Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9]([O:12][C@@H:13]([CH2:17][CH2:18][O:19][CH3:20])[C:14](O)=[O:15])(=[O:11])[CH3:10].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1>[C:9]([O:12][C@@H:13]([CH2:17][CH2:18][O:19][CH3:20])[C:14]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)=[O:15])(=[O:11])[CH3:10]
Reactant: Cc1ccc(N)nc1
Reactant: COCC[C@H](OC(C)=O)C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COCC[C@H](OC(C)=O)C(=O)Nc1ccc(C)cn1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
5-Methylpyridin-2-amine (CAS no. 1603-41-4) (460 mg, 4.26 mmol) was added to (S)-2-acetoxy-4-methoxybutanoic acid (Intermediate F3) (500 mg, 2.84 mmol), in THF (8 mL) under nitrogen. The resulting suspension was stirred at 23° C. for 30 minutes. 4-(4,6-Dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (CAS no. 3945-69-5) (1.18 g, 4.26 mmol) was added and the suspension stirred for 40 hrs. The reaction mixture was concentrated and purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane to afford (S)-4-methoxy-1-(5-methylpyridin-2-ylamino)-1-oxobutan-2-yl acetate (410 mg, 54%). 1H NMR (400 MHz, CDCl3) δ 2.13-2.28 (5H, m), 2.30 (3H, s), 3.31 (3H, s), 3.48-3.53 (2H, m), 5.37-5.40 (1H, m), 7.50-7.53 (1H, m), 8.09-8.11 (2H, m), 8.52 (1H, s); m/z (ESI+) (M+H)+=267; HPLC tR=1.22 min.
Reaction SMILES: [O:1]=[C:2]([C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[C:20]=1[CH3:26])[CH:3]([C:6]1[C:10]([CH2:11][CH3:12])=[N:9][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1)[C:4]#[N:5].[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>C1(C)C(C)=CC=CC=1>[CH3:29][C:28]([CH3:31])([CH3:30])[C:27]([O:1]/[C:2](/[C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[C:20]=1[CH3:26])=[C:3](\[C:6]1[C:10]([CH2:11][CH3:12])=[N:9][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1)/[C:4]#[N:5])=[O:32]
Reactant: CCc1nn(-c2ccccc2)nc1C(C#N)C(=O)c1c(C)c(C)nn1C
Reactant: CC(C)(C)C(=O)Cl
Solvent: Cc1ccccc1C
Product: CCc1nn(-c2ccccc2)nc1/C(C#N)=C(\OC(=O)C(C)(C)C)c1c(C)c(C)nn1C
Temperature: 70 °C
Yield: 93 %

