Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][C:12]([N:20]([CH3:22])[CH3:21])([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.CCOC(C)=O.CCCCCC>C(Cl)(Cl)Cl>[ClH:1].[ClH:1].[CH3:21][N:20]([CH3:22])[C:12]1([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1
Reactant: CN(C)C1(c2cccs2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CN(C)C1(c2cccs2)CCNCC1
Yield: 98 %

Procedure:
HCl gas was passed through a solution of 6 g (1 eq.) tert-butyloxycarbonyl-4-(dimethylamino)-4-(thiophen-2-yl)piperidine in 120 ml chloroform at 0° C. for 1 h. The reaction course was monitored by thin-layer chromatography (75% EtOAc/hexane). Once the conversion was complete, the solvent was removed under reduced pressure and 5.3 g (98%) of product were obtained in the form of a white solid.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([OH:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])C1C=CC=CC=1>[Pd].CO>[CH2:9]([OH:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([OH:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCC(O)CCCCCOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCC(O)CCCCCO
Yield: 9.7 %

Procedure:
The resulting compound, 1-benzyloxy-6-tetradecanol (16 g), was hydrogenated overnight using 100 mg of 10% palladium on activated carbon (Degussa A G; Frankfurt, Germany) in 100 ml of methanol to yield 1,6-tetradecandiol (11.1 g, 4.85 mmol). This diol compound, in 100 ml of methylene:pyridine (9:1), was treated with trityl chloride (13.5 g, 4.85 mmol). The mixture was stirred for 4 hours, then washed with ice-cold 10% HCl until the aqueous phase was acidic. Washing in brine then followed this until the aqueous phase was neutral. Solvent removal and chromatography on silica gel in hexane:ethylacetate (80:20) of the oil gave 20.1 g (87%) of the trityl alcohol. The chemical shift of the compound, detected by 1H-NMR, was as follows: 1H-NMR (CDCl3) δ 0.89 (t, 3H, CH3), 1.2-1.7 (m, 22H, CH2), 3.05 (m, 2H, CH2O), 3.55 (m, 1H, CH—O), 3.55 (m, 1H, CH—O), 7.2-7.5 (m, 15H, benzyl).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][CH:6]=[CH:7][N:8]=1.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH2:16]Cl)[CH:15]=1>C1COCC1.C(O)C>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH2:16][N:5]2[CH:6]=[CH:7][N:8]=[C:4]2[CH3:3])[CH:15]=1
Reactant: ClCc1cncc(Br)c1
Reactant: Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nccn1Cc1cncc(Br)c1
Yield: 53 %

Procedure:
To a stirred suspension of sodium hydride (0.54 g, 12.3 mmol) in THF (40 ml) at 20° C. was added 2-methylimidazole in portions over 45 min. 3-Bromo-5-(chloromethyl)-pyridine (1 g, 4.1 mmol) in ethanol (8 ml) was then added and this mixture was heated under reflux for 1 h under an argon atmosphere. After cooling and evaporation of solvents the residue was suspended in MeOH, filtered and adsorbed onto silica gel. Chromatographic elution with CH2Cl2/(2M NH3 MeOH)=98:2 afforded the title compound (0.56 g, 53%) as a yellow oil. MS: m/e=251.0 (M+).
Reaction SMILES: O.[OH-].[Li+].[Br:4][C:5]1[CH:14]=[C:13]([C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)=[O:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8]>O.O1CCCC1.CO>[Br:4][C:5]1[CH:14]=[C:13]([C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)=[O:16])[CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCc1cccc(O)c1)c1ccc(C(=O)O)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.7 %

