Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:16])[C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=[CH2:9].CO[CH:19](OC)[N:20](C)[CH3:21]>CN(C)C=O.O>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:16])[C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=[CH:9][N:20]([CH3:21])[CH3:19]
Reactant: COC(OC)N(C)C
Reactant: C=C(C(=O)c1sccc1Cl)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C=C(C(=O)c1sccc1Cl)c1ccncc1
Yield: 74.6 %

Procedure:
To a solution of 1-(3-chlorothiophen-2-yl)-2-(pyridin-4-yl)prop-2-en-1-one (1 eq, 27 mmol) in anhydrous N,N-dimethylformamide (40 mL) was added N,N-dimethylformamide dimethyl acetal (4 eq, 108 mmol). The reaction mixture was stirred under reflux for 1.5 h. The mixture was diluted with water (600 mL) and extracted with dichloromethane (4×200 mL) and ethylacetate (4×200 mL). The combined extracts were washed with water, brine, dried over Na2SO4 and concentrated. The obtained residue was purified by column chromatography on silica gel (DCM:MeOH, 40:1 to 20:1) to afford intermediate 5.9 g of 1-(3-chlorothiophen-2-yl)-3-(dimethylamino)-2-(pyridin-4-yl)prop-2-en-1-one (74% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([CH:9]=1)[C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][S:5]2.[Br:14][C:15]1[C:16]([C:21]2[NH:25][N:24]=[CH:23][N:22]=2)=[C:17]([NH2:20])[S:18][CH:19]=1>>[Br:14][C:15]1[C:16]([C:21]2[NH:25][N:24]=[CH:23][N:22]=2)=[C:17]([NH:20][C:11](=[O:13])[CH2:10][C:7]2[N:8]3[CH:9]=[C:2]([CH3:1])[N:3]=[C:4]3[S:5][CH:6]=2)[S:18][CH:19]=1
Reactant: Cc1cn2c(CC(=O)O)csc2n1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: Cc1cn2c(CC(=O)Nc3scc(Br)c3-c3ncn[nH]3)csc2n1

Procedure:
The title compound was synthesized from 2-(6-methylimidazo[2,1-b]thiazol-3-yl)acetic acid and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine according to protocol A. Retention time (min)=8.520, method [6], MS (ESI) 423.0 (M+H); 1F1 NMR (300 MHz, CD3Cl) δ 8.12 (s, 1H), 7.35 (s, 1H), 7.22 (s, 1H), 7.0 (s, 1H), 4.15 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.Cl[C:14]([O:16][CH2:17][Cl:18])=[O:15]>ClCCl>[C:14](=[O:15])([O:5][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])[O:16][CH2:17][Cl:18]
Reactant: O=C(Cl)OCCl
Reactant: CC(C)CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CCOC(=O)OCCl

Procedure:
3-Methyl-1-butanol (4.4 g) was dissolved in dichloromethane (75 ml) and pyridine (4.0 g) was added to it. The reaction mixture was cooled in an ice bath and chloromethyl chloroformate (6.5 g) was added to it with stirring. The cooling bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The dichloromethane solution was washed with water thrice and once with brine. The organic layer was dried over sodium sulfate and evaporated to furnish a colorless oil of desired product weighing 10.7 g which was the pure chloromethyl isopentyl carbonate. NMR (CDCl3) δ 0.95 (6H, d, J=5 Hz, CH(CH3)2), 1.66 (3H, m, CH2 and CH), 4.28 (2H, t, J=7 Hz, OCH2CH2) and 5.73 (2H, s, OCH2Cl). IR (film) 2950, 1783, 1265 cm-1.