Procedure:
In a 3 L-reaction flask, 156.8 g (0.45 mol) of 3-oxo-2-(2-phenyl-5-ethyl-1,2,3-triazol-4-yl)-3-(1,3,4-trimethylpyrazol-5-yl) propionitrile and 900 g of xylene were added, the temperature was raised to 70° C., and 162.7 g (1.35 mol) of pivaloyl chloride was added dropwise under reflux over 10 hours while removing hydrogen chloride under a reduced pressure at 68 to 71° C./10 to 13 kPa. After reacting as such for 5 hours, 740 g of a mixture of pivaloyl chloride and xylene was distilled off at 70° C. under a reduced pressure in order to remove excess pivaloyl chloride. After adding 156 g of warm water of 70° C., 70 g of 2.7% sodium hydrogen carbonate aqueous solution was added dropwise. After separating the resulting aqueous phase, the resulting organic phase was washed with 156 g of warm water of 70° C., the resulting aqueous phase was separated to obtain a xylene solution containing 181 g (yield 93.0%) of (2E)-3-(2,2-dimethylpropanoyloxy)-2-(2-phenyl-5-ethyl-1,2,3-triazol-4-yl)-3-(1,3,4-trim ethylpyrazol-5-yl) acrylonitrile. After distilling off most of xylene at 90° C. under a reduced pressure, 540 g of acetonitrile was added, and crystallization was carried out by gradually cooling from 70° C. After stirring at 0° C. for 1 hour, the resulting crystal was filtered, and dried to obtain 163.5 g (yield 84%) of (2E)-3-(2,2-dimethylpropanoyloxy)-2-(2-phenyl-5-ethyl-1,2,3-triazol-4-yl)-3-(1,3,4-trim ethylpyrazol-5-yl) acrylonitrile (melting point: 119° C.).
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@H:6]([OH:19])[CH2:5]1.[C:20]([O:24][C:25]([NH:27][CH2:28][C@H:29]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:30](O)=[O:31])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@H:29]([C:30]([N:16]2[CH2:15][CH2:14][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][C@@H:6]([OH:19])[C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:18][CH2:17]2)=[O:31])[CH2:28][NH:27][C:25](=[O:26])[O:24][C:20]([CH3:23])([CH3:21])[CH3:22])=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@H](CNC(=O)OC(C)(C)C)c4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (88 mg, 0.29 mmol) and (S)-3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoic acid (86 mg, 0.29 mmol) in DCM (10 mL) and Diisopropylethylamine (0.22 mL, 1.3 mmol) was added HBTU (110 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was dissolved in ethyl acetate (100 mL), washed with water (6×50 ml). The organic phase was dried and concentrated to give tert-butyl (S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropylcarbamate (116 mg, 78%). 1H NMR (CDCl3, 400 MHz) δ 8.51 (s, 1H), 7.34-7.20 (m, 4H), 5.15-5.09 (m, 2H), 4.15-4.05 (m, 1H), 3.87-3.85 (m, 2H), 3.78-3.38 (m, 7H), 3.22-3.19 (m, 1H), 2.20-2.10 (m, 2H), 1.48 (s, 9H), 1.41 (s, 9H), 1.14-1.12 (d, J=7.2 Hz, 3H). MS (APCI+) [M+H]+516.
Reaction SMILES: C(OC(=O)C)(=O)C.[I:8]I.OS(O)(=O)=O.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].[O-]S([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([I:8])=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: II
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(I)ccc1Cl
Temperature: 64 °C
Yield: 62 %

Procedure:
To a jacketed reactor, acetic acid (450 mL) and acetic anhydride (225 mL) is charged at 10° C. Then, to the above mixture, NalO4 powder (97.2 g) and Iodine (77.2 g) is added under stirring. While keep internal temperature at below 30° C., conc. H2SO4 (720 mL) is added dropwise. Then, 2-chloro-nitrobenzene (Rt=11.11 min) is added in one portion, and heat the mixture gradually to 64° C. The resulting mixture continues to be stirred for usually at least 2 hours until process monitor shows almost complete conversion. Then, the mixture is cooled down to room temperature, and transferred slowly into another jacketed reactor with pre-cooled cold Na2SO3 solution (250 g Na2SO3 in 2000 mL water). Collect the wet cake by filtration and wash the cake with water (450 mL×2), then purification of the cake with n-heptane crystallization to afford 2-chloro-5-iodonitrobenzene in 62% yield and 98% HPLC purity (Rt=15.75 min).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:27]1[CH2:32][CH2:31][O:30][CH:29]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:28]1>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH:29]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:28]2)=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Reactant: O=C(O)CCC1CNCCO1
Product: CCOC(=O)C1=C(CN2CCOC(CCC(=O)O)C2)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 45.2 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.67 g, 1.4 mmol) was reacted with 3-(morpholin-2-yl)propanoic acid (0.22 g, 1.4 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.35 g, 45%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:10]=1)=O)C.[OH-].[NH4+:33]>>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([S:19]([NH:18][C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[N:9]2[CH:10]=[C:6]([C:4]([NH2:33])=[O:3])[CH:7]=[N:8]2)(=[O:21])=[O:20])=[CH:23][CH:24]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: [NH4+]
Reactant: CCOC(=O)c1cnn(-c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Agent: [OH-]
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2cc(C(N)=O)cn2)cc1

Procedure:
1-[2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (synthesized according to general procedure D, 55 mg, 0.119 mmol) and 1 mL of ammonium hydroxide were stirred at 70° C. for 18 hours. The resultant solution was partitioned between saturated sodium bicarbonate and dichloromethane, and the aqueous layer extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was subsequently purified by flash column chromatography (0-100% ethyl acetate in hexanes) to yield 1-[2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-phenyl]-1H-pyrazole-4-carboxylic acid amide: MS (ES) M+H expected 433.1, found 433.0.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([CH2:10][CH2:11][OH:12])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CC(C)=O>[CH2:20]([O:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=1[CH2:10][CH2:11][OH:12])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: OCCc1cc(F)c(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: OCCc1cc(F)c(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.1 %

