Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([OH:30])[CH2:25]1>C(O)(C)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([OH:30])[CH2:25]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1CCC[C@@H](O)C1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@@H]1CCC[C@@H](O)C1
Temperature: 82 °C

Procedure:
A stirred suspension of 1-Benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (2.92 g, 8.65 mmol) and (1R,3R)-3-Amino-cyclohexanol (1.00 g, 8.68 mmol) in isopropyl alcohol (30 ml) was treated with N,N-diisoppropylethylamine (2.27 ml, 13 mmol) and heated at 82° C. overnight. LC/MS shows reaction complete. Reaction cooled to room temperature and used as is for the next step. LCMS (Method M, ESI): RT=2.52 min, m+H=417.3; 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([CH3:14])[CH:3]=1.[Br:15]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:7]([Br:15])=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([CH3:14])[CH:3]=1
Reactant: COC(=O)CCc1ccc(N)cc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)CCc1cc(Br)c(N)cc1C
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
A solution of Intermediate 8 (1.4 g) in acetonitrile (20 ml) was added with N-bromosuccinimide (1.4 g, WAKO) under ice cooling, stirred for 10 minutes under ice cooling, and then stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, then added with ethyl acetate (10 ml), and successively washed with saturated aqueous ammonium chloride, 5% aqueous sodium sulfite, saturated aqueous sodium hydrogencarbonate and saturated brine, the organic layer was dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Yamazen, n-hexane:ethyl acetate=3:1) to obtain the title compound (1.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[C:19](Cl)(=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:19](=[O:28])[CH:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:18])=[CH:21][CH:22]=1
Reactant: COc1ccc(C(=O)CCc2ccccc2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C(Cc2ccccc2)C(=O)c2ccc(OC)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-methoxyphenyl)-3-phenylpropan-1-one (1.0 equiv.) in THF at −78° C. was added dropwise 1.5 equiv. of [(CH3)2Si]2NLi. The solution was stirred for 1 h at −78° C., followed by addition of 1.2 equiv. of p-anisoyl chloride. The reaction mixture was stirred for 10 min at −78° C. and then for 22 h at rt, acidified with 10% citric acid, and extracted with EtOAc. The combined organic layers were washed with water and dried over Na2SO4. Removal of solvent in vacuo provided a crude solid which was purified by flash chromatography (CH2Cl2) to give 1,3-bis(4-methoxyphenyl)-2-benzylpropane-1,3-dione.
Reaction SMILES: [SH:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:23]([CH3:30])([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].Cl>CN(C)C=O.O>[CH2:27]([O:26][C:24](=[O:25])[C:23]([S:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=1)([CH3:30])[CH3:29])[CH3:28]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: COC(=O)c1cc([N+](=O)[O-])c(S)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Sc1cc(C)c(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 4-mercapto-2-methyl-5-nitrobenzoate (1.17 g) in N,N-dimethyl-formamide (20 ml) were added potassium carbonate (1.42 g), ethyl 2-bromoisobutyrate, and the mixture was stirred at 80° C. for 4 hours. After the reaction was complete, water and 2N hydrochloric acid were added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure. The obtained residue was purified by column chromatography to give a crude product of the title compound (3.56 g).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([NH:19][CH:20]=[CH:21][CH3:22])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[C:1]([NH:11][C@H:12]([C:17]([NH:19][CH:20]1[O:31][CH:21]1[CH3:22])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC=CNC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NC1OC1C
Reaction time: 8 h

Procedure:
N-(Cbz-leucinyl)-amino-propene (2.95 g, 9.7 mmol) was dissolved in methylene chloride (100 ml), then mCPBA (5.0 g, 29.1 mmol) was added and the reaction was stirred overnight. The reaction was diluted with saturated aqueous sodium bicarbonate, extracted with EtOAc, dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 50% EtOAc:hexanes).
Reaction SMILES: [CH2:1]([N:5]([CH2:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][CH2:25][C:26]([O:28]CC)=[O:27])=[C:22]([CH3:33])[CH:21]=1)[C:6]1[CH:11]=[N:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([N:5]([CH2:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:22]([CH3:33])[CH:21]=1)[C:6]1[CH:11]=[N:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cncc(-c2ccc(C)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cncc(-c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a solution of ethyl [4-({butyl[6-(4-methylphenyl)pyrazin-2-yl]amino}methyl)-2-methylphenoxy]acetate (39 mg, 0.087 mmol) in methanol (1 mL) and tetrahydrofuran (1 mL), was added 2M sodium hydroxide (1 mL). After shaking for 1 h at room temperature the solvent was evaporated and the residue was then acidified with 2M HCl and extracted CH2Cl2 (2×10 mL). The organic solution separated by hydrophobic frit and the solvents removed in vacuo to afford the title compound as a bright yellow solid (34 mg).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[Cl:38])[CH2:30][CH3:31])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:39]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:39])=[O:26])=[C:21]([O:28][CH:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[Cl:38])[CH2:30][CH3:31])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCC(Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(=O)OC)c1ccccc1Cl
Reactant: N
Solvent: CO
Product: CCC(Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1Cl