Reaction SMILES: [C:1]1([C:7]2([NH2:16])[CH2:15][CH2:14][CH:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.[CH3:26][O:27][C:28]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([S:41][CH3:42])[C:29]=1[C:30](Cl)=[O:31]>ClCCl>[CH3:26][O:27][C:28]1[CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=[C:33]([S:41][CH3:42])[C:29]=1[C:30]([NH:16][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:15][CH2:14][CH:13]2[N:9]([CH2:10][CH2:11][CH2:12]2)[CH2:8]1)=[O:31]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)Cl
Reactant: NC1(c2ccccc2)CCC2CCCN2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1(c2ccccc2)CCC2CCCN2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 55 mg (0.254 mmol) 6-phenyl-octahydro-indolizin-6-ylamine (example A.3) and 130 ul (0.762 mmol) N-ethyldiisopropylamine in dichloromethane (0.9 ml) was added drop-wise a solution of 63 mg (0.22 mmol) 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (example B.1) in dichloromethane (0.6 ml) at room temperature. The mixture was stirred at room temperature for 1 hour. The solution was washed once with a 2M sodium carbonate solution. The aqueous layer was extracted once with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified with flash column chromatography on silica eluting from n-heptane and ethyl acetate (0 to 50%) to provide 26 mg (y: 22%) of example 3 (2-methoxy-6-methylsulfanyl-N-(6-phenyl-octahydro-indolizin-6-yl)-4-trifluoromethyl-benzamide, diastereoisomer 1, first running compound) as a light yellow gum, MS (m/e): 465.2 (M+H+) and 49 mg (y: 41.5%) of example 4 (2-methoxy-6-methylsulfanyl-N-(6-phenyl-octahydro-indolizin-6-yl)-4-trifluoromethyl-benzamide, diastereoisomer 2, second running compound) as a white solid, MS (m/e): 465.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[C:13]1[N:18]=[N:17][C:16]([N:19]2[CH2:23][C@@H:22]3[CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][C@@H:21]3[CH2:20]2)=[CH:15][CH:14]=1.Cl.N>O1CCOCC1.CO>[CH2:20]1[C@@H:21]2[CH2:26][NH:25][CH2:24][C@@H:22]2[CH2:23][N:19]1[C:16]1[N:17]=[N:18][C:13]([C:3]2[CH:4]=[CH:5][C:6]([C:8]3[CH:9]=[N:10][NH:11][CH:12]=3)=[CH:7][C:2]=2[OH:1])=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3ccc(-c4ccc(-c5cn[nH]c5)cc4O)nn3)C[C@@H]2C1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CO
Product: Oc1cc(-c2cn[nH]c2)ccc1-c1ccc(N2C[C@H]3CNC[C@H]3C2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
To a solution of (3aR,6aS)-tert-butyl 5-(6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (75 mg, 0.167 mmol) in 1 mL of dioxane was added 4N HCl in dioxane (1 mL, 4.00 mmol). The reaction mixture was stirred at RT overnight, and then basified with 2N NH3 in MeOH to form a precipitate which was separated via centrifugation to provide a dark solid, 2-(6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin 3-yl)-5-(1H-pyrazol-4-yl)phenol (50 mg, 0.136 mmol, 82% yield) MS (M+1)=349.1.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:16][OH:17])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.C(N(CC)CC)C.[CH3:25][Si:26](Cl)([CH3:28])[CH3:27]>ClCCl>[CH3:25][Si:26]([CH3:28])([CH3:27])[O:1][CH2:2][C:3]1([CH2:16][O:17][Si:26]([CH3:28])([CH3:27])[CH3:25])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: OCC1(CO)c2ccccc2-c2ccccc21
Reactant: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OCC1(CO[Si](C)(C)C)c2ccccc2-c2ccccc21
Temperature: 0 °C
Yield: 88 %

Procedure:
1 g of 9,9-bis(hydroxymethyl)fluorene (4.4 mmol) was admixed with 20 ml of dichloromethane. The mixture was cooled in ice-water bath, and 1.9 ml of triethyl amine (13.2 mmol) was added thereto. Then 1.4 ml of trimethylsilyl chloride (11 mmol) was added drop-wise, and the mixture was stirred in ice-water bath for further 2 hours. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give 1.14 g of concentrate (yield 88%). MS (EI) m/e: 370(M+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[NH:20]1[CH2:23][CH:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:20]3[CH2:23][CH:22]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH2:21]3)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: C1CN(C2CNC2)CCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CN2CC(N3CCOCC3)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Reaction time: 65 h
