Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:10]=1)=O)([O-:3])=[O:2].[BH4-].[Na+].B(F)(F)F.CCOCC.C(OCC)(=O)C>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[CH2:7][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:10]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCCn1cc(C(=O)c2cccc([N+](=O)[O-])c2)c2ccccc21
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CCCn1cc(Cc2cccc([N+](=O)[O-])c2)c2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 35.9 %

Procedure:
To a solution of ethyl 4-[3-(3-nitrobenzoyl)indol-1-yl]butyrate (0.5 g) in tetrahydrofuran (10 ml) were added sodium borohydride (99.4 mg) and boron trifluoride etherate (0.485 ml) at -25° C., and the mixture was stirred at the same temperature for 2 hours. The mixture was poured into a mixture of ethyl acetate and ice water. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (25 g) eluting with a mixture of ethyl acetate and hexane (1:4) to give ethyl 4-[3-(3-nitrobenzyl)indol-1-yl]butyrate (173 mg) as a yellow oil.
Reaction SMILES: C[Al](C)C.[NH2:5][C@H:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1.[CH3:14][O:15][C:16]1[C:17]([CH3:26])=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19](OC)=[O:20]>C1(C)C=CC=CC=1>[N:8]12[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9]1)[C@H:6]([NH:5][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][CH:25]=[C:16]([O:15][CH3:14])[C:17]=1[CH3:26])[CH2:7]2
Reactant: COC(=O)c1cccc(OC)c1C
Reactant: N[C@@H]1CN2CCC1CC2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cccc(C(=O)N[C@@H]2CN3CCC2CC3)c1C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of trimethylaluminum (0.8 mmol) in toluene was slowly added to asolution of (S)-3-amino-1-azabicyclo[2.2.2]octane (0.1 g; 0.8 mmol) in toluene (5.0 mL) and the mixture stirred for 15 minutes. A solution of methyl 3-methoxy-2-methylbenzoate (0.1 g; 0.55 mmol) in toluene (2 mL) wasadded and the reaction mixture heated to reflux until, as indicated by thin-layer chromatography, the reaction had finished. The mixture was cooled to 0° C. and then carefully quenched with water (0.4 mL). The reaction mixture was stirred for an additional 30 minutes and then filtered washing with ethyl acetate (2×20 mL). Removal of the solvent from the combined filtrate gave (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-3-methoxy-2-methylbenzamide as a whitesolid (0.19 g, 0.686 mmol). Preparation of the hydrochloride salt from ethanol-hydrogen chloride gave (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-3-methoxy-2-methylbenzamide hydrochloride, m.p. 259°-261° C., [α]D25 -13.8° (c=0.16, H2O).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH:14]=O.O>C1(C)C=CC=CC=1>[CH2:1]([NH:8][CH2:14][C:10]1[S:9][CH:13]=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1nccs1
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(CNCc2nccs2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
A stirred solution of N-benzylamine (0.56 mL, 5.1 mmol) and 2-thiazolecarboxaldehyde (0.55 g, 4.9 mmol) in toluene was heated to reflux for 2 hours with azeotropic removal of water. The solution was cooled to room temperature and concentrated to an oil. This oil was dissolved in 15 mL of ethanol and treated with excess NaBH4 and the mixture stirred overnight. Acetone was added and the mixture stirred 30 minutes and concentrated to a soild mass. This mass was partitioned between 2N aqueous NaOH and 2 portions of ethyl ether. The combined ethereal extracts were washed with water, brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel to provide 0.59 g (57%) of the title compound.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][O:14][CH3:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:15][O:14][CH2:13][CH2:12][S:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(S)cc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCSc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
A mixture of 4-mercaptophenylboronic acid (1.0 g, 90%, 5.84 mmol), 1-bromo-2-methoxyethane (1.8 g, 13 mmol) and K2CO3 (2.70 g, 19.5 mmol) in CH3CN (20 mL) was stirred at ambient temperature overnight. After CH3CN was removed, water was added to the residue, and the solid was collected via filtration and washed with water to give 0.9 g of the crude (4-{[2-(methoxy)ethyl]thio}phenyl)boronic acid (75% pure by LC-MS). The crude boronic acid was used without further purification.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Na+].C([O:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)(=O)CC>>[OH:11][C:12]1[C:21]([C:12](=[O:11])[CH2:13][CH3:14])=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=1
Reactant: CCC(=O)Oc1ccc2c(c1)CCCC2
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Product: CCC(=O)c1cc2c(cc1O)CCCC2
Yield: 48.3 %

