Azzindani/Open_Reaction_Data huggingface dataset:
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].[NH2:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=1)[C:23]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)=[O:24].C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[C:23]([C:22]1[CH:21]=[C:20]([NH:19][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:33]=[CH:32][CH:31]=1)(=[O:24])[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1
Reactant: Nc1cccc(C(=O)c2ccncc2)c1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1ccncc1)c1cccc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (6 g) is added, at a temperature between 65° and 70° C., to a solution of 4-(3-aminobenzoyl)pyridine (4 g) and triethylamine (4.05 g) in dioxane (100 cc) which is heated to a temperature in the vicinity of 65° C., in the course of 15 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 6 hours and 30 minutes 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 (300 cc). The solution obtained is washed with distilled water (100 cc), with an aqueous 1N sodium hydroxide solution (100 cc) 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 (6.5 g) is thereby obtained, which is dissolved in boiling acetonitrile (300 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 16 hours. 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 (40 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-isonicotinoylphenyl)-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole7-carboxamide (5.5 g) in the form of white crystals, m.p. 186° C., is thereby obtained.
Reaction SMILES: [F:1][C:2]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([NH:21]C(=O)C)=[CH:20][C:7]=2[N:6]=1)([F:4])[CH3:3].[OH-].[Na+].CO>O>[F:4][C:2]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:8]2[CH:17]=[CH:18][C:19]([NH2:21])=[CH:20][C:7]=2[N:6]=1)([F:1])[CH3:3]
Reactant: CC(=O)Nc1ccc2c(c1)nc(C(C)(F)F)n2CC1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(F)(F)c1nc2cc(N)ccc2n1CC1CCOCC1
Temperature: 70 °C

Procedure:
A mixture of N-[2-(1,1-difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]acetamide (1.07 g, 3.17 mmol), 6 M aqueous solution of NaOH (5 mL) and MeOH (5 mL) was heated to 70° C. for 24 h. The reaction mixture was diluted with water (200 mL) and the product was extracted with EtOAc (4×100 mL). The combined organic layers were dried over anhydrous Na2SO4 and the solvent was concentrated to provide the title compound as white solid. Yield: 0.90 g (96%); MS (ESI) (M+H)+=296.2.
Reaction SMILES: C([O:4][C@@H:5]1[CH:24]=[CH:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=O)C.C(O[C@@H]1[C@H](Br)C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(=O)C)C1)(=O)C.C(=O)(O)[O-].[K+]>CO>[OH:4][C@@H:5]1[CH:24]=[CH:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1
Reactant: CC(=O)O[C@@H]1C=C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Agent: CC(=O)O[C@H]1C[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](C(C)=O)CC[C@@H]34)[C@@]2(C)C[C@H]1Br
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)C=C[C@]4(C)[C@H]3CC[C@]12C
Yield: 22.1 %

Procedure:
A solution of crude 3α-acetoxy-5α-pregn-1-en-20-one (4.0 g.) containing some 3α-acetoxy-2α-bromo-5α-pregnan-20-one, in dry methanol (120 ml.) was treated with potassium bicarbonate (4.5 g.), and the mixture was refluxed under nitrogen for 2 hours. The reaction mixture was concentrated in vacuo, then poured into water, and the product was extracted with methylene chloride. The extract was washed with water, dried (Na2SO4), and evaporated in vacuo. The residue (3.3 g.) was subjected to preparative layer chromatography. The more polar fraction, after crystallisation from methyl acetate, gave 3α-hydroxy-5α-pregn-1-en-20-one (780 mg), m.p. 150°-154°, [α]D + 28.9°. The less polar fraction after crystallisation from methyl acetate, gave 2α-bromo-3α-hydroxy-5α-pregnan-20-one (320 mg), m.p. 201°-204°, [α]D + 110.5°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:24]=[C:23]([C:25]2[CH:33]=[CH:32][C:31]3[N:30]4[CH2:34][CH:35]([N:37](C(OC(C)(C)C)=O)[CH3:38])[CH2:36][C:29]4=[CH:28][C:27]=3[CH:26]=2)[C:22]([CH3:46])=[C:21]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[CH2:1]([O:8][C:9]1[N:24]=[C:23]([C:25]2[CH:33]=[CH:32][C:31]3[N:30]4[CH2:34][CH:35]([NH:37][CH3:38])[CH2:36][C:29]4=[CH:28][C:27]=3[CH:26]=2)[C:22]([CH3:46])=[C:21]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccc3c(c2)cc2n3CC(N(C)C(=O)OC(C)(C)C)C2)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CNC1Cc2cc3cc(-c4nc(OCc5ccccc5)c(C(=O)OCc5ccccc5)c(OCc5ccccc5)c4C)ccc3n2C1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 62.3 %