Yield: 49.3 %

Procedure:
A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (235 mg, 0.82 mmol), 4-azetidin-3-ylmorpholine (122 mg, 0.86 mmol) and 4 Å powdered molecular sieves (300 mg) in DCE (8 mL) was stirred at room temperature for 3 h before the addition of sodium triacetoxyborohydride (346 mg, 1.63 mmol). The reaction mixture was stirred for 65 h then filtered through celite, washing with DCM. The organic phase was washed with brine and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) affording 2-Chloro-9-methyl-6-morpholin-4-yl-8-(3-morpholin-4-ylazetidin-1-ylmethyl)-9H-purine as a cream solid (165 mg, 49%). LCMS (Method A): RT 2.22 min [M+H]+ 408.2
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([CH:9]2[CH2:11][CH2:10]2)[C:7]2[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:3].[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>C(O)CCC>[NH2:20][C:21]1[N:22]=[CH:23][N:24]=[C:25]([NH:1][C@H:2]([C:4]2[N:8]([CH:9]3[CH2:10][CH2:11]3)[C:7]3[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=3[N:5]=2)[CH3:3])[C:26]=1[C:27]#[N:28]
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CNC(=O)c1cccc2nc([C@H](C)N)n(C3CC3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CNC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3C#N)n(C3CC3)c12
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of (S)-2-(1-aminoethyl)-1-cyclopropyl-N-methyl-1H-benzo[d]imidazole-7-carboxamide (95 mg, 0.37 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (56.8 mg, 0.368 mmol) and 1,1′-dimethyltriethylamine (128 μL, 0.74 mmol) in n-butanol (2 mL) was stirred at 120° C. for 5 h. After cooling to rt, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using 0 to 10% gradient of MeOH in DCM-EtOAc (1:1) as eluent to give 2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-1-cyclopropyl-N-methyl-1H-benzimidazole-7-carboxamide: 1H NMR (400 MHz, DMSO-d6) δ 8.45-8.40 (m, 1H), 8.05 (s, 1H), 7.66 (d, J=8 Hz, 1H), 7.62 (d, J=4 Hz, 1H), 7.31 (br, 2H), 7.24 (d, J=8 Hz, 1H), 7.19 (dd, J=8, 8 Hz, 1H), 5.89-5.81 (m, 1H), 2.83 (d, J=4 Hz, 3H), 1.62 (d, J=8 Hz, 3H), 1.12-1.04 (m, 2H), 0.95-0.79 (m, 2H); LC-MS (ESI) m/z 377.2 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH2:27][CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31])[CH:24]=4)[CH2:19][CH2:18][N:17]=3)[CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1>ClCCl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH2:27][CH2:28][CH2:29][S:30]([NH:4][CH2:1][CH2:2][CH3:3])(=[O:32])=[O:31])[CH:24]=4)[CH2:19][CH2:18][N:17]=3)[CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1
Reactant: O=S(=O)(Cl)CCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Reactant: CCCN
Solvent: ClCCl
Product: CCCNS(=O)(=O)CCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Propylamine (314 mg, 5.31 mmol) was dissolved in dichloromethane (3 mL) and a solution of 3-({1-[1-(4-chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-yl}oxy)propane-1-sulfonyl chloride (200 mg, 0.442 mmol) in dichloromethane (2 mL) was added dropwise. After 1 h stirring at room temperature the reaction mixture was diluted with dichloromethane (10 mL) and was washed with aqueous ammonium chloride solution (2×) and water (1×), dried (MgSO4) and concentrated in vacuo. The crude product (265 mg) was used for the next step without purification.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[C:9](OC)([O:10]C)[CH2:8][CH2:7][N:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:5]1)[CH3:2].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:1]([O:3][CH:4]1[C:9](=[O:10])[CH2:8][CH2:7][N:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:5]1)[CH3:2]
