Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:19]=[CH:18][C:8]2[O:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][O:12][C:7]=2[CH:6]=1)(=O)C.COC1C=CC2OC(C(OCC)=O)=COC=2C=1>>[OH:4][C:5]1[CH:19]=[CH:18][C:8]2[O:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][O:12][C:7]=2[CH:6]=1
Reactant: CCOC(=O)C1=COc2cc(OC(C)=O)ccc2O1
Agent: CCOC(=O)C1=COc2cc(OC)ccc2O1
Product: CCOC(=O)C1=COc2cc(O)ccc2O1

Procedure:
The compound of Example 7 is obtained by repeating Stages A, B, C, D, E, F and G of Example 1 starting from ethyl 6-methoxy- 1,4-benzodioxin-2-carboxylate.
Reaction SMILES: Cl.[CH2:2]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([CH2:10][CH2:11][C:12](Cl)=[O:13])=[CH:8][CH:7]=1)[CH:3]=[CH2:4].C(Cl)Cl.[OH:20][CH:21]([CH2:26][CH3:27])[C:22]([O:24][CH3:25])=[O:23].C(N(CC)CC)C>CCOCC>[CH2:2]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([CH2:10][CH2:11][C:12]([O:20][CH:21]([C:22]([O:24][CH3:25])=[O:23])[CH2:26][CH3:27])=[O:13])=[CH:8][CH:7]=1)[CH:3]=[CH2:4]
Reactant: C=CCNc1ccc(CCC(=O)Cl)cc1
Reactant: CCC(O)C(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCNc1ccc(CCC(=O)OC(CC)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 10.0 g. 4-(allylamino)hydrocinnamoyl chloride hydrochloride in 200 ml. methylene chloride is added dropwise a solution of 3 g. methyl 2-hydroxybutyrate and 5 g. triethylamine in 100 ml. ether. After 17 hours stirring at room temperature, the precipitate is collected and washed with several portions of ether. The ether solution is washed with water, dried and evaporated to yield 1-(methoxycarbonyl)propyl 4-(allylamino)hydrocinnamate as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH2:7][CH:8]=[O:9])[CH2:3][C:4](O)=[O:5].S(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:10])[CH:7]=[CH:8][O:9][C:4](=[O:5])[CH2:3]1
Reactant: CC(C)(CC=O)CC(=O)O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC1(C)C=COC(=O)C1

Procedure:
A solution of 1.05 g (7.28 mmol) of crude 3,3-dimethyl-5-oxopentanoic acid (from Example 8a) and 1 g (8.4 mmol) of thionyl chloride in 10 mL of benzene was heated under reflux for 62/3 hours. The reaction mixture was concentrated to give 3,4-dihydro-4,4-dimethyl-2H-pyran-2-one. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].C1COCC1.[C:14]([C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1)#[CH:15]>CCN(CC)CC>[C:14]([C:16]1[CH:17]=[C:18]([NH:22][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH:19]=[CH:20][CH:21]=1)#[CH:15]
Reactant: C#Cc1cccc(N)c1
Reactant: O=C(Cl)c1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#Cc1cccc(NC(=O)c2cccs2)c1
Temperature: 55 °C
Yield: 85 %

