Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.[CH3:19][O:20][C:21]([CH2:23]P(=O)(OCC(F)(F)F)OCC(F)(F)F)=[O:22].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH:48]([C:50]1[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:64])[F:63])[C:51]=1[C:52]([O:54][CH:55]([CH3:57])[CH3:56])=[O:53])=O>C1COCC1.C1(C)C=CC=CC=1>[CH3:19][O:20][C:21](=[O:22])/[CH:23]=[CH:48]\[C:50]1[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:64])[F:63])[C:51]=1[C:52]([O:54][CH:55]([CH3:57])[CH3:56])=[O:53]
Reactant: CC(C)OC(=O)c1c(C=O)cccc1C(F)(F)F
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C\c1cccc(C(F)(F)F)c1C(=O)OC(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 142.1 %

Procedure:
To a solution of 18-crown-6 (9.1 g, 34.6 mmol) in 100 mL of THF at −78° C. was added bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate (4.13 g, 12.98 mmol). Potassium bis(trimethylsilyl)amide (19.6 mL of a 15 wt % solution in toluene, 12.98 mmol) was added dropwise over 20 min and the mixture was stirred an additional 1 h at −78° C. Then there was added isopropyl 2-formyl-6-(trifluoromethyl)benzoate (1.5 g, 5.74 mmol) in 10 mL of THF and the resulting cloudy mixture was stirred at −78° C. for 1 h. The reaction was quenched with sat'd aq NH4Cl, diluted with EtOAc, washed with brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo. The residue was purified by flash chromatography (elution with 6:1 hexane/ethyl acetate) to afford 2.58 g (94%) of the title compound as an oil. 1H NMR (CDCl3): δ 7.66-7.62 (m, 2H), 7.51 (t, 1H, J=7.7 Hz), 7.11 (d, 1H, J=12.1 Hz), 6.11 (d, 1H, J=12.1 Hz), 5.26 (septet, 1H), 3.63 (s, 3H), 1.32 (d, 6H, J=6.0 Hz). LRMS (ESI): 339.19 (M+H+Na)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[C:10](=[O:16])[NH:11][C:12](=S)[NH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCC2C(=O)NC(SC)=NC=2)C=CC=CC=1.N1C=CC=NC1=O.[CH3:41][C:42]1[NH:46][CH:45]=[N:44][C:43]=1[CH2:47][S:48][CH2:49][CH2:50][NH2:51].[ClH:52]>>[ClH:52].[ClH:52].[CH3:41][C:42]1[NH:46][CH:45]=[N:44][C:43]=1[CH2:47][S:48][CH2:49][CH2:50][NH:51][C:12]1[NH:11][C:10](=[O:16])[C:9]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][N:13]=1
Reactant: O=c1[nH]c(=S)[nH]cc1CCc1ccccc1
Reactant: Cc1[nH]cnc1CSCCN
Agent: CSc1ncc(CCc2ccccc2)c(=O)[nH]1
Agent: Cl
Agent: O=c1nccc[nH]1
Product: Cc1[nH]cnc1CSCCNc1ncc(CCc2ccccc2)c(=O)[nH]1

Procedure:
5-(2-Phenylethyl)-2-thiouracil (1.8 g) was converted into 5-phenylethyl-2-methylthio-4-pyrimidone (m.p. 160°-161° ex ethanol) by the method described in Example 1(i). Reaction of this pyrimidone (1.55g) with 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (1.1 g) by the method described in Example 1(ii) gave an oil which was dissolved in 2N hydrochloric acid, the solution evaporated to dryness and the residue recrystallised from methanol to give 2-[2-(5-methyl-4-imidazolylmethylthio)-ethylamino]-5-(2-phenylethyl)-4-pyrimidone dihydrochloride, m.p. 214°-218°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:4][C:5]([CH3:20])=[C:6]([CH3:19])[C:7]=1[NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].[C:28](OCC)(OCC)(OCC)[CH3:29].Cl.N1C=CC=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:28][C:29]1[N:8]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:7]2[C:6]([CH3:19])=[C:5]([CH3:20])[N:4]=[C:3]([O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:2]=2[N:1]=1
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCNC(=O)OC(C)(C)C)c1C
Reactant: CCOC(C)(OCC)OCC
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc(Oc2ccccc2)c2nc(C)n(CCNC(=O)OC(C)(C)C)c2c1C
Yield: 100 %