Procedure:
To a mixture of aluminium chloride (120 g) and sodium chloride (52.6 g) at 160° was added, over 10 minutes, the product of step (a) (60 g). The mixture was then heated at 180° for 30 minutes, cooled and poured onto ice. The precipitate was extracted into ether and the extract was filtered and evaporated. The residue was twice crystallised from petroleum ether (40°-60°) to give 5,6,7,8-tetrahydro-2-hydroxy-3-propionylnaphthalene, (14.5 g) as a pale brown solid, m.p. 57°-58°.
Reaction SMILES: [OH:1][CH:2]([CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](O)=[O:4].Cl.[CH2:35]([O:37][NH2:38])[CH3:36]>>[CH2:35]([O:37][NH:38][C:3](=[O:4])[CH:2]([OH:1])[CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:23]1)[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:36]
Reactant: CCON
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Agent: Cl
Product: CCONC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 2-hydroxy-4-phenyl-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with O-ethylhydroxylamine hydrochloride. ESI-MS [M+H]+: 486.2
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[H-].[Na+].Br[CH2:21][CH2:22][CH3:23]>CN(C=O)C>[CH2:21]([O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12])[CH2:22][CH3:23]
Reactant: CCCBr
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O

Procedure:
Cytidine (16.5 g, 0.068 mol) was treated with sodium hydride (4.5 g) and bromopropane (15 ml) in DMF (150 ml) at room temperature for three days. The resulting reaction mixture was used directly in the next step (see Example 83).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([Cl:15])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:16][C:17]1[CH:21]=[CH:20][S:19][C:18]=1[C:22]([O:24][CH3:25])=[O:23].N1C=CC=CC=1>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:16][C:17]2[CH:21]=[CH:20][S:19][C:18]=2[C:22]([O:24][CH3:25])=[O:23])(=[O:13])=[O:12])=[C:7]([Cl:15])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1sccc1N
Reactant: CCCCc1ccc(S(=O)(=O)Cl)c(Cl)c1
Solvent: c1ccncc1
Product: CCCCc1ccc(S(=O)(=O)Nc2ccsc2C(=O)OC)c(Cl)c1
Yield: 49.3 %

Procedure:
A solution of 70 (2.5 g; 9.36 mmol) and methyl 3-aminothiophene-2-carboxylate (1.62 g; 10.30 mmol) in anhydrous pyridine (12.0 mL; 144 mmol) was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 20% v/v) to give the title compound as a clear oil (1.79 g).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CC#N>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:15]2[N:14]=[C:13]([C:9]3[S:8][C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[N:11][C:10]=3[CH3:12])[CH:18]=[CH:17][N:16]=2)=[CH:21][CH:22]=1
Reactant: COc1ccc(Nc2nccc(-c3sc(NC(=O)CCBr)nc3C)n2)cc1
Reactant: C1COCCN1
Solvent: CC#N
Product: COc1ccc(Nc2nccc(-c3sc(NC(=O)CCN4CCOCC4)nc3C)n2)cc1

