Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[O:4][CH2:5][CH2:6][OH:7].[H-].[Na+].Br[C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1>C1COCC1>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([O:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:11][C:10]([CH3:12])=[CH:9][C:8]=2[Cl:13])=[N:18][CH:19]=1
Reactant: Cc1cc(Cl)c(OCCO)c(Cl)c1
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)c(OCCOc2ccc(Br)cn2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
A sol. of 2-(2,6-dichloro-4-methyl-phenoxy)-ethanol (18.6 g, 84 mmol) in THF (360 mL) was cooled to 0° C. NaH (about 55% in oil, 6.60 g, about 153 mmol) was added in portions, and the mixture was stirred at rt for 30 min. A sol. of 2,5-dibrompyridine (18.0 g, 76.3 mmol) in THF (60 mL) was added dropwise, and the mixture was heated to reflux for 90 min. The mixture was allowed to cool to rt, and ice was added carefully. The solvents were partially removed under reduced pressure, and the residue was diluted with EtOAc. This mixture was washed with aq. sat. NH4Cl. The aq. layer was extracted back with EtOAc (2×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 3:97) yielded the title compound (22.7 g, 79%). LC-MS: tR=1.13 min; ES+: 378.08.
Reaction SMILES: [CH2:1]([CH:5]([CH:12]=[CH2:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:2][CH2:3][CH3:4].[C:14]([O-])(=[O:16])[CH3:15].C(OC(=O)C)(=O)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:14]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:12]=[CH2:13])(=[O:16])[CH3:15]
Reactant: C=CC(CCCC)CCCCCO
Reactant: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C=CC(CCCC)CCCCCOC(C)=O
Yield: 93 %

Procedure:
6- Butyloct-7-en-1-ol (800 mg, 4.34 mmol) was converted to the acetate in a standard procedure with acetic anhydride, pyridine and 4-dimethylaminopyridine (DMAP). Subsequent purification by PMLPC yielded 914 mg (93%) of 6-butyloct-7-en-1-yl acetate.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:11]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[O:21])=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2.Cl>C(Cl)(Cl)(Cl)Cl>[NH2:9][C:10]1[C:11]([C:20]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)=[O:21])=[CH:12][C:13]([Cl:1])=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1c(C(=O)c2ccc(F)cc2)ccc2cccnc12
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Nc1c(C(=O)c2ccc(F)cc2)cc(Cl)c2cccnc12
Temperature: 80 °C
Yield: 35.8 %

Procedure:
N-Chlorosuccinimide (0.12 g, 0.93 mmol) was added to a solution of (8-amino-quinolin-7-yl)-(4-fluoro-phenyl)-methanone 367 (0.25 g, 0.93 mmol) in CCl4 (3 ml) followed by HCl (cat) and the mixture was heated at 80° C. for 4 h. After cooling, the mixture was quenched with water and the aqueous phase was extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM as the eluent to give the title compound (0.1 g, 43%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([CH3:13])[C:6]([OH:12])=[CH:7][CH:8]=2)[N:3]=1.I[CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH:15]([O:12][C:6]1[C:5]([CH3:13])=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([CH3:1])=[N:3]2)=[CH:8][CH:7]=1)([CH3:17])[CH3:16]
Reactant: CC(C)I
Reactant: Cc1ccc2ccc(O)c(C)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc2ccc(OC(C)C)c(C)c2n1
Yield: 24.1 %