Procedure:
To a solution of 4,5-difluoro-2-(2-hydroxyethyl)phenol (450 mg, 2.58 mmol) in acetone (10 mL) was added K2CO3 (714 mg, 5.17 mmol) followed by (bromomethyl)benzene (0.461 mL, 3.88 mmol) and the resulting mixture was stirred at room temp for 16 h. Water was then added and the mixture was extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (5-30% EtOAc/hexane) to afford 2-(2-(benzyloxy)-4,5-difluorophenyl)ethanol (580 mg, 2.195 mmol, 85% yield) as viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.48-7.33 (m, 5H), 7.10-7.01 (m, 1H), 6.78 (dd, J=12.1, 6.7 Hz, 1H), 5.05 (s, 2H), 3.85 (q, J=6.0 Hz, 2H), 2.90 (t, J=6.4 Hz, 2H), 1.52 (t, J=5.5 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[NH:11][C:10]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].O>CN(C)C=O>[CH2:35]([O:34][C:32]([CH2:31][N:11]1[C:12]2[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=2[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[N:15][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:10]1=[O:27])=[O:33])[CH3:36]
Reactant: CC(C)(C)OC(=O)NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1C(=O)C(NC(=O)OC(C)(C)C)N=C(c2ccccc2F)c2ccccc21
Temperature: 5 °C
Yield: 100 %

Procedure:
To a solution of (3RS)-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one (5.88 g) in N,N-(1imethylformamide (100 ml) was added portionwise sodium hydride (60% dispersion in mineral oil, 0.76 g) under stirring and cooling at 5° C. The mixture was stirred under the same condition for 0.5 hour and at ambient temperature for 1 hour. To the mixture was added dropwise a solution of ethyl bromoacetate (3.19 g) in N,N-dimethylformamide (10 ml) under cooling in an ice-bath. After the addition was completed, the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was poured into water (300 ml) under vigorous stirring. The resultant precipitates were collected by filtration, washed with water and dried under reduced pressure over phosphorus pentoxide to afford (3RS)-1-ethoxycarbonylmethyl-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one (7.25 g) as a crystalline powder, which was used in a following reaction step without further purification.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[CH:10]=1.[Cl:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15](B(O)O)=[C:14]([F:23])[CH:13]=1>C(COC)OC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][N:5]3[CH:10]=2)=[C:14]([F:23])[CH:13]=1
Reactant: COc1cc(B(O)O)c(F)cc1Cl
Reactant: Brc1cn2ccccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: COCCOC
Product: COc1cc(-c2cn3ccccc3n2)c(F)cc1Cl
Yield: 61.7 %

Procedure:
A mixture of 0.8 g (4.1 mmol) of 2-bromoimidazo[1,2-a]pyridine, 0.8 g (4.2 mmol) of 4-chloro-2-fluoro-5-methoxyphenylboronic acid, and 0.2 g (0.28 mmol) of bis(triphenylphosphine)palladium(II) chloride were heated in 30 ml of glyme at reflux for 2 h. The reaction mixture was partitioned between 250 ml of ethyl acetate and 100 ml of water and the separated organic layer washed with brine and dried over magnesium sulfate. On evaporating in vacuo, the remaining residue was flash chromatographed on silice gel (1:1 hexane/ethyl acetate) to afford 0.7 g of the title compound (m.p. 139°-141° C.). NMR (CDCl3, 400 MHz): δ4.03 (s, 3H), 6.81 (t, 1H), 7.21 (m, 2H), 8.63 (d, 1H), 7.92 (d, 1H), 8.04 (s, 1H), 8.14 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[NH4+].[OH-].[CH:16](O)=O>>[S:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]2[NH:1][CH:16]=[N:8][C:7]=12
Reactant: Nc1nccc(-c2cccs2)c1N
Reactant: O=CO
Agent: [NH4+]
Agent: [OH-]
Product: c1csc(-c2ccnc3[nH]cnc23)c1
Yield: 96 %