Procedure:
A mixture of tert-butyl 2-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]ethylcarbamate (43.7 g, 117 mmol), triethyl orthoacetate (22.6 mL, 123 mmol), pyridine hydrochloride (4.4 g) and toluene (440 mL) was heated at reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure to provide a brown oil. The oil was dissolved in ethyl acetate (1 L) and washed with water (2×500 mL). The aqueous washes were combined and extracted with ethyl acetate (2×500 mL). The combined organics were washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure to provide 46.4 g of tert-butyl 2-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)ethylcarbamate as a white solid, m.p. 180–182° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](SCC(O)=O)=[S:7])=[CH:4][CH:3]=1.O.[NH2:16][NH2:17].C(O)(=O)C>[OH-].[Na+].C(Cl)Cl>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:16][NH2:17])=[S:7])=[CH:4][CH:3]=1
Reactant: O=C(O)CSC(=S)c1ccc(Cl)cc1
Reactant: NN
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: NNC(=S)c1ccc(Cl)cc1

Procedure:
To a mixture of (4-chloro-thiobenzoylsulfanyl)-acetic acid (8.31 mmol) in 9 mL of NaOH (1N) is added hydrazine hydrate (36.7 mL). Glacial acetic acid (2.7 mL) is then added to the solution and the mixture is vigorously stirred. The reaction mixture is diluted with CH2Cl2 and the organic layer dried over MgSO4 to yield 4-chloro-thiobenzoic acid hydrazide: LC/MS (ES+) 186.9 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14][S:15]([C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[CH:22]=1)(=[O:17])=[O:16].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>N1C=CC=CC=1>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([S:6][CH2:5][C:4]2[CH:27]=[CH:28][CH:29]=[C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[CH:3]=2)=[C:8]([NH:14][S:15]([C:18]2[O:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[CH:22]=2)(=[O:17])=[O:16])[CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a solution of N-{2-[(3-aminobenzyl)sulfanyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide (440 mg, 0.90 mmol) in pyridine (4 ml) was added methanesulfonyl chloride (70 μl, 0.90 mmol). The reaction was stirred at room temperature for 2 hours and was concentrated, diluted with 1M HCl, and extracted with EtOAc. The organic layer was dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (4% EtOAc in hexane) to yield the title compound (344 mg, 67%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[N:10][C:3]=12.[OH-:11].[K+].I[CH3:14]>CC(C)=O>[NH4+:5].[OH-:11].[CH3:14][N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([CH3:1])=[C:3]2[N:10]=[CH:9]1
Reactant: CI
Reactant: Cc1ccnc2[nH]cnc12
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccnc2c1ncn2C
Product: [NH4+]
Reaction time: 0.17 h

Procedure:
7-Methyl-3H-imidazo[4,5-b]pyridine (2.0 g, 15 mmol) was dissolved in acetone (60 ml) and treated with freshly ground KOH (4.21 g) followed by dropwise addition of iodomethane (10 ml). After 10 min, the reaction mixture was poured into satd. aq. NaHCO3 (25 ml) in water (25 ml) and extracted with DCM (4×80 ml). The organic layers were combined and dried over Na2SO4, filtered, and concentrated. SGC (DCM:MeOH:NH4OH =96:4:1 as eluant) yielded 3,7-dimethyl-3H-imidazo[4,5-b]pyridine (1.05 g). 1H NMR (CDCl3) δ 7.94 (s, 1H), 7.83 (d, 1H), 6.48 (s, 1H), 3.04 (s, 3H), 2.07 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)[CH2:9]1)=O)(C)(C)C>C(O)=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:17]2[CH2:18][CH2:19][N:14]([CH:10]3[CH2:9][NH:8][CH2:12][CH:11]3[OH:13])[CH2:15][CH2:16]2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C(N2CCN(Cc3ccc(Cl)cc3)CC2)C1
Solvent: O=CO
Product: OC1CNCC1N1CCN(Cc2ccc(Cl)cc2)CC1

