Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]CCCC.[I:29]I.S([O-])(O)=O.[Na+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[C:13]([I:29])=[C:12]([Cl:14])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)ccn1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: O=S([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1nccc(Cl)c1I
Temperature: -70 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
A solution of (4-chloro-pyridin-2-yl)-carbamic acid tert-butyl ester (CB Research and Development Inc., 5.0 g, 22.0 mmol), TMEDA (8 mL) in anhydrous THF (100 mL) was placed under a nitrogen atmosphere and cooled to −70° C. and treated dropwise with 2.5 M n-BuLi in hexanes (22.0 mL, 54.8 mmol) over a period of 30 min. The mixture was stirred at −70° C. for 1 h then treated dropwise with a solution of I2 (14 g, 110 mmol) in anhydrous THF (16 mL) at −70° C. After the addition was complete, the reaction was stirred at −70° C. for 30 min then allowed to warm to room temperature. The mixture was treated with a solution of sodium hydrogensulfite (16 g) in H2O (100 mL) and stirred for 30 min then extracted with EtOAc. The extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The product was purified by flash chromatography on SiO2 eluting with 0-5% MeOH/CH2Cl2 to give the title compound (5.8 g, 78%) as white solid. 1H NMR (DMSO-d6) δ 9.46 (s, 1H), 8.29 (d, 1H, J=5.6 Hz), 7.46 (d, 1H, J=5.0 Hz), 1.44 (s, 9H); MS(ESI−): m/z 352.99 (M−H)−.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)c1cccnc1
Product: O=C(Nc1nc2cccc(NCc3ccccc3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B2), 100 mg; 0.31 mmol; 1.0 eq.) and benzylamine (1.0 mL) as an oily solid (10 mg, 9%). HPLC, Rt: 2.46 min. (purity 85.8%). LC/MS, M+(ESI): 345.1, M−(ESI): 343.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH:16]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[H][H]>CCOC(C)=O.[Pt]=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13]2)=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(C2=CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 0.75 h

Procedure:
To a degassed solution of the title compound from Example 136 Step A (3.17 g, 9.99 mmol) in EtOAc (50 mL) was added platinum oxide (0.68 g, 3.00 mmol). The reaction flask was fitted with a hydrogen balloon attached to a 3-way adapter. The reaction mixture was then evacuated and back-filled with hydrogen. After this process was repeated three times, the reaction mixture was placed under a hydrogen atmosphere, and was stirred vigorously. After 45 min, the reaction mixture was filtered though Celite, rinsing with EtOAc. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by chromatography on silica gel (0 to 8% EtOAc in hexanes, 8% EtOAc in hexanes, then 8 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 264.0 [M-t-Boc]+; 1H NMR (500 MHz, CDCl3) δ 7.99 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.0 Hz, 2H), 4.37 (q, J=7.0 Hz, 2H), 3.92-3.76 (br m, 1H), 3.70-3.52 (br m, 1H), 3.48-3.34 (br m, 2H), 3.30 (t, J=10.0 Hz, 1H), 2.34-2.24 (br m, 1H), 1.99 (q, J=10.0 Hz, 1H), 1.48 (s, doubled (rotamers), 9H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][C:6](=[O:36])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:20]=2)=[O:15])=[CH:10][C:9]=1[C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)[CH3:2].CC(O)(C)C.[K].Cl>COCCOC>[Cl:34][C:30]1[CH:29]=[C:28]([C:27]2[C:9]3[C:8](=[CH:13][CH:12]=[C:11]([C:14]([C:16]4[S:17][CH:18]=[C:19]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:20]=4)=[O:15])[CH:10]=3)[NH:7][C:6](=[O:36])[C:5]=2[C:4]([O:3][CH2:1][CH3:2])=[O:37])[CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(C(=O)c2nc(-c3ccccc3)cs2)cc1C(=O)c1cccc(Cl)c1
Agent: Cl
Agent: [K]
Solvent: COCCOC
Solvent: CC(C)(C)O
Product: CCOC(=O)c1c(-c2cccc(Cl)c2)c2cc(C(=O)c3nc(-c4ccccc4)cs3)ccc2[nH]c1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
A mixture of intermediate (17) (0.048 mol) in DME (250 ml) was cooled on an ice bath and 2-methyl-2-propanol, potassium salt (0.096 mol) was added portionwise. The mixture was stirred at a low temperature for 15 min, poured out into ice water and acidified with HCl 3N. The precipitate was filtered off, washed with water, pasted up with CH3CN and diethyl ether, then dried, yielding 17.3 g (70%) of ethyl 4-(3-chlorophenyl)-1,2-dihydro-2-oxo-6-[(4-phenyl-2-thiazolyl)carbonyl]-3-quinolinecarboxylate (intermediate 18), mp 261° C.
Reaction SMILES: C(NC(C)C)(C)C.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[Br:16].[Cl:17]C(Cl)(Cl)C(C(Cl)(Cl)Cl)=O>C([Li])CCC>[Cl:17][C:14]1[C:9]([F:8])=[C:10]([Br:16])[CH:11]=[CH:12][C:13]=1[F:15]
Reactant: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Reactant: Fc1ccc(Br)c(F)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: Fc1ccc(Br)c(F)c1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 19 ml (0.135 mole) of diisopropylarnine in 125 ml of tetrahydroflran (TBF) cooled at −20° C. is added 80 ml of n-butyllithium (1.6 M in hexane). The temperature is raised to 0° C. for 5 minutes and lowered to −78° C. Then 25 g (0.129 mole) of 2,4-difluoro-bromobenzene is then added and the reaction is stirred at −65° C. for 2 hours. Then, 25 ml (0.164 mole) of hexachloroacetone is added and the solution is warmed at room temperature. After evaporation of the solvent, the residue is distilled under vacuum to give the desired product.
Reaction SMILES: [N:1]1([CH:6]2[CH2:20][C@@H:9]3[CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][C@@H:8]3[C:7]2=[O:21])[CH:5]=[CH:4][N:3]=[CH:2]1.[BH4-].[Na+]>CO>[OH:21][CH:7]1[C@@H:8]2[C@@H:9]([CH2:10][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:12]2)[CH2:20][CH:6]1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CC(n3ccnc3)C(=O)[C@H]2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H]2CC(n3ccnc3)C(O)[C@H]2C1
Temperature: 25 °C

