Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[O:9][C:10]([CH3:25])=[C:11]([CH2:13][O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][C:16]=2[O:23][CH3:24])[N:12]=1.CO.O>O1CCCC1>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[O:9][C:10]([CH3:25])=[C:11]([CH2:13][O:14][C:15]2[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[CH:17][C:16]=2[O:23][CH3:24])[N:12]=1
Reactant: COc1cc(C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(CO)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
Sodium borohydride (825 mg) was added to a solution of 4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzaldehyde (6.84 g) in tetrahydrofuran (50 ml)-methanol (50 ml) at 0° C. After stirring for 1 hour, the reaction mixture was poured into water to give 4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyl alcohol (6.98 g, yield 92%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([Mg]Cl)(C)C.[C:28]([CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:28]([OH:35])([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH:36]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]3)[CH:10]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cccnc2)CC1
Reactant: FC(F)(F)c1nc2ccc(I)cc2c(Cl)c1-c1ccccc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)(c2cccnc2)c2ccc3nc(C(F)(F)F)c(-c4ccccc4)c(Cl)c3c2)CC1
Temperature: 50 °C
Reaction time: 0.13 h

Procedure:
To a solution of 4-chloro-6-iodo-3-phenyl-2-(trifluoromethyl)quinoline (Intermediate 20: step b, containing about 13% molar of 4-chloro-3-phenyl-2-(trifluoromethyl)quinoline as impurity, 340 mg) in THF (4 mL) at −78° C. under N2 was added iPrMgCl (2.0 M in THF, 0.40 mL, 0.8 mmol). After stirring for 8 minutes, the cooling bath was removed, and stirring was continued for 20 minutes, then tert-butyl 4-nicotinoylpiperidine-1-carboxylate (225 mg, 0.770 mmol, Intermediate 21) was added in neat. After stirring at room temperature overnight, the mixture became clear brown and was heated at 50° C. for 1.5 hours. The mixture was quenched with saturated NH4Cl aqueous solution, and extracted with EtOAc. The extracts were dried over Na2SO4, filtered, and concentrated. The crude mixture was purified by flash column chromatography (silica gel, 20-100% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 9.17-9.35 (m, 1H), 8.50-8.88 (m, 2H), 8.29 (d, J=7.58 Hz, 1H), 8.24 (d, J=8.59 Hz, 1H), 7.82-8.00 (m, 1H), 7.47-7.57 (m, 4H), 7.21-7.33 (m, 2H), 4.08-4.26 (m, 2H), 2.69-2.99 (m, 3H), 1.82-1.92 (m, 1H), 1.53-1.80 (m, 3H), 1.47 (s, 4.5H), 1.41 (s, 4.5H); MS m/e 598.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8]C.N1CCOCC1.C1(N=C=O)C=CC=CC=1>C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[OH:8]
Reactant: COc1cnnc(Cl)c1OC
Solvent: O=C=Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCN1
Product: COc1cnnc(Cl)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
3-Chloro-4,5-dimethoxypyridazine (17.0 g) and morpholine (59.0 mL) were stirred at 100° C. for 2 hr, and cooled to 0° C. To the reaction mixture was added phenyl isocyanate (73.8 mL) at 0° C., and the mixture was stirred at the same temperature for 30 min, and diluted with ethyl acetate. The resulting solid was removed by filtration. The filtrate was concentrated, and the residue was purified by column chromatography (ethyl acetate/hexane-methanol/ethyl acetate) to give the title compound (9.61 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([OH:11])[CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].BrCBr>>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]2[O:10][CH2:9][O:8][C:6]=2[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(Br)cc(O)c1O
Agent: [K+]
Solvent: BrCBr
Product: COc1cc(Br)cc2c1OCO2
Yield: 52 %