Procedure:
The desired compound was prepared from 3-[4-(4-Chloro-benzyl)-piperazin-1-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester in a manner similar to that described in Example 5. 1H-NMR (300 MHz, DMSO, HCl salt): δ 2.80-3.60 (m, 12 H), 4.20-4.35 (m, 4 H), 7.51 (d, 2 H), 7.66 (d, 2 H). Retention Time (LC, method: Formic acid polar): 0.68 min. MS (M+H+): 296
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=1)([O-:22])=[O:21].CCN=C=NCCCN(C)C.Cl.[C:44]([NH:47][NH2:48])(=[O:46])[CH3:45]>CN(C=O)C.O>[C:44]([NH:47][NH:48][C:27](=[O:29])[C:26]1[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:31][CH:30]=1)(=[O:46])[CH3:45]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
HOBt (972 mg, 7.2 mmol) and DIEA (1.14 g, 8.9 mmol) were added to a stirred solution of 4-nitro-benzoic acid (1 g, 5.96 mmol) in DMF (6 mL). The reaction mixture was cooled to 10° C. EDCI.HCl (1.38 g, 7.2 mmol) followed by acetic acid hydrazide (490 mg, 6.6 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water and the product extracted with ethyl acetate. The organics were washed with saturated sodium bicarbonate solution followed by brine solution, dried over Na2SO4 and evaporated to afford 700 mg (55%) of 4-nitro-benzoic acid N′-acetyl-hydrazide. 1H NMR: (DMSO-d6): δ 10.7 (s, 1H), 10.0 (s, 1H), 8.4 (d, 2H), 8.1 (d, 2H), 1.9 (s, 3H).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:31])[CH2:7][CH2:8][C@@:9]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:14][C:13](=[O:15])[N:12]([C@H](C2C=CC(Br)=CC=2)C)[CH2:11][CH2:10]1)(=O)[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:2][C:1]1[O:31][C:6]([CH2:7][CH2:8][C:9]2([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:14][C:13](=[O:15])[NH:12][CH2:11][CH2:10]2)=[N:5][N:4]=1
Reactant: CC(=O)NNC(=O)CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: Cc1nnc(CCC2(c3ccccc3)CCNC(=O)O2)o1
Yield: 96.1 %

Procedure:
To a solution of N′-acetyl-3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanehydrazide (0.1 g, 0.21 mmol) in THF (2 mL) was added Burgess Reagent (75 mg, 0.315 mmol). The sealed vial was irradiated in the microwave at 100° C. for 15 min. The mixture was extracted with EtOAc (3×30 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to afford (R)-3-(S)-1-(4-bromophenyl)ethyl)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one (58 mg, yield: 59%). 1H NMR (CDCl3): δ1.49-1.51 (m, 3H), 2.23-2.26 (m, 2H), 2.30-2.33 (m, 2H), 2.42 (s, 3H), 2.43-2.45 (m, 1H), 2.49-2.54 (m, 1H), 2.87-2.91 (m, 1H), 3.06-3.09 (m, 1H), 5.61-5.63 (m, 1H), 6.76-6.78 (d, 2H), 7.20-7.22 (m, 2H), 7.26-7.33 (m, 2H), 7.35-7.37 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CCN=C=NCCCN(C)C.[CH:30]1[C:35]([N+:36]([O-:38])=[O:37])=[CH:34][CH:33]=[C:32](O)[CH:31]=1.CCN(C(C)C)C(C)C>C1COCC1.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13](=[O:18])[C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:7][C:3]=1[C:4]([O:6][C:32]1[CH:31]=[CH:30][C:35]([N+:36]([O-:38])=[O:37])=[CH:34][CH:33]=1)=[O:5]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.6 %