Procedure:
A dry 25 mL flask was charged with thiophene-2-carbonyl chloride and THF (5 mL) was added. 3-Ethynyl-phenylamine (0.905 g, 3.59 mmol) was added to the THF solution of the acid chloride followed by NEt3, and the mixture was allowed to stir at 55° C. The reaction mixture was then allowed to cool to room temperature and extracted with EtOAc (˜10 mL), 1M HCl (˜10 mL), followed by brine (˜10 mL). The combined organic extracts were combined and dried over anhydrous Na2SO4(S) and the concentrated. The crude residue was purified by chromatography (silica gel, gradient elution EtOAc/Hexanes 0 to 50%). The product containing fractions were concentrated to give the title compound as a tan solid (0.33 mg, 1.45 mmol, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:11]([NH:19][NH2:20])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCCCCC>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[N:20][NH:19][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNC(=O)c1ccccc1
Reactant: COc1ccccc1C=O
Solvent: CCCCCC
Product: COc1ccccc1C=NNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 1.5 g (7.3 mmol) 2-methoxybenzaldehyde and 1 g (7.3 mmol) benzhydrazide in 35 mL n-hexane was stirred overnight at room temperature. The precipitate was suctioned off, dried, and used without further purification (1.75 g).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:28])[CH:3]=1.[C:29]1([CH2:35][C:36]([N:38]=[C:39]=[O:40])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.CCCCCC>[CH3:24][N:23]([CH2:22][CH:19]1[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2]([NH:1][C:39]([NH:38][C:36](=[O:37])[CH2:35][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:40])=[CH:3][C:4]=3[F:28])[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:21][CH2:20]1)[CH3:25]
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Reactant: O=C=NC(=O)Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3F)ccn2)CC1
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(dimethylaminomethyl)piperidin-1-yl]carbonylamino}pyridine (62.7 mg) in tetrahydrofuran (4.0 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 1.6 ml) at room temperature, followed by stirring overnight. The reaction mixture was concentrated under reduced pressure. The resultant residue was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate) to provide the titled compound (48.0 mg, 54%) as white powder.
Reaction SMILES: [CH3:1]N(C=O)C.[CH3:6][C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]3[CH:23]=[C:24]([C:26]([OH:28])=[O:27])[S:25][C:18]=13)=[CH:11][CH:10]=2.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCOC(C)=O.CO>[CH3:1][O:27][C:26]([C:24]1[S:25][C:18]2[C:19](=[N:20][CH:21]=[CH:22][C:17]=2[O:16][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7]([CH3:6])=[CH:15]3)[CH:23]=1)=[O:28]
Reactant: Cc1cc2cc(Oc3ccnc4cc(C(=O)O)sc34)ccc2[nH]1
Reactant: CN(C)C=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2nccc(Oc3ccc4[nH]c(C)cc4c3)c2s1
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of DMF was added 7-(2-Methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridine-2-carboxylic acid (0.6 g, 1.85 mmol), DIEA (0.62 mL, 3.70 mmol), HATU (0.77 g, 2.03) and MeOH (0.5 mL). The solution was stirred for 3 h then 50 mL of EtOAc added and partitioned between 50/50 NaHCO3 (2×50 mL). The organic layer was dried over Na2SO4 then concentrated. Purification was through silica (50 mL) eluting with EtOAc/Hex (2:1). The purified fraction combined and concentrated to give 7-(2-Methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridine-2-carboxylic acid methyl ester as white foam (0.6 g, 96%). HPLC: Rt 4.01 min. (100% area). 1H NMR (CDCl3-d3, 400 MHz) δ: 8.42 (1H, d, J=5.6 Hz), 8.29 (1H, bs), 7.26-7.23 (2H, m), 6.85 (1H, dd, J=7.5, 1.6 Hz), 6.51 (1H, d, J=5.3 Hz), 6.17 (1H, s), 3.91 (3H, s), 2.40 (3H, s). LCMS (ACPI) M+H+ m/z: 339.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Br[C:11]1[S:12][CH:13]=[CH:14][N:15]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Brc1nccs1
Reactant: COc1cccc(O)c1
Solvent: CN(C)C=O
Product: COc1cccc(Oc2nccs2)c1
Yield: 60.6 %

Procedure:
3-Methoxyphenol (2.48 g, 20 mmol), 2-bromothiazole (3.28 g, 20 mmol) and Me4N+OH-.5H2O (3.62 g, 20 mmol) were heated in dry DMF (30 mL) under N2 (g) for 16 hours. The mixture was filtered and the filtrate was partitioned between H2O and EtOAc. Organic extracts were pooled, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica (CHCl3) to yield 2.51 g of 2[(3-methoxyphenyl)oxy]thiazole (GC-MS m/z 207 (M+)). A portion (2.42 g, 11.7 mmol) of this material was dissolved in dry CH2Cl2 (40 mL), and BBr3 (2.2 eq.) was added dropwise at about -10° C. under N2 (g). The mixture was allowed to warm to about 20° C., stirred 3 hours, and then poured into ice/H2O and extracted with CH2Cl2. Organic extracts were washed with 5% NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo to yield 3-[(thiazol-2-yl)oxy]phenol as an oil (1.3 g) which was used without further purification (GC-MS m/z 193 (M+)).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[CH3:37][O:38][CH2:39][C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH:42]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O1CCCC1>[C:25]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][NH:22][C:5]2[N:4]=[C:3]([CH2:2][NH:1][CH2:42][C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3[CH2:39][O:38][CH3:37])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COCc1ccccc1C=O
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COCc1ccccc1CNCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC)[C@@H](O)[C@H]3O)c2n1
Reaction time: 1 h
Yield: 60.6 %