Procedure:
To dimethylfonrnamide (400 mL) was added 1-bromo-3,4-dihydroxy-5-methoxybenzene (40 g, 182 mmol), potassium carbonate (75.7 g, 548 mmol), and dibromomethane (95.2 g, 548 mmol), followed by heating to reflux for 1 hour. The solvent was evaporated in vacuo, and the residue was taken up into ethyl ether, filtered, washed with saturated potassium carbonate solution, brine, 1N citric acid solution, and brine. The organic phase was dried over anhydrous magnesium sulfate and filtered through charcoal. The filtrate was concentrated in vacuo giving a crystalline precipitate which was filtered, washed with hexane, and dried in vacuo to a solid. This material was distilled at 2 mm Hg, 125° C., giving a crystalline solid, 21.7 g, 52% yield. NMR spectra and elemental analysis were consistent with the structure.
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[CH3:19][C:20]1[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=1[O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26].C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[CH3:19][C:20]1[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=1[O:22][C:23]1[CH:24]=[C:25]([NH:26][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Reactant: Cc1ccccc1Oc1cccc(N)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1ccccc1Oc1cccc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 28.2 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (9 g) is added, at a temperature between 61° and 65° C., to a solution of 3-(2-methylphenoxy)aniline (6 g) and triethylamine (6.1 g) in dioxane (150 cc) which is heated to a temperature in the vicinity of 60° C., in the course of 35 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 6 hours and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (400 cc). The solution obtained is washed twice with distilled water (200 cc in total), twice with an aqueous 1N sodium hydroxide solution (200 cc in total) and 5 times with distilled water (500 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. A crude product (7 g) is thereby obtained, which is dissolved in boiling acetonitrile (100 cc). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 1 hour. The crystals formed are separated by filtration, washed twice with acetonitrile cooled to a temperature in the vicinity of 4° C. (20 cc in total) and twice with diethyl ether (20 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-[3-(2-methylphenoxy)phenyl]-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (3.6 g), in the form of white crystals, m.p. 180° C. is thereby obtained.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+].[OH-].[K+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:5][CH2:4][N:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: CC1=NCCc2ccccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: CC1=NCCc2ccc([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
A solution of (±) 1-methyl-3,4-dihydroisoquinoline (2.57 g, 17.7 mmol) in conc. sulfuric acid (10 ml) was added dropwise to a stirred mixture of potassium nitrate (1.93 g, 19.1 mmol) in conc. sulfuric acid (10 ml) at −5° C. The mixture was allowed to reach room temperature over 2 h and then heated at 60° C. for 4 h. The reaction mixture was poured into ice-water (100 ml) and basified (pH 9) with KOH pellets. Extraction into dichloromethane (3×50 ml), drying over anhydrous sodium sulfate and evaporation in vacuo yielded the crude product. Purification by chromatography through silica gel, eluting with (0.5% 0.88 NH3: 4.5% CH3OH: 95% CH2Cl2) afforded the title compound as a dark brown oil (1.92 g, 57%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Li]CCCC>CN(C=O)C.CO>[C:13]1([S:19]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([CH3:3])=[CH:5]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reaction time: 0.25 h
Yield: 85 %

Procedure:
50% sodium hydride (1.1 g) was added to a solution of 3-methylindole (4 g) dissolved in anhydrous DMF (50 ml), keeping the temperature under 30° C. Stir for 15 minutes, then drip carefully the phenylsulphonyl chloride (4.7 ml) dissolved in anhydrous DMF (20 ml) and leave under stirring for 2 hours at 25° C. Then add methanol (5 ml) to decompose the possible present traces of BuLi; remove the solvent under reduced pressure, add water (20 ml) and extract exhaustively with methylenchloride. The organic phase is made anhydrous on sodium sulfate and the solvent is removed under reduced pressure. The residue (9.5 g) is ground in methylenchloride/hexane 1:1 to obtain N-(phenylsulphonyl)-3-methylindole (2 g) (m.p. 116-120° C.). The mother liquors are chromatographied to recover more product, eluting with methylenchloride/hexane 1:1. N-(phenylsulphonyl)-3-methylindole (7 g) is recovered from the intermediate fractions, removing the solvent under reduced pressure. Total reaction yield: 85%.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][NH:7][C:8]([NH2:10])=[S:9].[CH3:11][O:12][CH2:13][C:14](O)=O.[OH-].[Na+]>>[NH2:10][C:8]1[S:9][C:14]([CH2:13][O:12][CH3:11])=[N:6][N:7]=1
Reactant: COCC(=O)O
Reactant: NNC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COCc1nnc(N)s1
Yield: 69.8 %