Procedure:
To a solution of 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-5, 300 mg, 1.12 mmol) in THF (5 mL) were added EDCI (210 mg, 1.09 mmol), p-nitrophenol (154 mg, 1.10 mmol) and DIPEA (558 mg, 4.39 mmol) and the reaction mixture was stirred at rt for 4 h. Then water was added to the reaction mixture and it was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 222 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.36 (d, J=9.0 Hz, 2H), 8.20 (t, 1H), 7.97 (s, 1H), 7.62-7.59 (m, 3H), 7.51 (d, J=8.1 Hz, 1H), 4.30 (d, J=6.0 Hz, 2H), 1.11 (s, 9H).
Reaction SMILES: [C:1]([NH:4][C@H:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])(=[O:3])[CH3:2].[NH2:29][CH2:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37]([NH2:41])=[N:36][CH:35]=[CH:34]2.CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[NH2:41][C:37]1[C:38]2[C:33](=[CH:32][C:31]([CH2:30][NH:29][C:13]([C@@H:9]3[CH2:10][CH2:11][CH2:12][N:8]3[C:6](=[O:7])[C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:21][CH:22]=3)=[O:15])=[CH:40][CH:39]=2)[CH:34]=[CH:35][N:36]=1
Reactant: CC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: NCc1ccc2c(N)nccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
A mixture of 1-(2-(R)-acetylamino-3-biphenyl-4yl-propionyl)-pyrrolidine-2-(S)-carboxylic acid (0.120 g), 6-aminomethyl-isoquinolin-1-ylamine (0.058 g), N-methyl morpholine (0.11 mL) and 0.100 g of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) in 4.5 mL of dry N,N-dimethyl formamide was stirred for 3 h at ambient temperature. The mixture was concentrated and the remaining residue was purified by silica chromatography (dichloro-methane/methanol 8/2) to give 0.120 g (70%) of the title compound as a light yellow solid. (+)-APCI-MS: 536 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.O1CCOCC1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1
Reactant: C1CCNC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc(N2CCCC2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
2 g (0.012 mol) of 2-amino-6-chloro-3-nitropyridine, 30 ml of dioxane and 20 ml of water, and 1.8 g of pyrrolidine are charged to a fully equipped round-bottomed flask. The mixture is brought to 70° C. for one hour with stirring and then the mixture is poured onto an ice/water mixture with stirring. The precipitate formed is filtered off and dried. 2.2 g of yellow powder are obtained, Yd=88%.
Reaction SMILES: C(N([CH:7]([CH3:9])[CH3:8])CC)(C)C.Cl.C1(C[N:18]([C:22]2[NH:23][C:24]3[C:25]([N:41]=2)=[N:26][CH:27]=[C:28]([C:30]2[CH:31]=[CH:32][C:33]4[O:39][CH2:38][CH2:37][NH:36][CH2:35][C:34]=4[CH:40]=2)[CH:29]=3)[C:19](=[O:21])[OH:20])C=CC=CC=1.Cl[C:43]1[C:52]2[C:47](=[CH:48][CH:49]=[C:50]([CH3:53])[CH:51]=2)[N:46]=[CH:45][N:44]=1.O>CN1C(=O)CCC1>[C:7]1([CH2:8][O:20][C:19](=[O:21])[NH:18][C:22]2[NH:41][C:25]3=[N:26][CH:27]=[C:28]([C:30]4[CH:31]=[CH:32][C:33]5[O:39][CH2:38][CH2:37][N:36]([C:43]6[C:52]7[C:47](=[CH:48][CH:49]=[C:50]([CH3:53])[CH:51]=7)[N:46]=[CH:45][N:44]=6)[CH2:35][C:34]=5[CH:40]=4)[CH:29]=[C:24]3[N:23]=2)[CH:9]=[CH:28][CH:29]=[CH:24][CH:25]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)N(Cc1ccccc1)c1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2[nH]1
Reactant: Cc1ccc2ncnc(Cl)c2c1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2ncnc(N3CCOc4ccc(-c5cnc6[nH]c(NC(=O)OCc7ccccc7)nc6c5)cc4C3)c2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 175.3 %

Procedure:
Diisopropylethylamine (0.23 g, 1.76 mmol) was added to a solution of phenylmethyl[6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridin-2-yl]carbamate hydrochloride (0.2 g, 0.44 mmol) and 4-chloro-6-methylquinazoline (0.08 g, 0.44 mmol), in NMP (5 ml) at room temperature. The reaction mixture was heated to 90° C. for 30 minutes, and then cooled to room temperature. Water was added and the resulting suspension was stirred overnight. The precipitate was collected by filtration and dried under vacuum to give phenylmethyl{6-[4-(6-methylquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-3H-imidazo[4,5-b]pyridin-2-yl}carbamate (0.215 g, 87% yield). MS (EI) for C32H27N7O3: 558.1 (MH+).
Reaction SMILES: [NH:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(C(C)C)CC)(C)C.[C:29]1([CH3:44])[CH:34]=[CH:33][C:32]([S:35]([O:38][C@H:39]([CH3:43])[C:40](Cl)=[O:41])(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl>[C:29]1([CH3:44])[CH:30]=[CH:31][C:32]([S:35]([O:38][C@H:39]([CH3:43])[C:40]([N:1]2[C@@H:9]3[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]3)[CH2:3][C@H:2]2[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[O:41])(=[O:36])=[O:37])=[CH:33][CH:34]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCCC[C@@H]2N1
Reactant: Cc1ccc(S(=O)(=O)O[C@H](C)C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)O[C@H](C)C(=O)N2[C@H](C(=O)OCc3ccccc3)C[C@@H]3CCCC[C@@H]32)cc1
Reaction time: 1 h