Procedure:
2,8-Dimethylquinolin-7-ol (1.0 g, 2.31 mmol), 2-iodopropane (0.785 g, 4.62 mmol) and potassium carbonate (0.957 g, 6.93 mmol) in acetone (15 mL) were heated to 70° C. in a sealed tube for 18 hours. After cooling, water (20 mL) was added and the aqueous phase was extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 7-isopropoxy-2,8-dimethylquinoline (120 mg, 24.1% yield) as an oil
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=12.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[CH:2]1[N:1]=[CH:5][N:4]2[CH:9]=[C:8]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)[CH:7]=[CH:6][C:3]=12
Reactant: O=C(O)c1ccc2nccn2c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4cncn4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using imidazo[1,2-a]pyridine-6-carboxylic acid (Maybridge) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.67 (ddd, J=8.1, 4.8, 1.0 Hz, 1H), 7.76 (d, J=1.4 Hz, 1H), 7.78-7.92 (m, 2H), 8.21 (s, 1H), 8.46 (dt, J=8.2, 1.8 Hz, 1H), 8.83 (dd, J=4.7, 1.7 Hz, 1H), 9.27 (dd, J=2.2, 0.8 Hz, 1H), 9.69 (dd, J=1.7, 1.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 264 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5](=[CH:9][C:10]=1[N+:13]([O-:15])=[O:14])[C:6]([OH:8])=[O:7]
Reactant: O=[N+]([O-])[O-]
Reactant: COc1cc(Cl)ccc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1cc(Cl)c([N+](=O)[O-])cc1C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of 33 g of 4-chloro-o-anisic acid in sulfuric acid (100 ml) was added 20 g of potassium nitrate under ice-cooling and the resulting mixture was stirred for 2 hours. The reaction mixture was added to ice/water and extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, 41 g of the title compound was obtained as pale yellow crystals.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[O:14]1[C:19]2[CH:20]=[CH:21][C:22](N)=[CH:23][C:18]=2[O:17][CH2:16][CH2:15]1.C([O-])=O.[NH4+]>CO.[Pd]>[O:14]1[C:19]2[CH:20]=[CH:21][C:22]([NH:11][CH2:10][CH2:9][C:6]3[CH:7]=[N:8][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:4][CH:5]=3)=[CH:23][C:18]=2[O:17][CH2:16][CH2:15]1
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Reactant: Nc1ccc2c(c1)OCCO2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: FC(F)(F)c1ccc(CCNc2ccc3c(c2)OCCO3)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
A solution of 5 mmol (6-trifluoromethyl-pyridin-3-yl)-acetonitrile (prepared as per example 47, step 1) and 1.1 eq. 2,3-Dihydro-benzo[1,4]dioxin-6-ylamine in MeOH (20 mL) was treated with ammonium formate (5 eq.) and 10% Pd/C (200 mg) and stirred at 80° C. for 2 h. Filtration, concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (24%) as a light yellow oil. MS m/e: 325.0 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.[C:12]1([CH3:18])[CH:17]=C[CH:15]=[CH:14][CH:13]=1>CO>[CH2:13]([C:12]1[CH:17]=[N:8][C:7]([C:6]2[CH:10]=[CH:11][C:3]([F:2])=[CH:4][CH:5]=2)=[N:9][CH:18]=1)[CH2:14][CH3:15]
Reactant: N=C(N)c1ccc(F)cc1
Reactant: Cc1ccccc1
Agent: Cl
Solvent: CO
Product: CCCc1cnc(-c2ccc(F)cc2)nc1
Yield: 55 %

Procedure:
To a sodium methylate solution under agitation obtained by dissolving Na (2.8 g, 0.12 mol) in anhydrous methanol (20 c.c.) was added 4-fluorobenzamidine hydrochloride (10.5 g, 0.06 mol), followed by adding α-propyl-β-dimethylaminoacrolein (9.2 g, 0.06 mol), thereafter refluxing on heating for 3 hours with stirring, distilling off methanol under the atmospheric pressure after completion of the reaction, adding toluene (20cc) to the reaction residue to extract the resulting product, washing the extraction liquid with water, drying with anhydrous sodium sulfate, distilling off toluene and recrystallizing the remaining oily substance from ethanol (20 c.c.) to obtain the objective 5-propyl-2-(4-fluorophenyl)pyrimidine (7.0 g). Yield: 55%. M.P. 52.7° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:41][OH:42])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[F:38])=[CH:30][CH:31]=[C:26]4[C:25]([C:39]#[N:40])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:45])C>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:41][OH:42])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[F:38])=[CH:30][CH:31]=[C:26]4[C:25]([C:39]([NH2:40])=[O:45])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5ccc(-c6ccccc6F)nc54)c3CO)ncc2c1
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5ccc(-c6ccccc6F)nc54)c3CO)ncc2c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
In a 25 mL round-bottomed flask, 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-6-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (65 mg, 116 μmol) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (497 μg, 1.16 μmol, Eq: 0.01) were combined with Ethanol (853 μl) and Water (853 μl) to give a colorless solution. The reaction mixture was heated to 45° C. and stirred for 1 h. Mixture was concentrated in vacuo, then diluted with acetonitrile and water and filtered. The resultant filtrate was lyophilized to give 1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-6-(2-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid amide (61 mg, 91%, [M+H]+ 580).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[O:13])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl.S(Cl)(Cl)=O.[CH3:19]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[O:13])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:19])=[O:8]
Reactant: CO
Reactant: O=Cc1cc(Cl)cc(C(=O)O)c1O
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)cc(C=O)c1O