Procedure:
In a similar manner as described for example A5, 3.64 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-{[1-(2-chlorophenyl)propyl]oxy}thiophene-2-carboxylate and 115 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].O[C:17]1[C:18]([C:23]([O:25][CH3:26])=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=1>C(Cl)Cl>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][C:17]1[C:18]([C:23]([O:25][CH3:26])=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=1)(=[O:3])=[O:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ncccc1O
Solvent: ClCCl
Product: COC(=O)c1ncccc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triflic anhydride (5.0 g, 18.0 mmol) was added dropwise to a cold (0° C.) solution of methyl 3-hydroxypicolinate (2.5 g, 16.3 mmol) and TEA (2.5 mL, 18.0 mmol) in CH2Cl2 (80 mL). The mixture was stirred at 0° C. for 1 h before it was allowed to warm up to room temperature where it stirred for an additional 1 h. The mixture was then quenched with saturated NaHCO3 solution (40 mL) and the organic layer was separated, washed with brine, dried over MgSO4 and concentrated to give methyl 3-(trifluoromethylsulfonyloxy)picolinate (i.e. Cap-174, step a) (3.38 g, 73%) as a dark brown oil (>95% pure) which was used directly without further purification. 1H NMR (300 MHz, CDCl3) δ ppm 8.72-8.79 (1 H, m), 7.71 (1 H, d, J=1.5 Hz), 7.58-7.65 (1 H, m), 4.04 (3 H, s). Rt=1.93 min (Cond.-MD1); LC/MS: Anal. Calcd. for [M+H]+C8H7F3NO5S: 286.00; found: 286.08.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:13]([F:15])[F:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].[ClH:16].[H][H]>[Pd].CO>[ClH:16].[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([CH:13]([F:14])[F:15])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: [H][H]
Reactant: COC(=O)c1cc(C#N)ccc1C(F)F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(CN)ccc1C(F)F
Yield: 62.7 %

Procedure:
Purge a mixture of methyl 5-cyano-2-(difluoromethyl)benzoate (9.37 g, 44.4 mmol, 1.0 equiv), palladium (10% on carbon, 3.00 g, 2.82 mmol, 0.064 equiv), and methanol (50 mL) with nitrogen, then add hydrochloric acid (37 wt % aqueous, 8.0 mL, 105.6 mmol, 2.38 equiv), and stir the resulting suspension under 275 kPaG of hydrogen at room temperature overnight. Remove the solids by filtration, concentrate the filtrate under reduced pressure, and dry the resulting material in a 40° C. vacuum oven overnight to give the title compound as a light brown solid (7.01 g, 83%). MS (m/z) 216 (M+1).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16][C:15]2=[O:22])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:23].BrBr>O>[Br:23][C:14]1([C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)[C:15](=[O:22])[NH:16][C:17](=[O:21])[NH:18][C:19]1=[O:20]
Reactant: Br
Reactant: O=C1NC(=O)C(c2ccc(Oc3ccccc3)cc2)C(=O)N1
Agent: BrBr
Solvent: O
Product: O=C1NC(=O)C(Br)(c2ccc(Oc3ccccc3)cc2)C(=O)N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-(4'-phenoxyphenyl)barbituric acid (48 mg)in 0.23 ml of water, cooled at 0° C. and under stirring, are added 23 μl of 48% hydrobromic acid and successively 9 μl of bromine. After 2 hours at room temperature additional 9 μl of bromine are added and stirring is continued for 2 hours. The suspended solid is then filtered and washed with water, to give, after drying under vacuum at 60° C., 57 mg of the product, m.p. 125-127° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10](=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[C:11](=[O:13])[N:12]=2)[CH2:4][CH2:3]1.[NH2:28][CH2:29][C@H:30]([OH:40])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[OH:40][C@H:30]([CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[CH2:29][NH:28][CH:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:17]=[CH:16][C:15]([CH:14]=[C:10]3[S:9][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[N:12][C:11]3=[O:13])=[CH:20][CH:19]=2)[CH2:26][CH2:25]1
Reactant: CN1CCN(C2=NC(=O)C(=Cc3ccc(N4CCC(=O)CC4)cc3)S2)CC1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc(N4CCC(NC[C@H](O)COc5ccc(O)cc5)CC4)cc3)S2)CC1