Procedure:
Phosphoryl chloride (87 ml) was added dropwise to a vigorously stirred mixture of thiosemicarbazide (100 g), methoxyacetic acid (100 g) and petroleum ether b.p. 80°-100° (200 ml) maintained at 60°-70°. The temperature of the mixture was slowly raised to 95° and was kept at this temperature until the evolution of gas ceased. The solvent was evaporated and the residual syrup was dissolved in water (200 ml) to give a yellow solution which was adjusted to pH 7 by the addition of 10N NaOH. The mixture was filtered to give 5-amino-2-methoxymethyl-(1,3,4)-thiadiazole (111.25 g). Recrystallisation from water gave compound with m.p. 177°-179°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:18])[C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])[CH:5]=[CH:4][N:3]=1.[Cl:19][CH:20]1[CH2:22][CH:21]1[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:17])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:23]([C@H:21]2[CH2:22][C@H:20]2[Cl:19])=[O:24])[CH:7]=1)=[O:18]
Reactant: O=C(O)C1CC1Cl
Reactant: Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccnc(NC(=O)[C@H]2C[C@H]2Cl)c1)c1c(Cl)cccc1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
To a solution of N-(2-aminopyridin-4-yl)-2,6-dichlorobenzamide (150 mg, 0.54 mmol), 2-chlorocyclopropanecarboxylic acid (66 mg, 0.54 mmol) and HATU (381 mg, 1.08 mmol) in dry DMF (4.5 mL) was added DIPEA (144 mg, 1.08 mmol). The mixture was stirred at 110° C. in a microwave reactor for 1 hour. The mixture was cooled to room temperature and diluted with EtOAc (30 mL). The organic solution was washed with water (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give the desired compounds.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[CH:12]([Mg]Br)=[CH2:13].[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[C:6]2[C:7]=1[NH:8][CH:13]=[CH:12]2
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(F)c2[nH]ccc2c1
Reaction time: 1 h