Procedure:
(3aR,6aS)-tert-Butyl 5-(1H-imidazol-1-yl)-4-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (75 mg, 0.257 mmol) from Step 2 in methanol (2 mL) was cooled in a dry ice/acetone bath to −78° C., and sodium borohydride (11.69 mg, 0.309 mmol) was added. The reaction was allowed to warm to ambient temperature over 6 hours. Then the reaction mixture was partially concentrated, quenched with 10 mL of aqueous ammonium chloride, diluted with water, and extracted with 2×20 mL of ethyl acetate. The extracts were washed with brine, dried (Na2SO4) and filtered. The solvent was removed in vacuo. The crude product was purified using a 4 g silica gel cartridge with a gradient of 0-6% CH3OH (2 N NH3)/CH2Cl2 over 20 minutes to give (3aR,6aS)-tert-butyl 4-hydroxy-5-(1H-imidazol-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([NH:7][C:8](=[O:10])[O-:9])[CH3:6].C[O:12][C:13]1[C:14]([Cl:26])=[CH:15][C:16]2[CH:17]([CH3:25])[CH:18]3[CH2:22][NH:21][CH2:20][CH:19]3[C:23]=2[CH:24]=1>>[CH2:5]([NH:7][C:8](=[O:9])[O-:10])[CH3:6].[OH:12][C:13]1[C:14]([Cl:26])=[CH:15][C:16]2[CH:17]([CH3:25])[CH:18]3[CH2:22][NH:21][CH2:20][CH:19]3[C:23]=2[CH:24]=1
Reactant: COc1cc2c(cc1Cl)C(C)C1CNCC21
Agent: BrB(Br)Br
Agent: CCNC(=O)[O-]
Product: CC1c2cc(Cl)c(O)cc2C2CNCC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
BBr3 (0.3 mL, 0.30 mmol, 1 M in CH2Cl2) was added to a solution of N-Ethylcarbamate-5-methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 3, Step A) (46 mg, 0.15 mmol) at 0° C., and stirred overnight at room temperature. The reaction solution was quenched with H2O and filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The crude product was obtained without further purification. MS calculated for C15H18ClNO3+H: 296, observed: 296.
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH3:6][O:7][C:8](=[O:18])[CH2:9][N:10]1[CH:14]=[C:13]([CH2:15][CH2:16][NH2:17])[N:12]=[CH:11]1.[CH:19]1(O)[CH2:24][CH2:23]C[CH2:21][CH2:20]1>S(=O)(=O)(O)O>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH:6]1([O:7][C:8](=[O:18])[CH2:9][N:10]2[CH:14]=[C:13]([CH2:15][CH2:16][NH2:17])[N:12]=[CH:11]2)[CH2:23][CH2:24][CH2:19][CH2:20][CH2:21]1
Reactant: OC1CCCCC1
Reactant: COC(=O)Cn1cnc(CCN)c1
Agent: O=S(=O)(O)O
Product: NCCc1cn(CC(=O)OC2CCCCC2)cn1
Temperature: 110 °C