Procedure:
A solution of lithium hydroxide monohydrate (4.41 g, 105.1 mmol) in water (15 mL) was added to a solution of 2-bromo-4-[[[(3-hydroxyphenyl)methyl]amino]-carbonyl]benzoic acid, methyl ester (Example 14; 15.30 g, 42.0 mmol) in tetrahydrofuran/methanol (2:1, 21 mL). The solution was stirred at room temperature for 1 h, then it was concentrated to remove tetrahydrofuran and methanol. The remaining aqueous solution was extracted with ethyl acetate (15 mL) and the ethyl acetate extract was discarded. The aqueous layer was acidified with 1 M HCl (75 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (15 mL), dried (MgSO4), filtered, and evaporated to give 2-bromo-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoic acid (15.1 g, quantitative yield) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[C:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)(=[O:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[C:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:1][C:2]2[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=2)(=[O:21])=[O:20])=[CH:17][CH:18]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(Br)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CC(=O)c1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
To a 150 mL, round-bottomed flask was added 3-amino-5-bromo-2-chloropyridine (1 g, 5 mmol, Asymchem Laboratories, Morrisville, N.C.) and pyridine(10 mL). To this solution, 4-acetylbenzenesulfonyl chloride (2 g, 10 mmol, Sigma-Aldrich Corporation, St. Louis, Mo.) was added, the mixture was stirred at 25° C. for 15 h and at 100° C. for additional 2 h. The mixture was concentrated in high vacuo. The result brown oil was suspended in methanol (200 mL)-H2O (5 mL). To this suspension, K2CO3 (2 g, 14.4 mmol) was added and the mixture was stirred at 25° C. for 15 h. The methanol was removed in vacuum; the residue was treated with H2O. Filtration provided 4-acetyl-N-(5-bromo-2-chloropyridin-3-yl)benzenesulfonamide (0.5 g) as a brown solid. The filtrate was extracted by MeOH-DCM (10%) to provide additional 1.1 g of 4-acetyl-N-(5-bromo-2-chloropyridin-3-yl)benzenesulfonamide as a white solid. MS (ESI positive ion) m/z: 391 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 2.57 (s, 3H), 7.51-7.56 (m, 2H), 7.81 (d, J=8.41 Hz, 2H), 7.98 (d, J=8.41 Hz, 2H).
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:4]=[C:5]([S+:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[C:26]3[CH:33]=[CH:34][CH:35]=[CH:36][C:25]2=3)[CH:6]=[C:7]([CH3:23])[C:8]=1[O:9][CH2:10][C:11](=[O:22])[O:12][C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH3:14].[OH:37][C:38]12[CH2:47][CH:42]3[CH2:43][CH:44]([CH2:46][CH:40]([CH2:41]3)[CH2:39]1)[CH2:45]2.[Na].[C:49]([O:52][CH:53]([CH3:64])[C:54]([F:63])([F:62])[C:55]([F:61])([F:60])[S:56]([O-:59])(=[O:58])=[O:57])(=[O:51])[CH3:50].O>ClCCl>[OH:37][C:38]12[CH2:39][CH:40]3[CH2:46][CH:44]([CH2:43][C:42]([CH2:50][C:49]([O:52][CH:53]([CH3:64])[C:54]([F:63])([F:62])[C:55]([F:61])([F:60])[S:56]([O-:59])(=[O:58])=[O:57])=[O:51])([CH2:41]3)[CH2:47]1)[CH2:45]2.[CH3:23][C:7]1[CH:6]=[C:5]([S+:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[C:26]3[CH:33]=[CH:34][CH:35]=[CH:36][C:25]2=3)[CH:4]=[C:3]([CH3:2])[C:8]=1[O:9][CH2:10][C:11](=[O:22])[O:12][C:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:15])[CH3:14]
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: CC(=O)OC(C)C(F)(F)C(F)(F)S(=O)(=O)[O-]
Agent: Cc1cc(-[s+]2c3ccccc3c3ccccc32)cc(C)c1OCC(=O)OC(C)(C)c1ccccc1
Agent: [Br-]
Agent: [Na]
Solvent: ClCCl
Solvent: O
Product: CC(OC(=O)CC12CC3CC(CC(O)(C3)C1)C2)C(F)(F)C(F)(F)S(=O)(=O)[O-]
Yield: 84.6 %

Procedure:
5-(3,5-dimethyl-4-(2-oxo-2-(2-phenylpropan-2-yloxy)ethoxy)phenyl)-5H-dibenzo[b,d]thiophenium bromide (1.8 g, 3.21 mmol) and sodium 3-hydroxyadamantane-acetoxy-1,1,2,2-tetrafluorobutane-1-sulfonate (1.44 g, 3.37 mmol) were dissolved in dichloromethane (100 mL) and water (100 mL) and stirred at r.t. overnight. The dichloromethane layer was separated and the aqueous phase washed with dichloromethane (3×100 mL). The combined organic layers were washed with water (6×200 mL) and concentrated in vacuo to afford the title compound (2.44 g, 86%) as a white solid. 1H NMR (500 MHz, ((CD3)2SO) δ: 8.53 (d, J=8 Hz, 2H), 8.35 (d, J=8 Hz, 2H), 8.03 (t, J=7 Hz, 2H), 7.83 (d, J=8 Hz, 2H), 7.51 (s, 2H), 7.40 (d, J=8 Hz, 2H), 7.31 (dt, J=8, 0.5 Hz, 2H), 7.24 (dt, J=7.5, 1 Hz, 1H), 4.65 (s, 2H), 4.31 (t, J=6.5 Hz, 2H), 2.80-2.82 (m, 2H), 2.65 (tt, J=14, 6.5 Hz, 2H), 2.29 (s, 6H), 1.72-1.81 (m, 10H), 1.65-1.67 (m, 4H), 1.56-1.59 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[O:9]([CH2:16][C:17]1[CH:32]=[C:20]2[C:21](=[O:31])[NH:22][C@H:23]([CH2:25][O:26][Si](C)(C)C)[CH2:24][N:19]2[N:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].CNCCNC>C1(C)C=CC=CC=1.CCOC(C)=O.[Cu]I>[F:8][C:5]1[CH:6]=[CH:7][C:2]([N:22]2[C@H:23]([CH2:25][OH:26])[CH2:24][N:19]3[N:18]=[C:17]([CH2:16][O:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:32]=[C:20]3[C:21]2=[O:31])=[CH:3][CH:4]=1
Reactant: C[Si](C)(C)OC[C@@H]1Cn2nc(COc3ccccc3)cc2C(=O)N1
Reactant: Fc1ccc(Br)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2cc(COc3ccccc3)nn2C[C@@H](CO)N1c1ccc(F)cc1
Temperature: 140 °C
Reaction time: 24 h
Yield: 71.8 %