Procedure:
To a solution of 3-fluoro-4-nitrotoluene (3.1 g) in tetra hydrofuran (160 mL) was added vinyl magnesium bromide (1.0 mol/L tetra hydrofuran solution, 60.0 mL) at −40° C., and the mixture was stirred at the same temperature for 1 hour. To the mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was stirred at room temperature for 1 hour. The mixture was extracted with diethyl ether. The extract was washed with a saturated aqueous ammonium chloride solution, water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on amino-propylated silica gel (eluent: n-hexane/ethyl acetate=19/1-4/1) to give 7-fluoro-5-methyl-1H-indole (0.96 g). The title compound was prepared in a similar manner to that described in Reference Example 1 using this material instead of 4-methyl-1H-indole.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][CH:37]([F:40])[CH2:36][CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:33][CH:32]([N:34]5[CH2:39][CH2:38][CH:37]([F:40])[CH2:36][CH2:35]5)[CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: FC1CCN(C2CNC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCC(F)CC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.6 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.165 g, 0.42 mmol), 1-azetidin-3-yl-4-fluoropiperidine (0.1 g, 0.63 mmol) and 4 Å molecular sieves (0.8 g) in DCE (8 mL) was stirred for 18 h at room temperature. Sodium triacetoxyborohydride (0.179 g, 0.84 mmol) was added and the reaction mixture was stirred for 6 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) to give 491 as a yellow solid (0.1 g, 45%). LCMS (Method I): RT=2.52 min, [M+H]+ 534.2. 1H NMR (400 MHz, DMSO-d6): δ 8.03-7.99 (m, 1 H); 7.64-7.61 (m, 1 H); 7.26-7.21 (m, 2 H); 4.81-4.52 (m, 1 H); 4.51-3.96 (m, 4 H); 3.86 (s, 2 H); 3.79-3.76 (m, 7 H); 3.43 (t, J=6.3 Hz, 2 H); 3.26 (q, J=7.4 Hz, 2 H); 2.97 (t, J=6.3 Hz, 2 H); 2.95-2.91 (m, 1 H); 2.37-2.33 (m, 2 H); 2.18-2.13 (m, 2 H); 1.90-1.75 (m, 2 H); 1.76-1.64 (m, 2 H); 1.33 (t, J=7.4 Hz, 3 H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:26])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[C:27]([O:30][C@H:31]1[CH2:36][C:35](=[O:37])[O:34][C:32]1=[O:33])(=[O:29])[CH3:28].C(O)(=O)C>C1C=CC=CC=1>[C:27]([O:30][C@@H:31]([CH2:36][C:35]([NH:26][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[S:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][CH2:19]2)[N:11]=3)=[C:2]([F:1])[CH:3]=1)=[O:37])[C:32]([OH:34])=[O:33])(=[O:29])[CH3:28]
Reactant: Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: CC(=O)O[C@H]1CC(=O)OC1=O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC(=O)O[C@@H](CC(=O)Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(=O)O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzenamine (70 mg, 0.194 mmol) and (S)-(−)-2-acetoxysuccinic anhydride (34 mg, 213 μmol) was added benzene (1.9 mL) and acetic acid (55 μl, 0.968 mmol) before it was stirred at 80° C. for 1 h. The reaction mixture was concentrated before the regioisomers were separated via SFC (Column: Chiralpak IC, Mobile Phase: liquid CO2/40% MeOH) to give (2S)-2-acetoxy-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridin-2-yl)phenylamino)-4-oxobutanoic acid. MS (ESI) m/z: Calculated: 519.1; Observed: 520.1 (M++H).
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]2[CH:14]=[C:13]([O:15][CH2:16][C:17]3[S:18][CH:19]=[C:20]([CH:22]([CH3:24])[CH3:23])[N:21]=3)[CH:12]=[CH:11][N:5]2[C:6](=[O:10])[C:7]=1[CH:8]=O.CN(C)C=O.[C:30]([O:34][C:35]([CH:37]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>O1CCCC1>[OH:1][C:2]1[N:3]=[C:4]2[CH:14]=[C:13]([O:15][CH2:16][C:17]3[S:18][CH:19]=[C:20]([CH:22]([CH3:24])[CH3:23])[N:21]=3)[CH:12]=[CH:11][N:5]2[C:6](=[O:10])[C:7]=1/[CH:8]=[CH:37]/[C:35]([O:34][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:36]
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)c1csc(COc2ccn3c(=O)c(C=O)c(O)nc3c2)n1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)c1csc(COc2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(O)nc3c2)n1
Temperature: 100 °C
Yield: 62.4 %

Procedure:
2-Hydroxy-8-[(4-isopropyl-1,3-thiazol-2-yl)methoxy]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-carbaldehyde (45 mg, 0.13 mmol) dissolved in tetrahydrofuran (2 ml) and dimethylformamide (1 ml) was added with (tert-butoxycarbonylmethylene)triphenyl-phosphorane (60 mg, 0.16 mmol) and refluxed by heating at 100° C. for 2 hours. The reaction solution was returned to room temperature and concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (chloroform:methanol=20:1) to obtain 36 mg (62%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][NH:5][NH2:6].[C:11](/[CH:13]=[C:14](/[O-])\[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:12].[Na+].FC(F)(F)C(O)=O>O1CCOCC1>[NH2:12][C:11]1[N:5]([CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])[N:6]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=1
Reactant: NNCc1ccccc1Cl
Reactant: CCOC(=O)/C([O-])=C\C#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(N)n(Cc2ccccc2Cl)n1