Procedure:
By treatment of 3-bromo-N-{5-[2-(4-methoxy-phenylamino)-pyrimidin-4-yl]-4-methyl-thiazol-2-yl}-propionamide with morpholine. Anal. RP-HPLC: tR=12.7 min (0-60% MeCN, purity >90%). 1H-NMR (CDCl3) δ: 1.20 (m, 2H, CH2), 2.54-2.63 (m, 7H, CH3 and CH2), 3.34 (m, 2H, CH2), 3.80 (m, 5H, CH3 and CH2), 4.03 (m, 2H, CH2), 6.87-6.92 (m, 3H, pyrimidinyl-H and Ph-H), 7.17 (brs, 1H, NH), 7.53 (m, 2H, Ph-H), 8.35 (m, 1H, pyrimidinyl-H), 10.33 (brs, 1H, NH).
Reaction SMILES: C[O:2][C:3]([CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16](=[O:22])[CH2:15][CH2:14]3)[CH2:6]1)=O.[NH3:23]>CO>[CH3:21][N:17]1[C:18]2[C:13](=[CH:12][C:11]([N:7]3[CH2:6][C@H:5]([C:3]([NH2:23])=[O:2])[O:9][C:8]3=[O:10])=[CH:20][CH:19]=2)[CH2:14][CH2:15][C:16]1=[O:22]
Reactant: COC(=O)C1CN(c2ccc3c(c2)CCC(=O)N3C)C(=O)O1
Reactant: N
Solvent: CO
Product: CN1C(=O)CCc2cc(N3C[C@H](C(N)=O)OC3=O)ccc21
Yield: 84 %