Procedure:
Copper (I) iodide (41 mg, 0.22 mmol) was added to a stirred suspension of 4-bromofluorobenzene (0.24 mL, 2.17 mmol), (S)-2-phenoxymethyl-6-trimethylsilanyloxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (0.37 g, 1.08 mmol), K2CO3 (0.3 g, 2.17 mmol) and N,N′-dimethylethylenediamine (0.070 mL, 0.65 mmol) in toluene (8 mL) in a sealed tube and under nitrogen. The mixture was stirred at 140° C. for 24 hours. The mixture was diluted with AcOEt and washed with a 16% aqueous solution of NH4OH. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The residue was dissolved in MeOH (4 mL) and stirred at 100° C. for 10 minutes under microwave irradiation. The solvent was evaporated in vacuo and the residue purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 50/50). Desired fractions were collected and the solvents evaporated in vacuo to yield (S)-5-(4-fluoro-phenyl)-6-hydroxymethyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (285 mg, 71% yield) as an off-white foam. 1H NMR (400 MHz, CDCl3) δ ppm 2.21 (br. s., 1H), 3.57-3.68 (m, 1H), 3.81 (dt, J=10.9, 4.4 Hz, 1H), 4.13-4.20 (m, 1H), 4.61 (dd, J=13.4, 4.9 Hz, 1H), 4.81 (dd, J=13.4, 2.1 Hz, 1H), 5.10 (s, 2H), 6.95-7.03 (m, 4H), 7.09-7.18 (m, 2H), 7.27-7.35 (m, 4H).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH:18]1[N:22]=[CH:21][NH:20][C:19]=1[CH2:23][CH2:24][NH2:25]>>[C:1]([NH:3][C:4]([NH:25][CH2:24][CH2:23][C:19]1[N:20]=[CH:21][NH:22][CH:18]=1)=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])#[N:2]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: NCCc1cnc[nH]1
Product: Cc1nc[nH]c1CSCCN=C(NC#N)NCCc1c[nH]cn1
Reaction time: 3 h

Procedure:
A mixture of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (8.07 g) and histamine base (3.36 g) was heated for 3 hours at 100° and then for 3 hours at 130°-140°. The product was chromatographed on a column of silica gel with ethyl acetate/isopropyl alcohol (5:1) as eluent and crystallised by slow evaporation from isopropyl alcohol. Recrystallisation from water afforded the title compound, m.p. 170°-171°.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:37]([N:44]1[C:48]2=[N:49][CH:50]=[N:51][C:52](Cl)=[C:47]2[CH:46]=[N:45]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[CH2:37]([N:44]1[C:48]2=[N:49][CH:50]=[N:51][C:52]([O:36][C@@H:25]([CH2:24][O:23][CH2:22][CH2:21][O:20][Si:3]([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=3)=[O:27])=[C:47]2[CH:46]=[N:45]1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Clc1ncnc2c1cnn2Cc1ccccc1
Reactant: Cc1ccc(NC(=O)[C@@H](O)COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@H](COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)Oc2ncnc3c2cnn3Cc2ccccc2)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.1 %