Procedure:
193 g of 5-chloro-3-formyl-2-hydroxybenzoic acid are dissoved in 2 liters of methanol and the solution is saturated with hydrogen chloride. 100 ml of thionyl chloride are added to the solution and the mixture is refluxed for 8 hours. After cooling, the resultant crystals are collected by filtration and dried to give 190 g of methyl 5-chloro-3-formyl-2-hydroxybenzoate.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[CH2:6][CH2:7][CH:9]([C:8]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:15])[CH2:5][CH2:4]1)[C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCN(CC)CC
Reactant: OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)C1CCN(Cc2ccccc2)CC1
Yield: 96.4 %

Procedure:
0.278 g (0.00127 mol) of 1-benzylpiperidine-4-carboxylic acid was boiled at reflux in 5 ml of oxalyl chloride for 2 hrs. The excess oxalyl chloride was distilled off. The residue was taken up twice in toluene and concentrated each time. 0.3 g (99%) of 1-benzylpiperidine-4-carboxylic acid chloride was obtained as a pale beige solid. This was dissolved in 20 ml of toluene, treated with 0.265 ml (0.0019 mol) of triethylamine and 0.17 g (0.00165 mol) of benzyl alcohol and boiled at reflux for 18 hrs. After removal of the solvent the residue was chromatographed on silica gel with ether/hexane (1:2) as the eluent. 0.246 g (80%) of benzyl 1-benzylpiperidin-4-carboxylate was obtained as a yellow oil. MS: me/e=310 (C2H23NO2+).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:26]=[CH:25][C:8]([CH:9]=[CH:10][C:11]2[CH:16]=[C:15]([O:17]COC)[CH:14]=[C:13]([O:21]COC)[CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Na+].[I-].C[Si](Cl)(C)C>C(Cl)Cl.CC#N>[C:1]([O:4][C:5]1[CH:26]=[CH:25][C:8]([CH:9]=[CH:10][C:11]2[CH:12]=[C:13]([OH:21])[CH:14]=[C:15]([OH:17])[CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COCOc1cc(C=Cc2ccc(OC(C)=O)cc2)cc(OCOC)c1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(=O)Oc1ccc(C=Cc2cc(O)cc(O)c2)cc1
Reaction time: 0.25 h
Yield: 74 %

Procedure:
To a solution of 4′-acetoxy-3,5-bis(methoxymethoxy)stilbene (0.358 g, 1 mmol) in dry DCM (50 mL) and dry CH3CN (50 mL) were added NaI (1.8 g, 24 mmol) and freshly distilled TMSCl (1.52 g, 24 mmol). The mixture was stirred under argon for 15 minutes. The solution was diluted with DCM (50 mL) and washed with a fresh aqueous saturated solution of Na2S2O3 (3×40 mL) and saturated NaHCO3, and water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column and gave 0.20 g product (72%). Data are: 1H NMR (Aceton-d6, 300 MHz) δ 8.25 (s, 1H), 7.60 (m, 2H), 7.13-7.08 (m, 4H), 6.59 (d, 2H), 6.32 (t, 1H), 2.25 (s, 3H); 13C NMR (Aceton-d6, 75 MHz) δ 169.7, 159.7, 151.4, 140.4, 136.0, 130.0, 128.3, 128.3, 123.0, 106.1, 103.3, 21.1; HRMS (EI+) found 270.0889 M+, calcd 270.0892 for C16H16O4.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=1>C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CC(=O)O
Product: Cc1cc(N2CCN(Cc3ccccc3)CC2)ccn1
Yield: 97.4 %