Procedure:
A solution of (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (323 mg, 0.66 mmol), 2-(methoxymethyl)benzaldehyde (109 mg, 0.73 mmol) (Tetrahedron 4739, 47, 1991) and 1 drop of acetic acid in tetrahydrofuran (15 ml) was stirred at room temperature for 24 hr. Sodium triacetoxyborohydride (310 mg, 1.45 mmol) was then added and the reaction mixture stirred for 1 hr. At this point the solvent was partially removed under reduced pressure and the residue partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The solvent was removed from the organic layer under reduced pressure and the residue purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol (97:3) increasing in polarity to dichloromethane:methanol:ammonia (95:5:0.5). This gave the title compound (250 mg) as a foam. MS: 625 (MH+).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:14][C:15](=[O:23])[CH2:16][P:17]([O:21][CH3:22])([O:19][CH3:20])=[O:18])[CH2:10][C:11]([OH:13])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:24]1(C)C=CC(S(OC)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.C(OCC)(=O)C>[Si:1]([O:8][C@H:9]([CH2:14][C:15](=[O:23])[CH2:16][P:17]([O:19][CH3:20])([O:21][CH3:22])=[O:18])[CH2:10][C:11]([O:13][CH3:24])=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COP(=O)(CC(=O)C[C@H](CC(=O)O)O[Si](C)(C)C(C)(C)C)OC
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C[C@@H](CC(=O)CP(=O)(OC)OC)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.4 %

Procedure:
2.58 g (7.0 mmol.) of (R)-3-t-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoic acid was dissolved in 16 ml of acetone. To the acetone solution were added 6.52 g (35 mmol.) of methyl p-toluenesulfonate and 1.06 g (7.7 mmol.) of potassium carbonate, and the resulting mixture was vigorously stirred for 6 hours at room temperature to give a reaction solution. The reaction solution was mixed with 16 ml of water and then extracted with 20 ml of toluene. The toluene portion was dried over anhydrous magnesium sulfate and concentrated to give an oil. The oil was treated by column chromatography (eluent: ethyl acetate) to give 1.91 g (5.0 mmol.) of methyl (R)-3-t-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoate as an oil (yield: 71%).
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[NH:6][C:5]2[N:9]=[CH:10][CH:11]=[C:12]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([NH2:24])=[CH:16][CH:15]=3)[C:4]=2[N:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1[N:36]=[C:37]=[O:38]>>[NH2:1][C:2]1[C:7](=[O:8])[NH:6][C:5]2[N:9]=[CH:10][CH:11]=[C:12]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([NH:24][C:37]([NH:36][C:27]4[CH:28]=[C:29]([C:32]([F:33])([F:35])[F:34])[CH:30]=[CH:31][C:26]=4[F:25])=[O:38])=[CH:16][CH:15]=3)[C:4]=2[N:3]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1nc2c(Oc3ccc(N)c4ccccc34)ccnc2[nH]c1=O
Product: Nc1nc2c(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c4ccccc34)ccnc2[nH]c1=O

Procedure:
Method F2 was used with 2-amino-8-(4-aminonaphthalen-1-yloxy)pyrido[2,3-b]pyrazin-3(4H)-one and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene to afford the title compound as a slightly pink solid (73 mg, 89%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]1[N:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[N:28]=1)[C:6](=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH3:35][CH:36]([CH3:41])[CH2:37][C:38](Cl)=[O:39]>N1C=CC=CC=1>[CH3:35][CH:36]([CH3:41])[CH2:37][C:38]([NH:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]1[N:28]=[C:29]([CH3:34])[CH:30]=[C:31]([CH3:33])[N:32]=1)[C:6](=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:39]
Reactant: CC(C)CC(=O)Cl
Reactant: CCCCCCCCCCCCCC(=O)N(CCCN)CCCCCNc1nc(C)cc(C)n1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCC(=O)N(CCCCCNc1nc(C)cc(C)n1)CCCNC(=O)CC(C)C