Procedure:
A solution of Compound 3 (956 mg, 5.0 mmol) in formic acid (15 ml) was refluxed for 12 hours. To the reaction mixture, 24 ml of 28% NH4OH was added on an ice-cold bath. The resulting precipitate was filtered, washed with H2O and ethyl ether, and then dried at 60° C. for 12 hours to give 7-(2-thienyl)-3H-imidazo[4,5-b]pyridine (970 mg, 96%).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([C:6](O)=[O:7])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][N:45]1[C:54]2[C:49](=[CH:50][N:51]=[C:52]([CH3:55])[CH:53]=2)[CH:48]=[C:47]([C:56]2[CH:57]=[C:58]([NH:63]/[C:64](/[NH2:67])=[N:65]/O)[CH:59]=[CH:60][C:61]=2[CH3:62])[C:46]1=[O:68]>CN(C=O)C>[CH3:44][N:45]1[C:54]2[C:49](=[CH:50][N:51]=[C:52]([CH3:55])[CH:53]=2)[CH:48]=[C:47]([C:56]2[CH:57]=[C:58]([NH:63][C:64]3[N:65]=[C:6]([C:3]4([C:2]([F:10])([F:9])[F:1])[CH2:5][CH2:4]4)[O:7][N:67]=3)[CH:59]=[CH:60][C:61]=2[CH3:62])[C:46]1=[O:68]
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(C4(C(F)(F)F)CC4)n3)ccc1C)c(=O)n2C
Temperature: 100 °C

Procedure:
To a solution of 1-(trifluoromethyl)cyclopropanecarboxylic acid (9 mg, 0.06 mmol) in DMF (1 mL) were added DIPEA (31 μL, 0.18 mmol) and HATU (23 mg, 0.06 mmol). After stirring at rt for 15 min 17 (20 mg, 0.06 mmol) was added as a solution in DMF (0.5 mL). The reaction was stirred at rt until complete consumption of 17 was determined by LC/MS and then heated at 100° C. for 1 h. Subsequently the reaction was cooled to rt, filtered and purified by preparative LC/MS to give 1,7-dimethyl-3-(2-methyl-5-(5-(1-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one (A58). MS m/z 456.6 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:11]2[N:7]([CH:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:18][CH:17]=3)[C:10]=2[CH2:14][CH3:15])[CH:6]=1)(=[O:3])[CH3:2].[C:30]([O:34][CH3:35])(=[O:33])[C:31]#[CH:32].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:11]2[N:7]3[C:6]=1[C:31]([C:30]([O:34][CH3:35])=[O:33])=[CH:32][C:8]3=[C:9]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:18][CH:17]=1)[C:10]=2[CH2:14][CH3:15])(=[O:3])[CH3:2]
Reactant: C#CC(=O)OC
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)cn2cc(NC(C)=O)ccc12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(C(=O)OC)c3c(NC(C)=O)ccc1n23
Temperature: 90 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
A solution of 6-acetylamino-2-(4-benzyloxyphenyl)-1-ethylindolizine (38.5 g, 0.1 mol) in 3000 ml of toluene was stirred in a nitrogen atmosphere at 50° C. while methyl propiolate (10.2 ml, 0.115 mol) was added dropwise. The mixture was heated to 90° C. and stirring was continued for 3 hours. The mixture was cooled to 4° C. and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (22.6 g, 0.1 mol) was added in portions. The cooling source was removed and stirring was continued for 16 hours. The mixture was filtered through celite and the celite pad was washed several times with toluene. The combined filtrates were evaporated to app. 500 ml and 1000 ml of petroleum ether was added. The precipitate was filtered off and dried to yield 38.7 g (83%) of the title compound. M.p. 210-13° C. 1H-NMR (DMSO-d6, 200 Hz) δ: 1.38 (t, 3H), 2.27 (s, 3H), 3.15 (q, 2H), 3.96 (s, 3H), 5.18 (s, 2H), 7.20 (d, 2H), 7.35-7.55 (m, 5H), 7.75 (d, 2H), 7.90 (s, 1H), 8.13 (d, 1H), 8.95 (d, 1H), 11.78 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21]Br>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([O:17][CH2:21][CH2:20][CH2:19][Br:18])=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc2c(-c3ccc(Br)cc3)csc2c1
Reactant: BrCCCBr
Product: BrCCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1