Procedure:
Introduce into a reactor 200 g of benzyl (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylate and 1.5 liters of dichloromethane, and then bring the temperature of the reaction mixture to 0° C. and add 201 ml of diisopropylethylamine, followed by 202 g of (1R)-2-chloro-1-methyl-2-oxoethyl p-toluenesulphonate. Subsequently, bring the mixture to ambient temperature. After stirring for 1 hour at that temperature, wash the mixture with water. The solution of benzyl (2S,3aS,7aS)-1-[(2R)-2-{p-toluenesulphonyloxy}propionyl]octahydro-1H-indole-2-carboxylate so obtained is used as it is in the following Step.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]#[CH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1[CH2:17][CH2:16]COO1.C=O.[CH2:20]([NH:22][CH2:23]C)[CH3:21].[OH-].[Na+]>O1CCOCC1.C(O)(=O)C.O>[CH2:20]([N:22]([CH2:16][CH3:17])[CH2:23][C:11]#[C:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:21]
Reactant: CCNCC
Reactant: C1COOOC1
Reactant: C#CCCCc1ccccc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCN(CC)CC#CCCCc1ccccc1
Yield: 886.9 %

Procedure:
Maintain 5-phenylpent-1-yne (20 g) for 12 hours at 70° under nitrogen with water (6.2 cc), trioxan (1.2 g), 30% formalin (13.8 g), diethylamine (10 g), acetic acid (6.9 g), dioxan (62 cc) and cuprous chloride (0.35 g). Make the cooled solution alkaline with sodium hydroxide. Extract with ether and extract the ether extract itself with hydrochloric acid. Make the purified aqueous hydrochloride solution thus obtained alkaline again and extract with ether. Dry, evaporate the ether extract and distil the residue to obtain 1-diethylamino-6-phenylhex-2-yne (27.1 g), b.p. 104°-106°/0.2 mm.
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([NH:20][S:21]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)(=[O:23])=[O:22])=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([N:20]([CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[S:21]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)(=[O:23])=[O:22])=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(NCc1ccccc1)n1ccc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN(c1ccc2c(ccn2C(=O)NCc2ccccc2)c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
150 mg 5-(3,5-dichloro-phenylsulphonylamino)-indole-1-carboxylic acid-benzylamide are dissolved in 5 ml dimethylformamide. 109 mg potassium carbonate and 51 μl tert.butyl bromoacetate are added thereto. The mixture is stirred for 4 hours at ambient temperature, the solvent is eliminated in vacuo and the residue is divided between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried on magnesium sulphate. The solvents are eliminated in vacuo and the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 10:1 to 1:3).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]1(O)[CH2:24][CH2:23][C:18]2([O:22][CH2:21][CH2:20][O:19]2)[CH2:17][CH2:16]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]1[CH2:24][CH2:23][C:18]2([O:19][CH2:20][CH2:21][O:22]2)[CH2:17][CH:16]=1
Reactant: COCOc1ccc(C2(O)CCC3(CC2)OCCO3)c(OCOC)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCOc1ccc(C2=CCC3(CC2)OCCO3)c(OCOC)c1
Yield: 70.7 %

Procedure:
8-[2,4-Bis(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]decan-8-ol (1.40 g, 3.95 mmol) was placed in a 50 ml round bottomed flask equipped with magnetic stirrer and Dean-Stark apparatus. Toluene (30 ml) was added, followed by camphor sulphonic acid (10 mg). The stirred solution was then heated under reflux for 1 hr, cooled and saturated aqueous sodium bicarbonate solution (10 ml) added. The mixture was poured into a separating funnel and the phases separated. The aqueous phase was extracted with ethyl acetate (2×15 ml) and the combined organics were washed with brine (15 ml), dried over anhydrous magnesium sulphate, filtered and then concentrated in vacuo yielding an orange oil which was purified by flash column chromatography (SiO2, ethyl acetate/petroleum ether, 45:55, v/v) to afford the title product (0.94 g) as a colourless oil. δH(CDCl3) 1.84 (2H, t), 2.41-2.43 (2H, m), 2.56-2.62 (2H, m), 3.47 (6H, s), 3.98-4.02 (4H, m), 5.13 (4H, s), 5.58-5.63 (1H, m), 6.64 (1H, dd), 6.78 (1H, d), 7.08 (1H, d).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[NH2:27])[O:22][CH3:23].[ClH:28].N1C=CC=CC=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[Cl:28][C:20]1[CH:19]=[C:26]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:25]=[CH:24][C:21]=1[O:22][CH3:23]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Cl
Reactant: COc1ccc(N)c(Cl)c1
Agent: CCOC(C)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(Nc2c(C#N)cnc3cc(OC)c(OC)cc23)cc1Cl
Yield: 506.2 %

Procedure:
A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.158 g of 3-chloro-p-anisidine, 20 mg of pyridine hydrochloride, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 40 ml of water. To this mixture was added sodium carbonate and concentrated hydrogen chloride to adjust pH to 7. The product was collected, washed with water, and dried to give 0.324 g of 4-(3-chloro-4-methoxy-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 278-280° C.; mass spectrum (EI, m/e): M 369.0860.