Reactant: CCOC(=O)N1CCC(OC)(OC)C(OCC)C1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)N1CCC(=O)C(OCC)C1

Procedure:
A mixture of 34.1 parts of ethyl 3-ethoxy-4,4-dimethoxy-1-piperidinecarboxylate and 1110 parts of a sulfuric acid solution 1% in water was stirred and refluxed for 3 hours. The reaction mixture was cooled and saturated with sodium carbonate. The product was extracted with dichloromethane. The extract was washed with a small amount of water, dried, filtered and evaporated. The residue was stirred in petroleumether. The product was separated and distilled, yielding 21.1 parts of ethyl 3-ethoxy-4-oxo-1-piperidinecarboxylate bp. ±95° C. at 0.05 mm. pressure (intermediate 68).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:3]1.C(O[CH:23](OC(C)(C)C)[N:24]([CH3:26])[CH3:25])(C)(C)C>CN(C=O)C>[CH3:23][N:24](/[CH:26]=[C:8]1\[CH2:9][CH2:10][CH2:11][C:5]2[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:3][N:2]([CH3:1])[C:6]=2[C:7]\1=[O:12])[CH3:25]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: CCOC(=O)c1nn(C)c2c1CCCCC2=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C)c2c1CCC/C(=C\N(C)C)C2=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 1-methyl-8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-3-carboxylate (210 mg, 0.94 mmol) in DMF (2 mL), N,N-dimethylformamide di-tertbutyl acetal (0.68 mL, 2.82 mmol) was added. The mixture was stirred at 80° C. for 3 h. Solvent was removed under reduced pressure and the residue used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([NH2:23])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:24]([CH2:31][C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([NH:23][C:32](=[O:33])[CH2:31][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Reactant: O=C(Cl)COc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(NC(=O)COc3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
A mixture of 1 g (3.1 mmol) 4-(3-amino-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester, 0.793 g (4.65 mmol) phenoxyacetyl chloride and 2.2 g (21.7 mmol) triethylamine in 20 ml THF was stirred at room temperature for 30 min. The mixture was evaporated and 100 ml DCM were added. The organic phase was washed with 2×50 ml 0.1 M Na2CO3 aq. The combined aqueous phase was extracted with 2×100 ml DCM. The combined organic phases were dried with MgSO4 and evaporated to dryness. The residue was purified over silica eluting with ethyl acetate/hexane 1/1 to yield 1.15 g (81%) of the title compound as yellow solid. MS(ISP): 455.3 (M−H)−.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.[C:40]([O:44][C:45](=[O:57])[N:46]([C:48]1C=C(NC)C=[C:50](N)[CH:49]=1)C)([CH3:43])([CH3:42])[CH3:41]>>[C:40]([O:44][C:45](=[O:57])[N:46]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:33])[CH3:34])[C:14]2=[O:37])[CH:5]=1)[CH2:48][CH2:49][CH3:50])([CH3:43])([CH3:42])[CH3:41]
Reactant: CNc1cc(N)cc(N(C)C(=O)OC(C)(C)C)c1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Product: CCCN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained as the tri-hydrochloride salt by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that (3-amino-5-methylamino-phenyl)-methyl-carbamic acid tert-butyl ester (prepared in four steps from 3,5-difluoro-nitrobenzene) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-propyl-carbamic acid tert-butyl ester (Example 41, step a) according to the method of Example 41, step b. 1H NMR (DMSO-d6) 9.83 (1H, br s), 7.55-7.45 (2H, m), 7.26-7.14 (2H, m), 6.79 (2H, br s), 6.26 (1H, s), 4.77 (2H, s), 4.31-4.26 (1H, m), 3.96-3.91 (1H, m), 3.65 (4H, br s), 2.86 (1H, m), 2.72 (6H, m), 1.84-1.64 (6H, m), 1.34-1.10 (13H, m). Found: C, 55.92; H, 6.79; N, 12.84%; C30H40N6O3.3.0HCl requires: C, 56.11; H, 6.75; N, 13.09%.