Procedure:
The intermediate from Step 1 (˜0.18 mmol) was dissolved in trifluoroacetic acid (1 mL). After 1 min of stirring at room temperature, the mixture was partitioned in CH2Cl2 and aqueous 1 M K2CO3. The organic layer was removed, concentrated and chromatographed on silica gel (0-8% MeOH in CH2Cl2) to provide the product as a white powder (70 mg, 55%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.COCCOC>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:16][CH:15]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2ccc3ccccc3n2)cc1
Yield: 68.6 %

Procedure:
2-Chloroquinoline (5.0 g, 31 mmol) and 4-methoxyphenylboronic acid (5.5 g, 36 mmol) were dissolved in a solvent mixture containing 40 mL ethylene glycol dimethyl ether and 60 mL water containing 12.0 g K2CO3. To the stirred solution was added 1.6 g tetrakis(triphenylphosphine)palladium(O) and the mixture refluxed under N2 overnight. The cooled reaction mixture was then removed of water, extracted with methylene chloride three times. The combined organic phase was washed with portions of brine and then dried with anhydrous sodium sulfate, filtered, and evaporated of solvent to give 2-(p-methoxyphenyl)quinoline (5.0 g) after column chromatography (20% ethyl acetate in hexane).
Reaction SMILES: Br[CH:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH3:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[CH3:31][N:32]1[CH2:45][CH2:44][C:35]2[NH:36][C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][C:42]=3[C:34]=2[CH2:33]1>CN(C=O)C.[Cu]I>[CH3:31][N:32]1[CH2:45][CH2:44][C:35]2[N:36](/[CH:2]=[C:3](/[C:5]3[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=3)\[CH3:4])[C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][C:42]=3[C:34]=2[CH2:33]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(=CBr)c1ccc(S(C)(=O)=O)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(S(C)(=O)=O)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
1-(1-Bromoprop-1-en-2-yl)-4-(methylsulfonyl)benzene (241 mg, 0.9 mmol) was dissolved in DMF (2 mL) and potassium phosphate (424 mg, 2 mmol) was added followed by copper (I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol). 2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was added and the mixture purged with nitrogen for 2 min. The reaction mixture was stirred at 85° C. overnight. Water was added and the solid mass was filtered under vacuum. The crude compound was purified on silica gel (100-200 mesh) using 0-3% MeOH:DCM as eluent. Yield: 140 mg. 1H NMR (CD3OD, oxalate salt) δ (ppm): 8.02 (d, 2H), 7.90 (d, 2H), 7.32 (s, 1H), 7.19 (s, 1H), 7.10 (m, 2H), 4.56 (m, 2H), 3.70 (m, 2H), 3.18 (m, 5H), 3.10 (s, 3H), 2.42 (s, 1H), 2.04 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[NH2:22])=[O:16]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:22][C:21]2[CH:20]=[CH:19][S:18][C:17]=2[C:15]([O:14][CH3:13])=[O:16])=[O:12])=[CH:7][CH:8]=1
Reactant: COC(=O)c1sccc1N
Reactant: COc1ccc(CC(=O)O)cc1
Product: COC(=O)c1sccc1NC(=O)Cc1ccc(OC)cc1