Procedure:
Sodium hydride (90 mg, 2.25 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxy-N-(5-methylpyridin-2-yl)propanamide (538 mg, 1.12 mmol) (Intermediate AU2) in anhydrous THF (20 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 1-benzyl-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (Intermediate AL2) (250 mg, 1.02 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was neutralised with 1M citric acid, diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% EtOAc in isohexane to afford the product (540 mg, 77%). m/z (ES+) (M+H)+=687; HPLC tR=3.89 min.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[C:8](C)=[CH:7][N:6]=[C:5]([CH2:10][S:11][C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=3[N:13]=2)[C:4]=1[Cl:23].C(OCC)(=[O:27])C>>[CH3:1][N:2]([CH3:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:10][S:11]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=3[N:13]=2)=[O:27])[C:4]=1[Cl:23]
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(N(C)C)c3Cl)nc2c1
Reactant: CCOC(C)=O
Product: COc1ccc2[nH]c(S(=O)Cc3nccc(N(C)C)c3Cl)nc2c1

Procedure:
Substituting 2-(4-dimethylamino-3-chloro-2-pyridylmethylthio)-5-methoxy-(1H)-benzimidazole (3.43 g) for 2-(4-dimethylamino-3-chloro-5-methyl-2-pyridylmethylthio)-5-methoxy-(1H)-benzimidazole and using corresponding molar proportions of the other reagents in the method of Example 16, gave 2-(4-dimethylamino-3-chloro-2-pyridylmethylsulphinyl)-5-methoxy-(1H)-benzimidazole, (0.83 g), m.p. 113°-114° from ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.Cl[Pd]Cl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([O:10][CH3:9])[CH:16]=2)=[N:3][CH:4]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: Clc1ccc(Br)nc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(-c2ccc(Cl)cn2)ccn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 34.6 %

Procedure:
2-Bromo-5-chloropyridine (2.04 g, 10.6 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.50 g, 10.6 mmol), K2CO3 (4.38 g, 31.8 mmol) and PdCl2 (dppf) (0.40 g, 0.53 mmol) were stirred in DMSO (20 mL). The reaction mixture was degassed, then back-filled with N2. The reaction mixture was stirred at 80° C. in a pre-heated oil bath for 2 hours. After cooling, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered and concentrated. Flash chromatography (silica gel, hexanes/EtOAc), 100:0 to 50:50) afforded the title compound (810 mg, 34%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.67 (d, J=2.0 Hz, 1H), 8.27 (d, J=5.3 Hz, 1H), 7.79-7.75 (dd, J=8.8, 2.3 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.46-7.44 (dd, J=5.3, 1.5 Hz, 1H), 7.30 (s, 1H), 3.99 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=3)[C:12](=[O:26])[CH:11]=2)=[N:6][CH:7]=1.P(Br)(Br)[Br:28]>C(Cl)Cl>[Br:28][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][N:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=3)=[CH:11][C:12]2=[O:26])=[CH:19][CH:20]=1
Reactant: BrP(Br)Br
Reactant: O=c1cc(OCc2ccc(Br)cn2)ccn1CCc1ccc(CO)cc1
Solvent: ClCCl
Product: O=c1cc(OCc2ccc(Br)cn2)ccn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 150 mg (0.36 mmol) 4-(5-bromo-pyridin-2-ylmethoxy)-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (example 12.1a) in 8.0 mL of DCM is added at 0° C. 27 μL (0.29 mmol) phosphorus tribromide. The mixture is stirred 2 h at RT and the formed precipitate is collected. The product is washed with tert-butylmethylether and dried.
Reaction SMILES: [Na].Cl[CH:3]=[C:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][CH2:6][C:5]1=O.[Li+].[OH-].C([O:17][C:18](=[O:21])[CH2:19][SH:20])C>C(O)C.C1COCC1>[CH3:10][C:8]1([CH3:11])[CH2:7][CH2:6][C:5]2=[C:19]([C:18]([OH:21])=[O:17])[S:20][CH:3]=[C:4]2[CH2:9]1
Reactant: CCOC(=O)CS
Reactant: CC1(C)CCC(=O)C(=CCl)C1
Agent: [Li+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CCc2c(csc2C(=O)O)C1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a part (300 mL) of a freshly prepared solution of sodium (21 g, 875 mmol) in ethanol (500 mL), mercaptoacetic acid ethyl ester (50 mL) is added. The resulting solution is added over a period of 10 min to a solution of 2-chloromethylene-4,4-dimethyl-cyclohexanone (50 g, 290 mmol) in THF (170 mL). The mixture becomes warm (50° C.). Upon complete addition, the remaining part of the freshly prepared solution of sodium in ethanol (200 mL) is added to the reaction mixture. The mixture is stirred at rt for 15 min before 1 N aq. LiOH solution (300 mL) is added. The solution is refluxed for 3 h, then stirred at rt for 16 h. The THF and ethanol are removed under reduced pressure and the remaining dark solution is extracted with heptane/EA 3:1 (2×200 mL). The aq. phase is acidified by adding citric acid (30 g) and 2 N aq. HCl (200 mL) and then extracted three times with EA. The combined organic extracts are washed three times with sat. aq. NaHCO3 solution, dried over Na2SO4 and evaporated. The resulting dark brown oil is dissolved in acetonitrile at 60° C. and crystallised at 5° C. The crystals are collected, washed with acetonitrile and dried to give 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (31 g) as a slightly grey powder; LC-MS: tR=0.95 min, [M+1+CH3CN]+=252.18; 1H NMR (CDCl3): δ 7.15 (s, 1H), 3.05 (t, J=7.0 Hz, 2H), 2.47 (s, 2H), 1.58 (t, J=7.0 Hz, 2H), 0.97 (s, 6H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:13]=1[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])=[O:15])[C:8](=[O:11])[CH2:9]Br)(=[O:3])[CH3:2].[CH2:28]([N:30](CC)CC)[CH3:29].C(CN)O>C1C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:13]=2[C:14]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[O:15][CH2:29][CH2:28][N:30]2[CH2:9][C:8]1=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCN(C(=O)CBr)c1ccc(Cl)cc1C(=O)c1ccccc1F
Reactant: CCN(CC)CC
Solvent: NCCO
Solvent: c1ccccc1
Product: CC(=O)OCCN1C(=O)CN2CCOC2(c2ccccc2F)c2cc(Cl)ccc21
Reaction time: 65 h