Procedure:
2.29 g (14.60 mmol) of 1-(2-chlorobenzyl)hydrazine from Example 1 A are dissolved in 60 ml of dioxane under argon. To this are added 2.38 g 814.60 mmol) of sodium (1E)-1-cyano-3-ethoxy-3-oxo-1-propen-2-olate from Example 6 A and 2.66 g (1.80 ml; 23.36 mmol) of trifluoroacetic acid. The mixture is boiled under reflux overnight and reacted further without further workup. LC/MS (Method 2): Rt=2.45 min MS (EI): m/z=280 (M+H)+
Reaction SMILES: C([Mg]Cl)(C)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[C:9](I)[CH:8]=1.C[O:17][B:18](OC)[O:19]C.Cl>C1COCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[C:9]([B:18]([OH:19])[OH:17])[CH:8]=1
Reactant: COB(OC)OC
Reactant: CCc1ccc(Cl)cc1I
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCc1ccc(Cl)cc1B(O)O
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
i-Propylmagnesium chloride (2M in THF, 8.98 mL, 17.95 mmol) was added drop wise to a solution of 4-chloro-1-ethyl-2-iodobenzene (4.35 g, 16.3 mmol) in dry THF (40 mL) at −30° C. and the reaction mixture was stirred at the same temperature for 30 min, under argon. After this time, trimethylborate (3.63 mL, 32.6 mmol) was added drop wise and the reaction mixture was stirred at the same temperature for 1.5 h. HCl (1 M, 16 mL) was added and the reaction mixture extracted with EtOAc (3×50 mL). The combined organic layers were dried over sodium sulfate and, after removal of the solvent, a solid was obtained, which was triturated with hexane to obtain the title compound as a white solid (2.15 g, 72%).
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C1C=CC=CC=1.N1C=CC=CC=1>O>[CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Reaction time: 24 h
Yield: 916 %

Procedure:
4-n-Butylbenzoyl chloride (39, 2 g, 0.2 m) was added dropwise to a solution of 4-hydroxybenzaldehyde (24.4 g), (0.2 m) anhydrous benzene (320 ml) and dry pyridine (30 ml) with stirring. After completion of addition stirring was continued for 24 hours at room temperature. The resulting reaction mixture was poured into cold water. The organic layer was separated and washed with diluted hydrochloric acid solution, diluted potassium hydroxide solution and water, then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was crystallized from ethanol to yield p-(4'-n-butylbenzoyloxy)benzaldehyde (26.3 g, 46%) mp 49.7° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]([N:14]1[C:22]2[CH:21]=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[C:16]2[CH2:24][N:25]([CH3:28])[CH2:26][CH2:27][C:15]1=2)#[CH:13].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[CH3:28][N:25]1[CH2:26][CH2:27][C:15]2[N:14]([C:12]#[C:13][C:2]3[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=3)[C:22]3[CH:21]=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=3[C:16]=2[CH2:24]1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccc(S(N)(=O)=O)cc2)CCN(C)C1

Procedure:
A mixture of 4-bromobenzenesulfonamide (200 mg, 0.84 mmol), 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (391 mg, 1.0 mmol), TBAF.3H2O (793 mg, 2.5 mmol) and dichloro bis(triphenyl phosphine) palladium (II) (29 mg, 0.042 mmol) was stirred at 85° C. for 10 min. The reaction mixture was poured into water and extracted with EtOAc (3×50 mL). The organic layer was washed with water (3×100 mL), dried over anhydrous sodium sulfate and concentrated to afford crude material, which was purified by column chromatography using neutral alumina and 5% MeOH-DCM, followed by reverse phase HPLC to yield 4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-ylethynyl)-benzenesulfonamide. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.92 (d, 2H), 7.7 (d, 2H), 7.58 (d, 1H), 7.38 (s, 1H), 7.23 (d, 1H), 4.7 (d, 1H), 4.4 (d, 1H), 3.96 (m, 1H), 3.63 (m, 1H), 3.37 (m, 2H), 3.18 (s, 3H), 2.42 (s, 3H).