Procedure:
The title compound was prepared from 4-methoxyphenyl acetic acid (6.65 g, 40.2 mmol) and methyl-3-amino-2-thiophene carboxylate (6.30 g, 40.08 mmol) using protocol A to afford the coupled intermediate (7.40 g, 60%). Method [7] m/z 306.0 (M+H); retention time=5.907. 1H-NMR (CDCl3) δ 10.04, (broad s, 1H), 8.07 (d, J=5.5 Hz, 1H), 7.38 (d, J=5.5 Hz, 1H), 7.22 (d, J=8.3 Hz, 2H), 6.88 (d, J=8.3 Hz, 2H), 3.76 (s, 3H), 3.75 (s, 3H), 3.65 (s, 2H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.Br[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[O:21][C:20](=[O:28])[CH:19]=1>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[F:27][C:24]([F:25])([F:26])[C:22]1[O:21][C:20](=[O:28])[CH:19]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)[CH:23]=1
Reactant: O=c1cc(Br)cc(C(F)(F)F)o1
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
To a solution of commercially available 4-iodobenzotrifluoride (1.36 g, 5.00 mmol) in THF (13 mL) at −78° C. was added isopropylmagnesium chloride (2M in THF, 2.63 mL, 5.25 mmol) within 2 min keeping the internal temperature below −65° C., stirring was continued at −78 to −20° C. for 60 min. ZnCl2 (1M in THF, 5.50 mL, 5.50 mmol) was added, the cooling bath was removed, the mixture was allowed to reach 23° C. and stirred at 23° C. for 35 min. Pd(PPh3)4 (58 mg, 1 mol %) and 4-bromo-6-trifluoromethyl-pyran-2-one (example C.22 step 3) (1.22 g, 5.00 mmol) were added at 23° C. and stirring was continued at 23° C. for 30 min [slightly exothermic reaction; internal temperature rose to 45° C.]. Poured into ice cold 0.5 M HCl, extracted with EtOAc, washed with sat. NaHCO3-sol. and brine, dried over Na2SO4, evaporated and dried at HV to give an orange solid (1.55 g), which was purified by MPLC to give the title compound as a yellow solid (1.27 g, 82%). MS (EI) [(M)+]; mp 52° C.
Reaction SMILES: C[O:2][CH:3](OC)[CH:4]([CH3:26])[C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12]([CH2:13][C@@H:14]([OH:25])[CH2:15][C@@H:16]2[OH:24])=[CH:11][CH:10]=3)[CH2:7][CH2:6]1.CC1(C)COC(C([C@@H]2[C@]3(C)[C@H](C4[C@H](CC3)[C@]3(C)C(C[C@@H](OC(OC)=O)C[C@@H]3OC(OC)=O)=CC=4)CC2)C)OC1>>[OH:24][C@@H:16]1[C@@:17]2([CH3:18])[C:12](=[CH:11][CH:10]=[C:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:22]2([CH3:23])[C@H:8]3[CH2:7][CH2:6][C@@H:5]2[CH:4]([CH:3]=[O:2])[CH3:26])[CH2:13][C@@H:14]([OH:25])[CH2:15]1
Reactant: COC(OC)C(C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Product: CC(C=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 51 %

Procedure:
The reaction and workup procedures of Example 156 were repeated except that 100 mg of 21,21-dimethoxy-20-methyl-pregna-5,7-diene-1α,3β-diol was used in lieu of 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene to give 45 mg of 1α,3β-dihydroxypregna-5,7-diene-20-carbaldehyde showing the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:20]2[CH:30]=[CH:29][C:23]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])=[CH:22][CH:21]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=[N:11][N:12]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][CH2:39][NH:40]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>CN(C=O)C.C(Cl)Cl.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:20]2[CH:30]=[CH:29][C:23]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])=[CH:22][CH:21]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:38][CH2:39][NH2:40])=[N:11][N:12]=1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccccc4O)o3)n2)cc1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccccc4OCCN)o3)n2)cc1
Temperature: 25 °C
Yield: 67.1 %