Procedure:
A solution containing 1.5g (0.0033 M) of 2-[N-(2-acetoxyethyl)-N-(2-bromoacetyl)amino]-5-chloro-2'-fluorobenzophenone, 0.5 ml of triethylamine and 0.23g (0.0036 M) of ethanolamine in 15 ml of benzene was kept at room temperature for 65 hours and then was partitioned between 25 ml of ethyl acetate and 25 ml of water. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was partioned between 20 ml of ether and 20 ml of 1N hydrochloric acid. The acid layer was separated and extracted with 25 ml of ethyl acetate. The organic layer was then washed with 20 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated to dryness. The residual oil was crystallized from ether and recrystallized from a mixture of methanol and water to give the above named product as white prisms, m.p. 120°-123°.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:21]=[CH:20][C:8]([CH2:9][S:10][C:11]2[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([OH:3])=[O:2].Br[C:23]1[C:32]2[C:27](=[C:28]([Cl:33])[CH:29]=[CH:30][CH:31]=2)[N:26]=[N:25][C:24]=1[CH3:34]>>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:27]=1[N:26]=[N:25][C:24]([CH3:34])=[C:23]2[C:13]1[CH:12]=[C:11]([S:10][CH2:9][C:8]2[CH:20]=[CH:21][C:5]([CH2:4][C:1]([OH:3])=[O:2])=[CH:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccc(CSc2cccc(B(O)O)c2)cc1
Reactant: Cc1nnc2c(Cl)cccc2c1Br
Product: Cc1nnc2c(Cl)cccc2c1-c1cccc(SCc2ccc(CC(=O)O)cc2)c1

Procedure:
The title compound was prepared from 3-(4-carboxymethyl-benzylsulfanyl)-phenylboronic acid and 4-bromo-8-chloro-3-methylcinnoline according to the procedure of Step 4 Example 6. MS (ESI) m/z 435; HRMS (ESI, [M+H]+ 435.0924.
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH3:15])=[CH:5][CH:4]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[N:28]([CH3:29])[CH2:27][CH2:26][C:25]([C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][N:40]([CH3:47])[CH:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[CH:35][CH:34]=3)=[O:31])=[CH:24][C:23]=2[CH:48]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[CH3:29][N:28]1[C:22]2[CH:21]=[CH:20][C:19]([C:3]3[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH3:15])=[CH:5][CH:4]=3)=[CH:48][C:23]=2[CH:24]=[C:25]([C:30]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([CH2:39][N:40]([CH3:47])[CH:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[CH:37][CH:38]=2)=[O:31])[CH2:26][CH2:27]1
Reactant: CN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
In a mixture of water:ethanol:toluene (1:1:10, v/v, 18.0 ml) were dissolved 4-(2-propoxyethoxy)phenyl borate (242 mg) and 7-bromo-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (436 mg). To the solution was added potassium carbonate (299 mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (42 mg), and the mixture was heated to reflux under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (30 g, ethyl acetate:ethanol:triethylamine=180:20:1) and recrystallized from ethanol/hexane to give 1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 12) (186 mg, 35%) as yellow crystals.