Procedure:
To a stirred solution of 3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester (Step 4, 150 mg, 0.49 mmol) in MeOH (1 mL) is added 2.0 M NH3 in MeOH (1 mL, 2.0 mmol). The reaction mixture is then heated at 50–60° C. until all of the solid disappears. Solvent is removed and the residue is dissolved in 20% MeOH/CH2Cl2 and purified by silica gel chromatography (10% MeOH/CH2Cl2) to give the title compound as a white solid (120 mg, 84%), 1H NMR (300 MHz, DMSO) δ 7.85 (br S, 1H), 7.60 (br S, 1H), 7.45–7.08 (m, 3H), 5.01 (dd, 1H), 4.25 (t, 1H), 3.99 (dd, 1H), 3.23 (s, 3H), 2.86 (t, 2H), 2.50 (m, 2H); MS for C14H15N3O4 m/z 290.5 (M+H)+.
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22]C(C)(C)C)=O)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1.[C:34]([O:38][C:39]([NH:41][CH2:42]C(O)=O)=[O:40])([CH3:37])([CH3:36])[CH3:35].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O>[C:1]([NH:9][C@@H:10]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH2:42][NH:41][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)[C@H](CCCCNC(=O)CNC(=O)OC(C)(C)C)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of Compound 9 (4.4 g, 12.1 mmol) in CH2Cl (5.0 mL) was treated with 4 N HCl-dioxane (10.0 mL) and stirred for 3 h at 25° C. Solvent and excess acid were removed under reduced pressure, and the residue was dissolved in DMF (150 mL) and treated with N-((tert-butyloxy)carbonyl)glycine (2.2 g, 12.1 mmol), PyBrOP (7.0 g, 15 mmol), and i-Pr2NEt (8.4 mL, 48.4 mmol) and stirred at 25° C. After 12 h the reaction mixture was diluted with EtOAc (500 mL) and washed with 10% aqueous HCl (3×250 mL), 5% aqueous Na2CO3 (250 mL) and saturated aqueous NaCl (250 mL), dried Na2SO4) and evaporated. Flash Chromatography (SiO2, EtOAc) provided 4.6 (90%) of Compound 10 as colorless oil: [α]D25−10.3 (c 0.30, CH3OH); 1H NMR (CDCl3, 400 MHz) δ 7.84 (m, 2H), 7.51 (m, 1H), 7.44 (m, 2H), 6.91 (d, J−7.6 Hz, 1H), 6.35 (brt, J−5.3 Hz, 1H), 5.22 (m, 1H), 4.76 (m, 1H), 3.76 (s, 3H), 3.70 (brt, J−6.3 Hz, 4H), 3.26 (m, 2H), 1.95 (m, 1H), 1.84 (m, 1H), 1.57-1.30 (m, 4H), 1.41 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 173.0, 169.7, 167.3, 156.5, 133.7, 131.8, 128.6, 127.2, 81.8, 52.5, 52.3, 44.3, 38.7, 32.0, 28.9, 28.3, 22.4; IR (film) νmax 3318, 2954, 1718, 1647, 1535, 1491 cm−1; MALDIFTMS m/z 444.2108 (M+Na+, C21H31N3O6 requires 444.2110).
Reaction SMILES: [F:1][C:2]([F:14])([CH:10]([OH:13])[CH2:11][CH3:12])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(Cl)(Cl)Cl.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21].C(N(CC)CC)C>O>[C:19]([O:13][CH:10]([CH2:11][CH3:12])[C:2]([C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])([F:14])[F:1])(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: CCC(O)C(F)(F)C(=O)OC(C)(C)C
Reactant: C=C(C)C(=O)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)OC(C)(C)C
Temperature: 55 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
A 25 mL reactor was charged with 1.50 g (5.6 mmol) of t-butyl 2,2-difluoro-3-hydroxypentanoate and 15 mL of chloroform, 10 mg of NONFLEX MBP, 1.17 g (11.2 mmol, 2 eq) of methacrylic chloride, and 0.87 g (8.6 mmol, 1.5 eq) of triethylamine, followed by stirring at 55° C. for 24 hr. Then, 15 mL of water was added, followed by extraction with chloroform one time. The obtained organic layer was washed with saturated sodium hydrogencarbonate and water, followed by removal of water with magnesium sulfate. After conducting filtration, chloroform was distilled off, thereby obtaining 1.57 g of the target 1-(t-butoxycarbonyl)-1,1-difluoro-2-butyl methacrylate. Upon this, purity was 58%, and yield was 58%.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:20])=[CH:3]\[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[C:9]([Cl:19])[CH:8]=1)=[O:5].[C:21](OCC)(OCC)(OCC)[CH3:22]>>[Cl:19][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[CH:3]=[C:2]([CH3:20])[N:1]=[C:21]2[CH3:22])[CH:12]=[CH:11][C:10]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: CCOC(C)(OCC)OCC
Reactant: C/C(N)=C/C(=O)Nc1ccc(N2CCOCC2)c(Cl)c1
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(Cl)c2)c(C)n1
Temperature: 150 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
A mixture of (Z)-3-amino-N-(3-chloro-4-morpholinophenyl)but-2-enamide (2.0 g, 6.76 mmol) and triethyl orthoacetate (20 mL) was stirred at 150° C. for 12 h. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a pale yellow solid (1.63 g, 76%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1.CN(C)C=O.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>C(N(CC)CC)C>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33](=[O:34])[NH:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1
Reactant: Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Reactant: O=C=Nc1ccccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12)Nc1ccccc1F
Yield: 36.6 %

