reaction mixture was allowed to stir at room temperature for 12 h. The solvent was removed in vacuo and the residue dissolved in dichloromethane and washed with saturated aqueous sodium sulfite. The solvent was removed in vacuo and purification by flash column chromatography (silica, ethyl acetate:hexanes 1:19) afforded 3.16 g (74%) of as a light yellow oil. HRMS EI m/e 307.8846 (M)+, Calc'd. 307.8848. [α]D25=+24.8 (c 1% in methanol).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[C:4]=2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[N:7]=1.[CH3:30][C:31]1[C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34].C(=O)([O-])[O-].[K+].[K+]>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>[CH2:13]([N:12]([CH2:15][CH3:16])[CH2:11][CH2:10][CH2:9][NH:8][C:6]1[N:7]=[C:2]([C:39]2[C:31]([CH3:30])=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33]([OH:35])=[O:34])[C:3]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[C:4]=2[N:5]=1)[CH3:14]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1C(=O)O
Reactant: CCN(CC)CCCNc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
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: O
Solvent: C1COCCO1
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 150 °C
Yield: 109.2 %

Procedure:
To the compound 4-chloro-2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (176 mg, 0.418 mmol) in dioxane (4.5 mL) and water (1.5 mL) was added 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (173 mg, 0.626 mol), potassium carbonate (289 mg, 2.09 mmol) and tetrakis(triphenylphosphine)palladium(0) (24.2 mg, 0.0259 mmol). The mixture was heated with microwave at 150° C. for 15 min. The mixture was filtered. Separation by HPLC with TFA afforded the title compound (238 mg, 99%). LC-MS m/z 522 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:4]=[C:3]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:3]1[N:2]([CH3:1])[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:4]=1)(=[O:29])=[O:28]
Reactant: Cn1c(CCCCCO)nnc1-c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(CCCCCOS(C)(=O)=O)nnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 116 %

Procedure:
To a solution of 5-(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)-1-pentanol (127 mg, 0.52 mmol) in DCM (5 ml) was added trietylamine (0.62 mmol) and methansulfonyl chloride (0.57 mmol). The solution was stirred at r.t. for 2 h and quenched with saturated NaHCO3. The organic layer was dried over Na2SO4 and concentrated to give the title compound as light yellow oil (195 mg). MS (m/z): 324[MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]([N:15]2[N:19]=[CH:18][C:17]3([CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:16]2)SC)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:24].[CH2:25]([NH2:27])[CH3:26].O>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]([N:15]2[N:19]=[CH:18][C:17]3([CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:16]2)[NH:27][CH2:25][CH3:26])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:24]
Reactant: CCN
Reactant: CSC(=NS(=O)(=O)c1ccc(N)c(F)c1)N1CC2(C=N1)CCCC2
Solvent: O
Solvent: CO
Product: CCNC(=NS(=O)(=O)c1ccc(N)c(F)c1)N1CC2(C=N1)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a solution of 840 mg 4-amino-N-[(2,3-diaza-spiro[4.4]non-3-en-2-yl)-methylsulfanyl-methylene]-3-fluoro-benzenesulfonamide (crude) in 25 mL MeOH was added 3.43 mL of a 70% aqueous solution of ethylamine. The mixture was stirred for 1 h. at room temperature, water was added, and the mixture was extracted with DCM. The combined organic layers were dried over MgSO4 and evaporated to dryness. The residue was purified by flash chromatography (EA/PA 3:1) to give 260 mg (33% over 2 steps) of 4-amino-N-[(2,3-diaza-spiro[4.4]non-3-en-2-yl)-ethylamino-methylene]-3-fluoro-benzenesulfonamide as a brown oil. 1H NMR (400 MHz, CDCl3) δ 1.16 (t, J=7.2 Hz, 3H), 1.57-1.87 (m, 7H), 3.43-3.53 (m, 2H), 3.82 (s, 2H), 4.02-4.07 (m, 2H), 6.77 (t, J=8.4 Hz, 1H), 6.80 (s, 1H), 7.50-7.58 (m, 2H) [NH2 invisible].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1.[CH:17]1(B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([C:2]2[CH:3]=[C:4]([NH2:16])[CH:5]=[N:6][C:7]=2[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[CH2:19][CH2:18]1
Reactant: COc1cccc(-c2ncc(N)cc2Br)c1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Product: COc1cccc(-c2ncc(N)cc2C2CC2)c1
Yield: 68 %

Procedure:
Obtained (0.1 g, yield 68%) following the procedure described in Intermediate 27, starting with 5-bromo-6-(3-methoxyphenyl)pyridin-3-amine (Intermediate 40) (0.61 mmol, 0.172 g), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.68 mmol, 0.123 ml).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.Cl.[OH:15][NH2:16].C(=O)(O)[O-].[Na+].O>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[N:16][OH:15])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc2c(c1)CC(=O)CC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CC(=NO)CC2
Yield: 78.4 %

Procedure:
A mixture of 7-methoxy-2-tetralone (0.50 g, 2.8 mmol), hydroxyl amine hydrochloride (0.38 g, 5.6 mmol) and sodium bicarbonate (0.47 g, 5.6 mmol) in methanol (20 mL) was heated to reflux for 3 h. The mixture was poured into water (15 mL) and extracted with chloroform. The organic phases were combined, washed with brine, and concentrated to give a white solid. Precipitation from ethyl acetate/hexane gave the title compound (420 mg, 79%) as a granular solid. MS(ES) m/e 191 [M+H]+.