Reaction SMILES: [C:1]([S@@:5](/[N:7]=[CH:8]/[C:9]1[N:13]([CH3:14])[CH:12]=[C:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:10]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Mg]Br>C(Cl)Cl>[CH3:2][C:1]([CH3:4])([S@@:5]([NH:7][C@@H:8]([C:9]1[N:13]([CH3:14])[CH:12]=[C:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:10]=1)[CH3:22])=[O:6])[CH3:3]
Reactant: Cn1cc(C(=O)OC(C)(C)C)cc1/C=N/[S@@](=O)C(C)(C)C
Reactant: C[Mg]Br
Solvent: ClCCl
Product: C[C@@H](N[S@@](=O)C(C)(C)C)c1cc(C(=O)OC(C)(C)C)cn1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of (S,E)-tert-butyl 5-((tert-butylsulfinylimino)methyl)-1-methyl-1H-pyrrole-3-carboxylate (3.0 g, 10 mmol) in DCM (60 mL) was slowly added methylmagnesium bromide (13.3 mL, 3.0 M in ether) at −78° C. After stirring at −78° C. for 1 h, the solution was warmed to rt and stirred for 2 h. The reaction was quenched with sat. NH4C1 solution. After separation, the organic phase was washed with brine (5 mL), dried (Na2SO4) and concentrated. Flash column chromatography (petroleum ether:EtOAc, 10:1 to 1:1) afforded tert-butyl 5-((R)-1-((S)-1,1-dimethylethylsulfinamido)ethyl)-1-methyl-1H-pyrrole-3-carboxylate (2.2 g, 70%). 1H (CDCl3, 400 MHz) δ 7.15 (s, 1H), 6.47 (s, 1H), 4.48 (m, 1H), 3.62 (s, 3H), 3.18 (m, 1H), 1.68 (d, J=6.6 Hz, 3H), 1.52 (s, 9H), 1.19 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[C:20]([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[CH2:23][CH2:24][NH:25][CH:26]3[CH3:31])=[CH:19][CH:18]=[CH:17][N:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][CH:29]=[CH:30][C:21]=4[C:20]4[C:15]([F:14])=[N:16][CH:17]=[CH:18][CH:19]=4)[CH:26]3[CH3:31])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c(-c3cccnc3F)cccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cccc(-c3cccnc3F)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(2-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][NH:19][C:20]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21].C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:8][C:6]1[N:5]=[C:4]([CH3:9])[N:3]=[C:2]([N:25]2[CH2:26][CH2:27][CH:22]([C:20]([NH:19][CH2:18][C:12]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=3[Cl:10])=[O:21])[CH2:23][CH2:24]2)[N:7]=1
Reactant: O=C(NCc1ccc(Cl)cc1Cl)C1CCNCC1
Reactant: Cc1nc(Cl)nc(Cl)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Cl)nc(N2CCC(C(=O)NCc3ccc(Cl)cc3Cl)CC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.6 %

Procedure:
To a 25 mL round-bottomed flask was added 2,4-dichloro-6-methyl-1,3,5-triazine (800 mg, 2.79 mmol) and N-[(2,4-dichlorophenyl)methyl]-4-piperidinecarboxamide (859 mg, 2.79 mmol) in acetonitrile (8.7 mL). Diisopropylethylamine (1.46 mL, 8.36 mmol) was added to give a yellow suspension. The reaction mixture was stirred at room temperature for 15 minutes, at which time LC-MS showed the reaction was complete. This suspension was filtered through a Buchner funnel to afford 1-(4-chloro-6-methyl-1,3,5-triazin-2-yl)-N-[(2,4-dichlorophenyl)methyl]-4-piperidinecarboxamide (596 mg, 1.44 mmol, 52%) as a white solid which was used in the next step without further purification. MS (ES) m/e 416 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([OH:25])=O)=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN(C=O)C.[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1>C1COCC1>[Cl:26][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:21])([CH3:22])[O:20][C:16]=3[C:15]([C:23]([N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)=[O:25])=[CH:14][C:12]=2[N:13]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1(C)Cc2c(c(C(=O)N3CCOCC3)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 14.2 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-3, 0.060 g, 0.152 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.098 g, 0.304 mmol), TEA (0.5 mL), DMF (1.0 mL), THF (5.0 mL) and morpholine (0.062 g, 0.304 mmol) to afford 0.010 g of the desired product. 1HNMR (DMSO-d6): δ 1.41 (s, 6H), 2.96 (s, 2H), 3.37 (s, 4H), 3.56 (s, 4H), 6.64 (s, 1H), 8.40 (s, 2H), 10.82 (s, 1H), 11.26 (s, 1H); MS [M+H]+: 462.23.
Reaction SMILES: [C:1]([C@H:5]1[O:9][C:8](=[O:10])[C@@:7]([C@@H:17]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.C(OCC)C>[C:1]([C@H:5]1[O:9][C:8](=[O:10])[C@@:7]([C@@H:17]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)([C@@H]2CCC(=O)C2)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)([C@@H]2CCC(O)C2)O1
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of 169 mg of the (2R,5R)-2-(t-butyl)-5-((1R)-3-oxocyclopentyl)-5-phenyl-1,3-dioxolan-4-one, as obtained in Step 1 of Referential Example 1, in 2 ml of methanol, 71 mg of sodium borohydride was added under cooling with ice, followed by 30 minutes' stirring at the same temperature. The reaction liquid was diluted with diethyl ether, washed with water and with saturated brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, 157 mg of the title compound was obtained as a colorless oily substance.