Procedure:
[4-(2-Amino-ethyl)-imidazol-1-yl]-acetic acid methyl ester sulphate (1 g, 3.6 mmol) is suspended in cyclohexanol (50 ml) and treated with concentrated sulphuric acid (5 drops). The reaction mixture is heated to 110° C. for 4 hours and concentrated in vacuo. The residue is dissolved in saturated sodium bicarbonate solution and the mixture is concentrated in vacuo. The resulting solid is triturated with methanol, filtered and the filtrate is reduced in vacuo. The crude solid is dissolved in water, washed with DCM and the aqueous portion is concentrated in vacuo to yield the title product.
Reaction SMILES: [CH2:1]([C:8]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]2[O:30][CH:29]([CH2:31]Br)[CH2:28][C:27]=2[CH:33]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:1]([C:8]1([OH:14])[CH2:13][CH2:12][N:11]([CH2:31][CH:29]2[CH2:28][C:27]3[CH:33]=[C:23]([O:22][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:24]=[CH:25][C:26]=3[O:30]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCC1Cc2cc(OCc3ccccc3)ccc2O1
Reactant: OC1(Cc2ccccc2)CCNCC1
Product: OC1(Cc2ccccc2)CCN(CC2Cc3cc(OCc4ccccc4)ccc3O2)CC1

Procedure:
The title compound MS: m/e=430.6 (M+H+) was prepared from 4-(benzyl)-piperidin-4-ol and 5-benzyloxy-2-(RS)-bromomethyl-2,3-dihydro-benzofuran.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([Mg]Br)[CH:12]([CH3:14])[CH3:13].O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:10])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[Mg]Br
Reactant: O=CCc1cccc(F)c1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(O)Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
97 mg of 3-fluorobenzeneacetaldehyde and 0.386 mL of isobutyl magnesium bromide (2 M/diethyl ether solution) were dissolved in of 0.2 mL of THF, followed by stirring at room temperature for 1 hour. After completion of the reaction, water was added to the reaction liquid, followed by extraction with chloroform, and the organic layer was then washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using PLC (ethyl acetate:hexane=1:2) to obtain 102 mg (yield 74%) of a title compound as a pale yellow oily substance.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([S:9][CH3:10])[CH:6]=[C:5]([CH2:11][NH:12][CH:13]=O)[N:4]=1.P(Cl)(Cl)(Cl)=O.O1CCOCC1.C(=O)(O)[O-].[Na+]>O>[CH3:1][S:2][C:3]1[N:4]2[CH:13]=[N:12][CH:11]=[C:5]2[CH:6]=[C:7]([S:9][CH3:10])[N:8]=1
Reactant: CSc1cc(CNC=O)nc(SC)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CSc1cc2cncn2c(SC)n1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
A mixture of 3.00 g (13.1 mmole) of 2,4-bis(methylthio)-6-formylaminomethylpyrimidine, 2.25 g (14.2 mmole) of phosphorous oxychloride and 50 ml of dioxane was stirred at 20° C. for 20 hours, then heated at reflux for 0.5 hour. The mixture was poured into 100 ml of water, neutralized with solid sodium bicarbonate and extracted with chloroform. The chloroform extracts were combined, washed with water and dried over magnesium sulfate. Evaporation of the solvent provided a light yellow solid, 5,7-bis(methylthio)imidazo[1,5-c]pyrimidine. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH2:15])=[C:10]([N+:16]([O-])=O)[C:9]2=[O:19])=[CH:5][CH:4]=1>C(O)C.[Pd]>[NH2:16][C:10]1[C:9](=[O:19])[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=2)[CH:13]=[CH:12][C:11]=1[CH2:14][CH3:15]
Reactant: C=Cc1ccn(Cc2ccc(OC)cc2)c(=O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCc1ccn(Cc2ccc(OC)cc2)c(=O)c1N
Reaction time: 4 h
Yield: 76.7 %