Procedure:
A mixture of 4-[5-amino-6-[5-(2-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-N,N-dimethyl-benzamide (50 mg, 0.1228 mmol) in DMF (1.000 mL) was stirred at room temperature and potassium carbonate (25.46 mg, 0.1842 mmol) added. The resulting suspension was heated at 60-65° C. and tert-butyl N-(2-bromoethyl)carbamate (30.28 mg, 0.1351 mmol) was added slowly. After addition is complete the reaction mixture was heated overnight at 65° C. The reaction mixture was cooled to room temperature and water (2 mL) added slowly and the mixture stirred at room temperature for 20 min. A precipitate formed and was isolated by filtration and washed with water (3×5 mL). The solid was re-dissolved in CH2Cl2 and dried (MgSO4), filtered and evaporated to dryness. The solid was triturated with DCM/Ether, and filtered to leave a yellow solid. The yellow solid was in CH2Cl2 (1 mL) and TFA (150 μL, 1.947 mmol) added and the resulting solution stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and the residue taken up in a mixture of MeOH/ CH2Cl2 (4 mL) and passed through a bicarbonate cartridge eluting with MeOH/DCM. The filtrate was evaporated to dryness and then triturated with acetonitrile to give the product as a yellow solid (36.7 mg, 69% yield) 1H NMR (400 MHz, DMSO) d 2.98 (s, 3H), 3.02 (s, 3H), 3.31 (t, 2H), 4.41 (t, 2H), 7.30 (t, 1H), 7.40 (d, 1H), 7.56 (d, 2H), 7.69-7.71 (m, 2H), 7.87 (s, 3H), 8.04 (dd, 1H), 8.16 (d, 2H) and 9.01 (s, 1H) ppm; MS (ES+) 446.28
Reaction SMILES: C[O:2][C:3](=[O:33])[C@@H:4]([NH:22][C:23](=[O:32])[C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:31])[CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH3:21])[C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1.[OH-].[Li+].O>C1COCC1>[Cl:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([Cl:30])[C:24]=1[C:23]([NH:22][C@@H:4]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:9]=[CH:10][C:11]([N:14]([CH3:21])[C:15]2[N:16]=[CH:17][CH:18]=[CH:19][N:20]=2)=[CH:12][CH:13]=1)[C:3]([OH:33])=[O:2])=[O:32]
Reactant: COC(=O)[C@H](C/C=C/c1ccc(N(C)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(c1ccc(/C=C/C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1)c1ncccn1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 81.3 %

Procedure:
A solution of (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (1.28 g) in THF (45 ml) was cooled to 0° C. To the solution, 0.1N aqueous lithium hydroxide solution (40 ml) was added, and the resulting mixture was stirred at 0° C. for 40 minutes. Water (50 ml) was added to the reaction solution, and the resulting mixture was washed with ether. Aqueous layer was acidified by adding 1N hydrochloric acid in small portions thereto, and extracted twice with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated to dryness to obtain (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid (1.01 g).
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[CH:10][N:11]([CH:12]([CH2:16][CH3:17])[CH2:13][O:14][CH3:15])[C:7]=2[CH:6]=[CH:5][N:4]=1.[I-].[Na+].Cl[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:15][O:14][CH2:13][CH:12]([N:11]1[C:7]2[CH:6]=[CH:5][NH:4][C:3](=[O:2])[C:8]=2[C:9]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:10]1)[CH2:16][CH3:17]
Reactant: CCC(COC)n1cc(-c2ccc(S(N)(=O)=O)cc2)c2c(OC)nccc21
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: CCC(COC)n1cc(-c2ccc(S(N)(=O)=O)cc2)c2c(=O)[nH]ccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
To a solution of 4-(4-methoxy-1-(1-methoxybutan-2-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl)benzenesulfonamide (21.0 mg) in acetonitrile (2 mL) were added sodium iodide (20.2 mg) and chloro(trimethyl)silane (0.068 mL), and the mixture was stirred overnight at 50° C. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate to ethyl acetate/methanol) to give the title compound (10.9 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])[CH:6]=[CH:7][CH:8]=1.[C:22](OC(=O)CCC)(=O)[CH2:23]CC>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH2:14][CH2:22][CH3:23])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N(CCNC(C)=O)c2ccccc2)c1
Reactant: CCCC(=O)OC(=O)CCC
Product: CCCC(=O)NCCN(c1ccccc1)c1cccc(OC)c1