Procedure:
The title compound was prepared from 1-{4-[2-(4-methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one (which was obtained in Intermediate 29) and (2S)-1-amino-3-(4-hydroxy-phenoxy)-propan-2-ol (which was obtained in Intermediate 5) according to the procedure of Example 1 as a yellowish solid; mp>210° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.80-1.95 (m, 2 H), 2.24 (s, 3 H), 2.40-4.00 (m, 18 H), 6.64(d, J=8.9 Hz, 2 H), 6.73 (d, J=8.9 Hz, 2 H), 7.00(d, J=8.9 Hz, 2 H), 7.45(d, J=8.9 Hz, 2 H), 7.52 (s, 1 H), 8.89(brs, 1 H); MS (ES) m/z: 276.6 ((M+2H)2+, 100%); 552.0(MH+, 10%); HRMS Calcd. for C29H38N5O4S (MH+): 552.2645. Found: 552.2634.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9].Cl[C:13]([F:18])([F:17])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:17][CH:13]([F:18])[O:11][C:4]1[CH:3]=[C:2]([F:1])[C:7]([CH2:8][OH:9])=[C:6]([F:10])[CH:5]=1
Reactant: OCc1c(F)cc(O)cc1F
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCc1c(F)cc(OC(F)F)cc1F
Temperature: 100 °C
Reaction time: 2 h

Procedure:
1 g of 3,5-difluoro-4-(hydroxymethyl)phenol (6.245 mmol, 1 eq.) were dissolved in 16 ml of DMF 1.047 g of sodium chloro(difluoro)acetate (6.87 mmol, 1.1 eq.), 2.442 g of cesium carbonate (7.494 mmol, 1.2 eq.) and 400 μl of water were added. The mixture was stirred at 100° C. bath temperature for 2 hours under nitrogen atmosphere. Then the reaction mixture was partitioned between water and ethyl acetate. The separated aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo. The residue was purified by flash chromatography to yield 763.3 mg (3.63 mmol, 58.2%) of the analytically pure target compound.
Reaction SMILES: [N+:1]([C:4]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:20])[NH:9]2)([O-:3])=[O:2].[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[N+:1]([C:4]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][S:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:20])[NH:9]2)([O-:3])=[O:2]
Reactant: O=c1ccc2c([N+](=O)[O-])c(OCCCCBr)ccc2[nH]1
Reactant: Sc1ccccc1
Product: O=c1ccc2c([N+](=O)[O-])c(OCCCCSc3ccccc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 122 from 5-nitro-6-(4-bromo-butoxy)-carbostyril [m.p. 250° C., prepared by nitration of 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril] and thiophenol.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[C:14]([C:15]([OH:17])=O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][NH2:23]>C(OCC)C>[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][NH:23][C:15]([C:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[NH:12][CH:13]=1)=[O:17]
Reactant: CN(C)CCCN
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Solvent: CCOCC
Product: CN(C)CCCNC(=O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Yield: 35.9 %

Procedure:
This compound is prepared according to synthesis 79 from 75 mg (0.33 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 75) and 46 μL (0.36 mmol) of 3-dimethylaminopropylamine. After trituration in diethyl ether, 37 mg (36%) of N-(3-dimethylamino-propyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide is obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([CH:13]1[CH2:15][CH2:14]1)=[O:12].[CH:16]([O-])=[O:17].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:16]=[O:17])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([CH:13]1[CH2:15][CH2:14]1)=[O:12]
Reactant: O=C[O-]
Reactant: O=C(NCc1ccc(I)cc1Cl)C1CC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(CNC(=O)C2CC2)c(Cl)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
In a solution of 2.20 g of N-[(2-chloro-4-iodophenyl)methyl]cyclopropanecarboxamide and 0.57 g of sodium formate in 20 mL of N,N-dimethylformamide in an autoclave, 0.26 g of dichlorobis(triphenylphosphine) palladium (II) was added, and stirred under carbon monoxide atmosphere of 1.5 MPa at 90° C. for 1 hour. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, and diluted with 60 mL of ethyl acetate and washed with water (30 mL×2). The organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous magnesium sulfate in that order, the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluted with ethyl acetate to obtain 1.20 g of the aimed product as white crystal.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[C:13](OC)[C:12](OC)=[C:11](OC)[CH:10]=2)[CH:4]=1.CC(C1C=CC([C:30]([F:33])([F:32])[F:31])=CC=1)=O>>[Cl:1][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:30]([F:33])([F:32])[F:31])=[CH:11][CH:10]=2)[CH:4]=1
Reactant: COc1cc(-c2cc(CCl)n(C)n2)cc(OC)c1OC
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Product: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CCl