Procedure:
A mixture of 1-(4-methoxybenzyl)-4-vinyl-3-nitro-2-pyridone (0.21 g, 0.73 mmol) in ethanol (30 mL) with 10% Pd/C (0.26 g) was hydrogenated at 40 psi in a Parr apparatus for 4 hours. The catalyst was removed by filtration and the solvent was evaporated to give 3-amino-1-(4-methoxybenzyl)-4-ethyl-2-pyridone (0.17 g, 0.56 mmol, 76%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][NH:23][CH2:22][CH2:21][CH2:20]1)=[O:17])([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C>>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:23]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:18][C:16](=[O:17])[O:15][C:12]([CH3:13])([CH3:11])[CH3:14])[CH2:24]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccncc2[N+](=O)[O-])C1
Yield: 99 %

Procedure:
The method of Example 1 was followed using 1 eq each of 4-chloro-3-nitropyridine, (R)-3-N-Boc-amino piperidine and diisopropylethylamine yielding (R)-tert-butyl 1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate, (99%). LCMS (m/z): 323.1 (MH+); LC Rt=2.13 min.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:21]=CC=C[C:15]=2[CH:16]=O)=[CH:9][C:8]=1[C:22]([F:25])([F:24])[F:23]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH:4]([C:3]1[CH:2]=[CH:21][C:14]([O:13][C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[C:8]([C:22]([F:24])([F:23])[F:25])[CH:9]=2)=[CH:15][CH:16]=1)=[CH2:5]
Reactant: [Li]CCCC
Reactant: O=Cc1ccccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
To a suspension of methyl(triphenyl)phosphonium bromide (5.56 g, 15.57 mmol) in anhydrous tetrahydrofuran (THF) (50 mL) was added BuLi (9.5 ml, 15.20 mmol) dropwise at 0° C. The reaction mixture was turned to clear and stirred for 15 min at 0° C., then a solution of -{[4-chloro-3-(trifluoromethyl)phenyl]oxy}benzaldehyde (4.07 g, 13.54 mmol) in THF (10 mL) was added. The reaction mixture was warmed to rt and stirred for 1 h, quenched by sat. NH4Cl, and then concentrated. The residue was dissolved in ethyl acetate (100 mL), washed with water, and brine, dried over anhydrous sodium sulfate, concentrated. Purification via ISCO afforded the title compound (3.0 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:14]([N:15]4[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]4)=[N:13][C:12]4[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:11]=4[NH:10][C:9]=3[S:27][C:4]=2[CH:3]=1.[Cl:28]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:28][CH2:26][C:24]1[CH:23]=[CH:22][C:12]2[N:13]=[C:14]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[C:8]3[C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=4[S:27][C:9]=3[NH:10][C:11]=2[CH:25]=1
Reactant: Cc1ccc2c(c1)Nc1sc3cc(F)ccc3c1C(N1CCN(C)CC1)=N2
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CN1CCN(C2=Nc3ccc(CCl)cc3Nc3sc4cc(F)ccc4c32)CC1

Procedure:
3-Fluoro-8-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine is dissolved in carbon tetrachloride and reacted with 2,2′-azobis(isobutylonitrile) in the presence of N-chlorosuccinimide to give 8-chloromethyl-3-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[N:10][C:9]=2[O:15][CH:16]2[CH2:19][CH2:18][CH2:17]2)=[CH:4][CH:3]=1.Cl.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([NH:14][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)[CH:11]=[N:10][C:9]=2[O:15][CH:16]2[CH2:19][CH2:18][CH2:17]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)n1
Agent: Cl
Product: O=C(Nc1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)n1)c1cccnc1

Procedure:
The title compound was synthesized in analogy to Example 48 e, using 6-(4-chloro-phenyl)-5-cyclobutoxy-pyrazin-2-ylamine (example 50c) and nicotinoyl chloride hydrochloride as starting materials; LC-MS (UV peak area/ESI) 97.4%, 381.1096 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=3[F:22])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[C:4]([OH:29])[CH:3]=1.Br[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=3[F:22])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[C:4]([O:29][CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:3]=1
Reactant: BrCC1CCCC1
Reactant: N#Cc1ccc(Cn2c(-c3ccc(Cl)cc3O)nc3cc(F)c(F)cc32)c(F)c1
Product: N#Cc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 19, from 4-[2-(4-chloro-2-hydroxy-phenyl)-5,6-difluoro-benzoimidazol-1-ylmethyl]-3-fluoro-benzonitrile and bromomethyl-cyclopentane (CAS Reg. No. 3814-30-0). Brown sticky solid (78%). MS (Turbo Spray): m/z=496.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][C:3]=1[CH:4]=[O:5].[Li+].[CH3:19][CH:20]([N-:22]C(C)C)C>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][C:3]=1[CH:4]([OH:5])[CH2:19][C:20]#[N:22]
Reactant: O=Cc1cc(OCC2CCCCC2)ccc1Br
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC#N
Product: N#CCC(O)c1cc(OCC2CCCCC2)ccc1Br