Procedure:
The title compound was prepared according to the method previously described for the preparation of 5b, by hydrogenation of nitrile (4b) followed by N-acylation with butyric anhydride. Yield (5n): 80%; mp 50-52° C. (petroleum ether); 1H-NMR (CDCl3): δ 0.92 (t, 3H), 1.59 (m, 2H), 2.10 (t, 2H), 3.52 (m, 2H), 3.76 (s, 3H), 3.89 (t, 2H), 5.71 (brs, 1H), 6.55-6.61 (m, 3H), 7.02-7.31 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH2:13])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:21]=[C:22](Cl)OC(Cl)(Cl)Cl>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]3[N:9]2[C:22](=[O:21])[NH:13][N:12]=3)=[CH:4][CH:3]=1
Reactant: NNc1cnc2ccc(Br)cc2n1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1[nH]nc2cnc3ccc(Br)cc3n12

Procedure:
To the solution of 7-bromo-2-hydrazinylquinoxaline (200 mg, 0.83 mmol) in dichloromethane (5 mL) was added triethylamine (0.175 mL, 1.2 mmol), then the solution of diphosgene (0.055 mL, 0.46 mmol) in dichloromethane was added dropwise at 0° C. with stirring under nitrogen atmosphere. After stirring at r.t. for 5 h, the solvent was removed under vacuum, the residue was washed with water, and dried in vacuo to afford the title product 8-bromo-[1,2,4]triazolo[4,3-a]quinoxalin-1(2H)-one as yellow solid in 82% yield (180 mg). m/z 265 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]>[Ni].CO>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ni]
Solvent: CO
Product: CC(C)N1CCN(Cc2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 124.7 %

Procedure:
A suspension of 1-isopropyl-4-(4-nitro-benzyl)-piperazine (5.7 g, 21.65 mmol) and Raney Nickel (2 g) in MeOH (100 mL) is stirred for 6 h at rt, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated to afford 6.3 g of the title compound as a white solid: ESI-MS: 234.1 [M+H]+; tR=0.95 min (System 1).
Reaction SMILES: [N:1]1([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]5[CH:28]=[CH:27][N:26]([Si](C(C)C)(C(C)C)C(C)C)[C:23]5=[N:24][CH:25]=4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F-].[Cs+]>C(#N)C>[N:1]1([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]5[CH:28]=[CH:27][NH:26][C:23]5=[N:24][CH:25]=4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(-c3ccc4ncnc(N5CCc6ccccc65)c4c3)cnc21
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: c1ccc2c(c1)CCN2c1ncnc2ccc(-c3cnc4[nH]ccc4c3)cc12
Yield: 30.1 %

Procedure:
0.19 g of 4-(2,3-dihydroindol-1-yl)-6-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]-pyridin-5-yl)quinazoline and 0.08 g of caesium fluoride in 1 ml of acetonitrile are stirred at 25° C. in a flask until the reaction is complete (HPLC check, about 24 hours). A precipitate precipitates out of the reaction solution. This is filtered off, rinsed with water and dried, giving 0.04 g of 4-(2,3-dihydroindol-1-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinazoline as white solid (yield 31%, content 97%); MS-FAB (M+H+)=363.9; Rf (polar method): 1.71 min;
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:20][CH3:21])=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]3[CH2:16][CH2:17][CH2:18][C:11]=3[C:10]=2[CH:19]=1.Cl.[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH3:24].C(O)(C)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O>[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:33][CH2:34][N:35]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[C:7]([O:20][CH3:21])=[CH:8][C:9]3[O:14][C:13](=[O:15])[C:12]4[CH2:16][CH2:17][CH2:18][C:11]=4[C:10]=3[CH:19]=2)[CH2:36][CH2:37]1)[CH3:24]
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCl)CCC3
Reactant: CCOc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CCOc1ccccc1N1CCN(CCCOc2cc3c4c(c(=O)oc3cc2OC)CCC4)CC1
Yield: 72 %

Procedure:
Method B (40 h at 50° C.); starting materials: 8-(3-chloropropoxy)-2,3-dihydro-7-methoxycyclopenta[c][1]benzopyran-4(1H)-one (example 83) and 1-(2-ethoxyphenyl)piperazine hydrochloride; yield 72%; fusion point 169°-170° C. (from isopropanol). Fumarate: method E; yield 85%; fusion point 159°-161° C. (from acetone).