Procedure:
In analogy to example 27.1, 3-(4-Bromo-phenyl)-benzo[b]thiophen-6-ol and 1,3-dibromopropane were converted to yield 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[b]thiophene, MS: 424 (M, 2Br).
Reaction SMILES: [CH3:1][C:2]1[C:9]2[CH:8]=[CH:7][S:6][C:5]=2[S:4][CH:3]=1.[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:10][C:3]1[S:4][C:5]2[S:6][CH:7]=[CH:8][C:9]=2[C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc2sccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1c(Br)sc2sccc12
Yield: 36.7 %

Procedure:
3-Methylthieno[2,3-b]thiophene (Step 1, 450 mg, 2.92 mmol) was dissolved in carbon tetrachloride (7 mL) under nitrogen. N-Bromosuccinimide (0.52 g, 2.92 mmol) and benzoyl peroxide (75% in water; 0.10 g, 0.29 mmol) were added and the reaction heated to reflux for 6 hours. The solvent was removed in vacuo and the residue taken up in dichloromethane then filtered onto a column of silica and eluted with isohexane to give 2-bromo-3-methylthieno[2,3-b]thiophene (0.25 g, 37%). 1H NMR (500 MHz, CDCl3) δ 7.38 (1H, d, J=5.2 Hz), 7.13 (1H, d, J=5.2 Hz), 2.34 (3H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>O>[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Reactant: Cc1ccccc1B(O)O
Solvent: O
Product: Cc1ccccc1-c1ccc(C(C)CNS(C)(=O)=O)cc1

Procedure:
The title compound was prepared from the product of Example 1 as described in Example 100 with the exception that 2-methylbenzeneboronic acid was used instead of 2-formylbenzeneboronic and 10 mL of water was added to the reaction mixture.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14]C(OCC2C=CC=CC=2)=O)[C@H:10]([OH:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[C@H:10]([OH:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](O)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](O)C1

Procedure:
To a stirred solution of (±)-cis-4-benzyloxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.365 mmol, 0.128 g)) in methanol (3 mL) was added 10% palladium on carbon (0.07 g, wet). The resultant reaction mixture was subjected to hydrogenation using a balloon full of hydrogen for 2 h. The catalyst was filtered through a pad of celite. The pad was washed with methanol (10 mL), and the combined filtrate was concentrated under reduced pressure to get (±)-cis-4-amino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.[H-].[Na+].BrC[C:11]([O:13][CH3:14])=[O:12]>C1COCC1>[CH3:14][O:13][C:11](=[O:12])[CH2:2][S:1][CH2:6][CH2:5][CH2:4][SH:3]
Reactant: C1CSCSC1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CSCCCS
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
An ice-cold solution of 1,3-dithiane (2.0 mL, 19.9 mmol) in THF (40 mL) was treated with NaH (819 mg, 20.5 mmol). After 30 min., methyl bromoacetate (1.9 mL, 20.0 mmol) was added and the mixture stirred for 3.5 h at room temperature. The reaction was quenched by addition of MeOH and then 50 mL 1 M HCl. The mixture was extracted with ether (2×50 mL) and the combined ether solution washed with saturated sodium bicarbonate solution (50 mL) and brine (50 mL) and then was dried (MgSO4), filtered and evaporated. Purification by flash chromatography on silica gel (10-15% ethyl acetate/hexanes) gave 971 mg (5.38 mmol, 27%) of the thiol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:35])=[C:21]([NH:25][S:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[NH4+:36].[OH-]>>[NH2:36][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:35])=[C:21]([NH:25][S:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)N1CCOCC1
Agent: [OH-]
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)N3CCOCC3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 21 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-4-morpholinesulfonamide (96 mg, 0.177 mmol) in NH4OH (4 mL), heated in a microwave reactor for 40 min at 120° C. the title compound was obtained as a yellow solid (20 mg, 22% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.86 (s, 1H), 7.87 (d, J=5.3 Hz, 1H), 7.54 (td, J=6.8, 3.5 Hz, 1H), 7.19-7.31 (m, 2H), 6.54 (s, 2H), 5.80 (d, J=5.3 Hz, 1H), 3.68 (t, J=4.4 Hz, 4H), 3.48-3.55 (m, 4H), 3.43 (t, J=4.4 Hz, 4H), 2.96-3.03 (m, 4H). MS (ESI): 521.8 [M+H]+.