Procedure:
A solution of 1-benzylpiperazine (6.8 g) and 4-chloro-2-methylpyridine (4.9 g) in acetic acid (20 ml) was heated under reflux for 15 hours, and then concentrated under reduced pressure. The residue was dissolved in water, and the reaction mixture was basified with potassium carbonate and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with basic silica gel column (ethyl acetate) to obtain the title compound as a brown oil (10 g, quantitative).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:34]=[CH:33][C:10]([O:11][C:12]2[CH:13]=[C:14]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:32])[CH2:29][O:30][CH3:31])[CH:26]=2)[C:15]([NH:17][C:18]2[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=2)=[O:16])=[CH:9][CH:8]=1)=O.O.[NH2:37]N>C(O)C>[CH3:31][O:30][CH2:29][C@H:28]([CH3:32])[O:27][C:25]1[CH:24]=[C:14]([CH:13]=[C:12]([O:11][C:10]2[CH:33]=[CH:34][C:7]([C:5]3[CH:4]=[CH:3][NH:2][N:37]=3)=[CH:8][CH:9]=2)[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)/C=C/N(C)C)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COC[C@H](C)Oc1cc(Oc2ccc(-c3cc[nH]n3)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 100 °C
Yield: 98.4 %

Procedure:
A mixture of 3-{4-[(2E)-3-(dimethylamino)prop-2-enoyl]phenoxy}-5-[(1S)-2-methoxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (100 mg, 0.209 mmol) and hydrazine hydrate (0.204 mL, 4.18 mmol) in ethanol (3 mL) was heated to 100° C. for 5 minutes in a ‘Smith Creator’ microwave. The volatiles were removed in vacuo to give the product as a colourless foam (92 mg).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:13]([C:17]([NH:19][CH2:20][C:21]4([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:18])=[C:12]([Cl:29])[CH:11]=[CH:10][C:9]=3[N:8]=2)[CH2:3]1.[CH3:30][C:31]([Si:34]([CH3:40])([CH3:39])[O:35][CH2:36][CH:37]=O)([CH3:33])[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl>[Si:34]([O:35][CH2:36][CH2:37][NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:13]([C:17]([NH:19][CH2:20][C:21]4([OH:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)=[O:18])=[C:12]([Cl:29])[CH:11]=[CH:10][C:9]=3[N:8]=2)[CH2:3]1)([C:31]([CH3:33])([CH3:32])[CH3:30])([CH3:40])[CH3:39]
Reactant: N[C@H]1CCN(c2ccc3c(C(=O)NCC4(O)CCCCCC4)c(Cl)ccc3n2)C1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCN[C@H]1CCN(c2ccc3c(C(=O)NCC4(O)CCCCCC4)c(Cl)ccc3n2)C1
Reaction time: 0.08 h

Procedure:
2-[(3S)-3-Aminopyrrolidin-1-yl]-6-chloro-N-[(1-hydroxycycloheptyl)methyl]-quinoline-5-carboxamide (17.6 g) was suspended in dichloromethane (300 ml) and molecular sieves (17.6 g) were added under a nitrogen atmosphere. [[(1,1-dimethylethyl)-dimethylsilyl]-oxy]acetaldehyde (7.2 ml) was added dropwise with stirring over 5 minutes and the mixture was stirred at room temperature for 6 hours. Sodium triacetoxyborohydride (17.9 g) was added in one portion and the mixture was stirred at room temperature for a further 17 hours before water (10 ml) was added, the mixture was stirred at room temperature for 30 minutes, concentrated onto silica in vacuo and purified by flash column chromatography (SiO2, 1:2:97-1:8:91 7M NH3 in methanol:methanol:dichloromethane as gradient elution) to afford the subtitle product as a colourless solid (16.0 g). Impure fractions (4.1 g) were repurified by flash column chromatography (SiO2, 1:2:97-1:8:91 7M NH3 in methanol:methanol:dichloromethane as gradient elution) to afford a second crop of the subtitle product (2.8 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]3=[O:20])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[Br:28][C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>ClCCl>[Br:28][C:29]1[CH:30]=[C:31]([S:35]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)[C:15](=[O:20])[CH2:16]2)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1
Reactant: O=C1CNCCN1CC1CCN(c2ccncc2)CC1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CN(S(=O)(=O)c2cccc(Br)c2)CCN1CC1CCN(c2ccncc2)CC1
Yield: 26 %

Procedure:
To a solution of 1-[1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone (2.74 g) and triethylamine (1.67 ml) in dichioromethane (50 ml) was added dropwise at 0° C. 3-bromobenzenesulfonyl chloride (2.56 g), and the mixture was stirred at 0° C. for 1 hour. The reaction solution was diluted with dichioromethane, was washed with water and saturated brine, dried (MgSO4) and concentrated, and the residue was purified with silica gel column chromatography (acetone methanol=9:1=>1:1) and washed with water to give colorless crystals of 4-(3-bromobenzenesulfonyl)-1-[1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone (1.28 g). A part of the crystals were treated with hydrochloric acid to give colorless crystals of the title compound as hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CCN(CC)CC.[Cl:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>C(C(C)=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:20](=[O:21])[CH2:19][CH2:18][Cl:17])=[CH:5][CH:4]=1
Reactant: O=C(Cl)CCCl
Reactant: COc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: COc1ccc(NC(=O)CCCl)cc1
Temperature: 10 °C
Yield: 66.1 %