Procedure:
Reaction of 2-bromo-5-(cyclohexylmethoxy)benzaldehyde with acetonitrile in the presence of LDA was conducted following the procedure given for Example 4 to give 3-(2-bromo-5-(cyclohexylmethoxy)phenyl)-3-hydroxypropanenitrile. Yield (0.49 g, 79%): 1H NMR (400 MHz, MeOD) δ 7.40 (d, J=8.8 Hz, 1H), 7.23 (d, J=2.8 Hz, 1H), 6.77 (dd, J=8.8, 2.4 Hz, 1H), 5.20 (dd, J=6.8, 4.4 Hz, 1H), 3.77 (d, J=6.8 Hz, 2H), 2.91 (dd, J=16.8, 4.0 Hz, 1H), 2.74 (dd, J=16.8, 6.8 Hz, 1H), 1.66-1.88 (m, 6H), 1.18-1.36 (m, 3H), 1.02-1.16 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH3:16])([CH3:15])[C:9](=[O:14])[N:10]([CH:11]3[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.[C:17]1([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[NH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH:11]1([N:10]2[C:4]3[CH:3]=[C:2]([N:24]=[C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:7]=[CH:6][C:5]=3[C:8]([CH3:16])([CH3:15])[C:9]2=[O:14])[CH2:13][CH2:12]1
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(Cl)ncc21
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC1(C)C(=O)N(C2CC2)c2cc(N=C(c3ccccc3)c3ccccc3)ncc21
Temperature: 100 °C

Procedure:
To a suspension of 6-chloro-1-cyclopropyl-3,3-dimethyl-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (1.789 g, 7.56 mmol), diphenylmethanimine (2.05 g, 1.9 ml, 11.3 mmol, Eq: 1.5) and sodium tert-butoxide (1.23 g, 12.8 mmol) in toluene (48 ml) were added tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (156 mg, 151 mol) and BINAP (94.1 mg, 151 mol). The reaction mixture was heated to 100° C. for 18 hours and then diluted with dichloromethane. Silica gel was added and the solvent was evaporated. The crude material was purified by flash chromatography on silica gel using heptane/EtOAc as eluent. The title compound was obtained as brown crystals (2.31 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][S:11][C:10]2=[NH:14])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][S:11][C:10]2=[N:14][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N=C1SCCN1Cc1ccc(Cl)nc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(N=C1SCCN1Cc1ccc(Cl)nc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(2-Chloro-5-pyridinylmethyl)-2-iminothiazolidine (227 mg, 1.1 mmol) and triethylamine (110 mg, 1.1 mmol) were dissolved in 10 ml of acetonitrile, into which, benzoyl chloride (141 mg, 1.0 mmol) dissolved in acetonitrile 5 ml was added under cooling with ice, and stirred at room temperature overnight. After distilling the solvent off under reduced pressure followed by extraction with ethyl acetate, the ethyl acetate layer was washed with 2N-hydrochloric acid, saturated aqueous sodium bicarbonate, and water in this order, and the ethyl acetate layer was dehydrated and dried, and then the ethyl acetate layer was distilled off, and remaining oil was purified by a silica gel column chromatography to obtain the intended substance. The crude crystal of the intended substance was washed with hexane. Yield: 160 mg (65%). Melting point: 133° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4].[O:12]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[O:12]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4])=[O:22])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Reactant: N[C@H](CO)Cc1ccccc1
Product: O=C(N[C@H](CO)Cc1ccccc1)c1ccccc1Oc1ccccc1
Yield: 103.7 %

Procedure:
7.3 g (48 mmol) of (S)-2-amino-3-phenyl-1-propanol were reacted with 10.7 g (50 mmol) of 2-phenoxybenzoic acid by the method of procedure 3c. 17.3 g (100%) of the product were obtained.