Procedure:
The primary amine XV was treated with 3-methylbutanoyl chloride in pyridine in the manner described above (C). The crude product was chromatographed on a 24 g silica gel column (BioSil A) of dimensions 1 cm (id)×30 cm, developed with 30% acetone/CHCl3. Five ml fractions were collected. The pure product was found in tubes 14-22, 128 mg.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23].[C:24](=[O:26])=[O:25]>C1COCC1.CCCCCC>[Br:16][C:17]1[C:18]([F:23])=[C:19]([CH:20]=[CH:21][CH:22]=1)[C:24]([OH:26])=[O:25]
Reactant: Fc1ccccc1Br
Reactant: O=C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1cccc(Br)c1F
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
To a stirred solution of 2,2,6,6-tetramethylpiperidine (31.1 g, 0.22 mol) in THF (200 mL) was added dropwise a solution of butyl lithium (0.22 mol) in hexane (146.7 mL) at −10° C. The mixture was stirred for 1.5 h at −10° C. and the fluoroarene (1-bromo-2-fluorobenzene) in THF (100 mL) was consecutively added to the solution at −75° C. The mixture was stirred for 2 h at −75° C., before being poured on excess of CO2 gas. Then the reaction mixture was warmed to room temperature and stirred over night. After evaporation of the solvent, the residue was dissolved in water (150 mL), washed with diethyl ether (2×50 mL), acidified (to pH 1) and the solid was filtered off and dried under vacuum to give 24.3 g of the title compound as a white solid (yield: 55%).
Reaction SMILES: Br[C:2]1[C:10](Cl)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=O.ClC1C2[C:19]3([O:25]C(=O)C=2C=CC=1)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3.CO.Cl>[Pd]>[CH2:4]([N:22]1[CH2:23][CH2:24][C:19](=[O:25])[CH2:20][CH2:21]1)[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1
Reactant: O=C(O)c1cccc(Cl)c1Br
Reactant: O=C1OC2(CCNCC2)c2c(Cl)cccc21
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C1CCN(Cc2ccccc2)CC1

Procedure:
Following the general procedure described in J. Org. Chem. 1976, 41, 2628, from 2-bromo-3-chloro-benzoic acid (the preparation of which is described in J. Org. Chem. 203, 68, 2030) and 1-benzyl-piperidin-4-one was prepared 7-chloro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one, after debenzylation (Pd/C, H2, MeOH/HCl), as a white solid. ES-MS m/e (%): 238.7 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C(N(C(C)C)C(C)C)C.Cl[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]([C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[CH:7]([C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)CNC(c1ccccc1)c1ccc(Cl)cc1
Reactant: C=CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N(CC(=O)OCC)C(c1ccccc1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
(RS)-{[(4-Chloro-phenyl)-phenyl-methyl]-amino}-acetic acid ethyl ester (18 g, 59 mmol) was dissolved under nitrogen in DCM (1500 mL), N-ethyldiisopropylamine (12.2 mL, 71 mmol) was added, cooled in ice and treated with a solution of allyl chloroformate (6.4 mL, 71 mmol) in DCM (50 mL). Stirring at 20° C. was continued for 16 h. The solution was extracted with 1 M citric acid (200 mL) and 50% NaCl solution. The crude product was purified by chromatography on silica gel in heptane with a gradient of ethyl acetate from 0-50% in 60 min. One obtained 18.1 g (78%) of colorless oil. MS: m/z=388 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH3:16])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[C:22]1([S:28][CH2:29][CH2:30][CH2:31]Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:16])[CH2:31][CH2:30][CH2:29][S:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCCN1CCc2cc(OC)c(OC)cc2CC1=O
Reactant: ClCCCSc1ccccc1
Agent: Cl
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCCSc1ccccc1)CC2