Procedure:
A three-necked flask was charged with p-Anisidine (50 g), Et3N (40.43 g) and methyl ethyl ketone (100 ml). The resulting slurry was cooled to 10° C. and 3-chloropropionyl chloride (50.74 g) was slowly added. The temperature was allowed to rise to 60° C. during the addition. The mixture was then refluxed for 1 hour and cooled to 50° C. The solids were collected by filtration, washed with water, and dried at 50° C. to constant weight to give N-(4-methoxyphenyl)-3-chloropropionamide (56.42 g, 86.8%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([CH3:12])[C:9]=1[C:10]#[N:11])(=[O:3])[CH3:2].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:16]([O:15][C:13]([C:7]1[S:6][C:5]2[N:4]([C:1](=[O:3])[CH3:2])[C:19]([C:20](=[O:21])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:10]([NH2:11])[C:9]=2[C:8]=1[CH3:12])=[O:14])[CH3:17]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)c1sc(NC(C)=O)c(C#N)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1sc2c(c1C)c(N)c(C(=O)c1ccccc1)n2C(C)=O
Yield: 80.4 %

Procedure:
250 g of 2-acetamido-3-cyano-4-methyl-5-ethoxycarbonylthiophene, prepared in accordance with the method of K. Gewald, are refluxed for 24 hours in 1500 ml of acetone with 250 g of α-bromoacetophenone and 220 g of potassium carbonate; the whole is then precipitated in 4000 ml of ice-water. The resulting precipitate is filtered, washed with 1000 ml of an iced mixture of water/ethanol (1/1), then dried and finally washed with 1000 ml of a cold mixture of cyclohexane/benzene (9/1). In this manner 295 g of 2-ethoxycarbonyl-3-methyl-4-amino-5-benzoyl-6-acetylthieno[2,3-b]pyrrole are obtained, m.p.: 188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[F:69][CH:70]1[CH2:75][CH2:74][N:73]([CH2:76][CH2:77][NH2:78])[CH2:72][CH2:71]1>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([NH:78][CH2:77][CH2:76][N:73]2[CH2:74][CH2:75][CH:70]([F:69])[CH2:71][CH2:72]2)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11]
Reactant: NCCN1CCC(F)CC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCCN1CCC(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
To a mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (156 mg, 0.3 mmol), triethylamine (0.084 mL, 0.6 mmol) and BOP reagent (199 mg, 0.45 mmol) in DMF (0.5 mL) was added 2-(4-fluoro-piperidin-1-yl)-ethylamine (48 mg, 0.32 mmol) in DMF (0.5 mL). The mixture was stirred at rt for overnight. After the usual workup, the residue was purified on a silica gel column to give 110 mg (57%) of the titled compound. MS m/z 645 [M−1].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[CH2:26][N:27]1[CH:31]=[C:30](C2OC(C)(C)C(C)(C)O2)[C:29]([CH3:41])=[N:28]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:30]3[C:29]([CH3:41])=[N:28][N:27]([CH2:26][C:25]4[CH:42]=[CH:43][CH:44]=[C:23]([F:22])[CH:24]=4)[CH:31]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: Cc1nn(Cc2cccc(F)c2)cc1C1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cn(Cc4cccc(F)c4)nc3C)c3cc(Br)cnc32)cc1
Yield: 78.5 %

Procedure:
Using similar reaction conditions as described in step-i of example-1,5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Intermediate 1) (300 mg, 0.709 mmol) was coupled with 1-(3-fluorobenzyl)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 12) (270 mg, 0.851 mmol) using sodium carbonate (220 mg, 2.12 mmol) and Pd(PPh3)2Cl2 (25 mg, 0.035 mmol) in acetonitrile/water (10/2.5 ml) to afford 300 mg (78.5% yield) of the pure product after column purification using 40% ethyl acetate in hexane as eluent. MS: m/z=539.2 (M+1).