Procedure:
The preparation is carried out as in Example 36 but from 2 g of 8-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one hydrochloride, 40 ml of dimethylformamide, 1.3 g of triethylamine and 1.76 g of 2-fluorophenyl isocyanate. There is obtained 1 g of 8-[3-(2-fluorophenyl)ureido]-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one in the form of a beige solid melting above 260° C. (Analysis, % calculated C: 64.00, H: 3.76, F: 5.06, N: 18.66, O: 8.52, % found C: 64.0, H: 3.5, F: 4.6, N: 18.6).
Reaction SMILES: O=S1(=O)C2C=CC=CC=2CN(C2C=C(NCC3OCCN(C(OC(C)(C)C)=O)C3)C3C(=CC=C(C)C=3)N=2)CC1.Cl[C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[C:48]([Cl:51])[CH:49]=2)[N:44]=[C:43]([N:52]2[CH2:58][C:57]3[CH:59]=[CH:60][CH:61]=[CH:62][C:56]=3[S:55](=[O:64])(=[O:63])[CH2:54][CH2:53]2)[CH:42]=1.[NH2:65][CH:66]1[CH2:69][N:68]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:67]1>>[Cl:51][C:48]1[CH:49]=[C:50]2[C:45](=[CH:46][CH:47]=1)[N:44]=[C:43]([N:52]1[CH2:58][C:57]3[CH:59]=[CH:60][CH:61]=[CH:62][C:56]=3[S:55](=[O:64])(=[O:63])[CH2:54][CH2:53]1)[CH:42]=[C:41]2[NH:65][CH:66]1[CH2:67][N:68]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:69]1
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(Cl)ccc3n2)Cc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3CN(C(=O)OC(C)(C)C)CCO3)c2c1
Product: CC(C)(C)OC(=O)N1CC(Nc2cc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccc(Cl)cc23)C1

Procedure:
The title compound was prepared in analogy to tert-butyl 2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-ylamino]-methyl}-morpholine-4-carboxylate in Example 21-1 by using 4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and tert-butyl 3-aminoazetidine-1-carboxylate.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[C:19]3[C:27](=[O:37])[N:28](C(OC(C)(C)C)=O)[CH2:29][C:18]=3[C:17]=2[F:38])[CH2:13][CH2:12][O:11][CH2:10]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[C:19]3[C:27](=[O:37])[NH:28][CH2:29][C:18]=3[C:17]=2[F:38])[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cccs2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1COCC[C@H]1Nc1nc(-c2cccs2)c2c(c1F)CNC2=O
Yield: 83.5 %

Procedure:
A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-7-fluoro-3-oxo-4-(thiophen-2-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (30 mg, 0.055 mmol) in TFA/DCM (1:1, 10 mL) was stirred at RT for 2 h. The solvent was removed and the resulting crude material was reconstituted in MeOH/DCM (20 mL) and purified via preparative HPLC. The collected fractions were combined and stripped to dryness via rotary evaporation to yield the title compound (16 mg, 85%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.79 (d, J=9.76 Hz, 1H), 2.12 (qd, J=12.94, 5.13 Hz, 1H), 3.56-3.68 (m, 1H), 3.75 (d, J=11.72 Hz, 1H), 3.89 (br s, 1H), 4.02 (d, J=11.72 Hz, 2H), 4.28-4.37 (m, 1H), 4.38-4.49 (m, 2H), 7.10-7.20 (m, 1H), 7.28 (d, J=4.88 Hz, 1H), 7.59-7.70 (m, 1H), 7.93 (br s, 2H), 8.52 (s, 1H), 9.02 (dd, J=3.91, 0.98 Hz, 1H). [M+H] calc'd for C16H17FN4O2S, 349; found, 349.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:19])=O>C1C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([Cl:19])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCCCOCc1ccccc1
Solvent: c1ccccc1
Product: O=C(Cl)CCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the acid 29 (4.98 g, 24 mmol) in dry benzene (40 ml), was added oxalyl chloride (2.5 ml, 28.8 mmol, 1.2 equiv) dropwise. A drying tube was placed on the flask and the reaction was stirred for 90 min at room temperature. The reaction was concentrated in vacuo and used directly in the next step: 1H NMR (400 MHz, CDCl3) δ 7.38-7.27 (m, 5H), 4.50 (s, 2H), 3.51-3.40 (t, 3J=6.4 Hz, 2H), 2.95-2.90 (t, 3J=7.2 Hz, 3H), 1.87-1.78 (m, 2H), 1.71-1.63 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 173.958, 138.519, 128.949, 128.787, 128.630, 127.862, 73.197, 69.551, 47.032, 28.618, 22.329.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:19][C:20]2[CH:21]=[CH:22][C:23]3[O:27][N:26]=[C:25]([CH3:28])[C:24]=3[CH:29]=2)[C:9]2[C:10]([C:16]([OH:18])=O)=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([CH3:15])[C:13]=3[CH3:14])[C:16](=[O:18])[N:19]2[C:20]2[CH:21]=[CH:22][C:23]3[O:27][N:26]=[C:25]([CH3:28])[C:24]=3[CH:29]=2)=[CH:4][CH:3]=1
Reactant: Cc1noc2ccc(NC(c3ccc(Cl)cc3)c3c(C(=O)O)nn(C)c3C)cc12
Solvent: CO
Solvent: ClCCl
Product: Cc1noc2ccc(N3C(=O)c4nn(C)c(C)c4C3c3ccc(Cl)cc3)cc12