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-methylamine and 3-phenylthiopropylchloride analogously to Example 3. M.p. of the hydrochloride: 130°-140° C.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[C:5]2[C:8]([N:12]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH:13]([CH3:15])[CH3:14])=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[Cl:23][C:24]1[CH:30]=[C:29]([CH3:31])[C:27]([NH2:28])=[C:26]([O:32][CH3:33])[CH:25]=1>C(OCC)(=O)C>[ClH:1].[Cl:23][C:24]1[CH:30]=[C:29]([CH3:31])[C:27]([NH:28][C:2]2[N:6]([CH3:7])[C:5]3[C:8]([N:12]([C:16]4[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=4)[CH:13]([CH3:14])[CH3:15])=[CH:9][CH:10]=[CH:11][C:4]=3[N:3]=2)=[C:26]([O:32][CH3:33])[CH:25]=1
Reactant: CC(C)N(c1ccc(Cl)cc1)c1cccc2nc(Cl)n(C)c12
Reactant: COc1cc(Cl)cc(C)c1N
Solvent: CCOC(C)=O
Product: COc1cc(Cl)cc(C)c1Nc1nc2cccc(N(c3ccc(Cl)cc3)C(C)C)c2n1C
Product: Cl
Temperature: 120 °C
Reaction time: 19 h
Yield: 5.7 %

Procedure:
A mixture of 2-chloro-N-(4-chlorophenyl)-N-isopropyl-1-methyl-1H-benzimidazol-7-amine (30 mg, 0.90 mmol) and 4-chloro-2-methoxy-6-methylaniline (46 mg, 0.27 mmol) was stirred at 120° C. for 19 h. The mixture was dissolved in ethyl acetate (30 ml), washed with saturated aqueous sodium bicarbonate (15 ml) and water (10 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was purified by reverse phase HPLC (acetonitrile containing 0.1 trifluoroacetic acid/water containing 0.1% trifluoroacetic acid). The fraction was concentrated to dryness, dissolved in methanol (10 ml) and treated with 2 M hydrogen chloride in diethyl ether (2 ml) and evaporated in vacuo to give 7.8 mg (19%) of the title compound as a powder.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:12]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([NH2:31])=[O:30])=[CH:27][CH:26]=2)[N:11]=1>O>[ClH:9].[ClH:9].[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)=[C:12]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([C:29]([NH2:31])=[O:30])=[CH:32][CH:33]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: NC(=O)c1ccc(Nc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: O
Product: Cl
Product: NC(=O)c1ccc(Nc2nc(N[C@H]3CC[C@H](N)CC3)nc3c2ncn3C2CCCC2)cc1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
The operation is carried out as in Stage 2 of Example 6 and 800 mg of trans-1,4-diaminocyclohexane is introduced at ambient temperature under agitation then the reaction medium is heated at approximately 150° C. until melting and 249 mg of the product obtained in Stage 1 above is added, the reaction medium is left under agitation for 4 hours 30 minutes then left to return to ambient temperature. Then 10 ml of water is added, followed by extracting with 10 ml of methylene chloride containing 25% of methanol, drying, filtering, evaporating to dryness and taking up in 5 ml of ethanol. 2 ml of 1.4 N HCl in ethanol is added, followed by evaporating, leaving to crystallize, separating and washing with ethanol then drying at a temperature of approximately 60° C. In this way 207 mg of expected product is obtained in the form of colourless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([S:12]([CH3:15])(=[O:14])=[O:13])=[N:9][C:5]2=[N:6][C:7]=1[I:8].C(N(CC)CC)C.Cl[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[N:11]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[N:9]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:5]2=[N:6][C:7]=1[I:8]
Reactant: CS(=O)(=O)c1nc2nc(I)c(Cl)cc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(Cl)c(I)nc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-Chloro-5-iodo-2-(methylsulfonyl)-1H-imidazo[4,5-b]pyridine (for preparation see WO 2012116145; 1.5 g) and triethylamine (875 μL) are dissolved in tetrahydrofurane (12 mL), cooled to 0° C. and treated with (2-(chloromethoxy)ethyl)trimethylsilane (SEM-CI; 890 μL). The mixture is stirred for 30 minutes while warming to room temperature. Then the mixture is partitioned between saturated aqueous NH4Cl and ethylacetate. The organic phase is washed with water and brine. After drying (MgSO4) the solvents are evaporated in vacuo to give the title compound. LC (method 1): tR=1.22 min; Mass spectrum (ESI+): m/z=488 [M+H]+.