Procedure:
5-chloromethyl-1-methyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazole was prepared in analogy to the preparation of 5-chloromethyl-1-methyl-3-(3,4,5-trimethoxy-phenyl)-1H-pyrazole described by Kodama et al. (U.S. Pat. No. 6,472,386), but starting from 4-trifluoromethylacetophenone instead of 3′4′5′-trimethoxyacetophenone.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[C:23]([OH:25])=[O:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.Br[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>C(Cl)Cl>[N:18]1([C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]([O:25][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:24]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)CBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)COC(=O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A solution of (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carboxylic acid (Fmoc-Pro-OH) (5.00 g, 14.8 mmol) in methylene chloride (59 mL) was mixed with N-ethyldiisopropylamine (DIPEA) (7.77 mL, 44.5 mmol) and tert-butyl 2-bromoacetate (4.34 g, 22.2 mmol) with stirring at room temperature, and the reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was washed with a saturated aqueous ammonium chloride solution, and the organic layer was extracted with methylene chloride. The resulting organic layer was washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford (S)-1-((9H-fluoren-9-yl)methyl) 2-(2-(tert-butoxy)-2-oxoethyl) pyrrolidine-1,2-dicarboxylate (Fmoc-Pro-HOGly-OtBu) (Compound SP631) (6.40 g, 14.2 mmol, 96%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[CH:2]1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO>CN(C=O)C>[CH2:21]([N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[CH:2]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1cnc2[nH]cc(-c3c[nH]c4cnccc34)c2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: c1ccc(Cn2cc(-c3c[nH]c4cnccc34)c3cccnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
60 mg (0.16 mmol) of 3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrrolo[2,3-c]-pyridine (“A18”) are added to a suspension, kept under argon, of 20 mg (0.5 mmol) of sodium hydride (60% in paraffin) in 1 ml of DMF. After stirring at room temperature for one hour, 25 μl (0.26 mmol) of benzyl bromide are added, and the mixture is stirred at room temperature for 19 hours. Methanol is added to the reaction mixture, which is subsequently evaporated, and the residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent: 3-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrrolo[2,3-c]pyridine as colourless solid;
Reaction SMILES: [CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][NH:16][CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][N:23]=1>>[CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][N:16]([CH2:26][C:25]4[CH:24]=[N:23][C:22]([O:21][CH3:20])=[CH:29][CH:28]=4)[CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C=O)cn1
Reactant: CC(C)n1ncc2c(=O)[nH]c([C@@H]3CNC[C@H]3C)nc21
Product: COc1ccc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C(C)C)c(=O)[nH]3)C2)cn1

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-isopropyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and 6-methoxynicotinaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.02 (s, 2H), 7.72 (m, 1H), 6.77 (d, J=8.3 Hz, 1H), 3.90 (s, 3H), 3.73-3.53 (m, 2H), 3.39-3.33 (m, 1H), 3.30 (m, 1H), 2.8 (m, 1H), 2.55-2.40 (m, 1H), 1.9 (m, 1H), 1.57-1.53 (m, 2H), 1.52-1.47 (m, 6H), 1.19 (d, J=6.6 Hz, 3H). MS: (M+H m/z=383.2).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][SH:5].[C:6](Cl)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[SH:5][CH2:4][CH2:3][CH2:2][NH:1][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCCS
Reactant: O=C(Cl)c1ccccc1
Product: O=C(NCCCS)c1ccccc1

Procedure:
N-(3-Mercaptopropyl)benzamide (4) was prepared from 1A and benzoyl chloride by the procedures described in Examples 1-3.