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)(3-methylbenzo[d]isoxazol-5-ylamino)methyl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (Step 33.5). tR: 4.70 min (HPLC 1); tR: 1.03 min (LC-MS 2); ESI-MS: 393 [M+H]+ (LC-MS 2); Rf=0.50 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.08 (s, 3H) 2.44-2.57 (m, 3H) 3.85 (s, 3H) 6.52 (s, 1H) 7.29 (s, 4H) 7.63 (d, J=9.0 Hz, 1H) 7.73 (dd, J=9.0, 2.0 Hz, 1H) 8.01 (d, J=1.6 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[CH3:13][O:14][C@@H:15]([CH3:18])[CH2:16][OH:17].[OH-].[Li+]>>[CH3:13][O:14][C@@H:15]([CH3:18])[CH2:16][O:17][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: CO[C@@H](C)CO
Agent: [Li+]
Agent: [OH-]
Product: CO[C@@H](C)COc1ccc(C(=O)O)cn1
Temperature: 75 °C
Yield: 67 %

Procedure:
The title compound was synthesized as described for Intermediate example I-81 in 67% yield starting from ethyl 6-chloronicotinate and (s)-(+)-2-methoxypropanol. The reduction was performed using 3 equiv of lithium hydroxide while heating to 75° C. for 3 h. The final aqueous solution was extracted with ethyl acetate in order to collect the product; 1H NMR (400 MHz, CD3OD) δ ppm 8.77 (d, 1 H), 8.21 (dd, 1 H), 6.87 (d, 1 H), 4.27-4.40 (m, 2 H), 3.69-3.81 (m, 1 H), 3.42 (s, 3 H), 1.24 (d, 3 H); MS (ESI) m/z 212[M+H+], m/z 210 [M−H+].
Reaction SMILES: C1N2CN3CN(C2)CN1C3.N12CCCN=C1CCCCC2.[CH3:22][C:23]1[O:24][CH2:25][CH:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1>ClCCl.[Cu](Br)Br>[CH3:22][C:23]1[O:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1
Reactant: COC(=O)C1COC(C)=N1
Agent: Br[Cu]Br
Agent: C1N2CN3CN1CN(C2)C3
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)c1coc(C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.2 %

Procedure:
Hexamethylenetetramine (11.7 g, 5.00 mmol) and 1,8-diazabicyclo(5,4,0)undec-7-ene were added to a stirred suspension of copper bromide (18.7 g, 83.85 mmol) in dichloromethane (50 mL) at 0° C. and purged with argon gas for 20 min. To the mixture was added methyl 2-methyl-4,5-dihydrooxazole-4-carboxylate (3 g, 20.97 mmol) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for a further 12 h. The solvent was removed in vacuo and the resulting residue partitioned between ethyl acetate and 1:1 saturated aqueous ammonium chloride and ammonium hydroxide. The organic layer was separated and the aqueous layer extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with 1:1 saturated aqueous ammonium chloride and ammonium hydroxide, 10% aqueous citric acid, saturated sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford methyl 2-methyloxazol-4-carboxylate (1.1 g, 34%) as a solid.