Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[NH:16][C:9]1[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([CH2:5][S:2][CH3:1])[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: C[S-]
Reactant: Cc1cccc(Nc2ncnc3ccc(CBr)cc23)c1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSCc1ccc2ncnc(Nc3cccc(C)c3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38 %

Procedure:
Sodium methanethiolate (0.141 g) was added to a stirred mixture of 6-bromomethyl-4-(3'-methylanilino)quinazoline (0.6 g), triethylamine (0.203 g) and DMF (2 ml). The mixture was stirred at ambient temperature for 4 hours. The mixture was evaporated and the residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained an oil which was triturated under a mixture of hexane and diethyl ether to give 4-(3'-methylanilino)-6-methylthiomethylquinazoline (0.205 g), m.p. 134°-136° C.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:24])[C@H:10]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:11][C:12](=[O:16])[C:13](=O)[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:13](=[CH2:14])[C:12](=[O:16])[NH:11][C@@H:10]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=C1C(=O)N[C@@H](Cc2ccccc2)C(=O)N1Cc1ccccc1
Yield: 52.6 %

Procedure:
Using a Dean-Stark trap whose trap part was filled with molecular sieves 3A, a solution of N-2-oxo-propanoyl-L-phenylalanine benzylamide from Example 3a (100 mg, 0.31 mmol) in toluene (20 mL) was refluxed in the presence of p-TsOH.H2O (1.8 mg, 0.0093 mmol, 0.03 eq) for 24 h. After removal of the solvent, the residue was purified by a silica gel chromatography to yield 50 mg (53%) of title compound as a white solid: mp 124-127° C., 1H NMR (300 MHz, CDCl3) δ 7.01-7.35 (m, 10H), 6.84 (br s, 1H), 5.60 (s, 1H), 5.01 (d, J=15.7 Hz, 1H), 4.85 (d, J=15.7 Hz, 1H), 4.76 (s, 1H), 4.49-4.52 (m, 1H), 3.36 (dd, J=3.7, 13.6 Hz, 1H), 3.12 (dd, J=7.7, 13.6 Hz, 1H); HRMS (EI): m/z 306.1369 (M+) (calcd for C19H18N2O2: 306.1368). Enantiomeric excess was determined to be >99% using chiral HPLC with a CHIRALCEL OD column.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[C:15]([OH:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[OH-].[Na+].Cl[CH:22]([F:24])[F:23]>O>[F:23][CH:22]([F:24])[O:16][C:15]1[C:7]([F:6])=[C:8]([CH:12]=[C:13]([F:18])[C:14]=1[F:17])[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1cc(F)c(F)c(O)c1F
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc(F)c(F)c(OC(F)F)c1F
Reaction time: 0.5 h

Procedure:
20 ml of dimethylformamide, followed by 4.97 g (0.026 mole) of 2,4,5-trifluoro-3-hydroxybenzoic acid [(XXIII), X=X'=F], were added in portions, whilst ice-cooling, to a solution of 2.18 g (0.052 mole) of sodium hydroxide in 5 ml of water. Thereafter the solution was stirred for 30 minutes, whilst ice-cooling. The reaction mixture was then transferred to a 200 ml stainless steel autoclave, and 100 ml of dimethylformamide containing 24.0 g (0.277 mole) of chlorodifluoromethane were added to it. The mixture was then stirred at between 100° and 110° C. for 5 hours under pressure. At the end of this time, the reaction mixture was poured into water and extracted with chloroform. The chloroform extracts were washed with water and dried over anhydrous sodium sulfate; the solvent was then removed by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel using a 9:1 by volume mixture of ethyl acetate and ethanol as the eluent, to afford 2.00 g of 3-difluoromethoxy-2,4.5-trifluorobenzoic acid as a colorless powder.
Reaction SMILES: [C:1]1([C@H:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>C(#N)C>[OH:10][CH2:9][C@H:7]([NH:8][C:12]1[S:11][CH2:17][C:15](=[O:16])[N:14]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CSC(=S)N1
Reactant: N[C@@H](CO)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(N[C@@H](CO)c2ccccc2)=N1
Temperature: 0 °C
Reaction time: 48 h
Yield: 50 %

Procedure:
To a suspension of (R)-(−)-2-phenylglycinol (15.34 g, 111.82 mmol) and rhodanine (14.65 g, 110 mmol) in acetonitrile (200 mL) was added DIPEA (20.03 mL, 115 mmol) at room temperature. Then, it gave a clear solution within 2 min and this solution was cooled to 0° C. To this, mercuric chloride (31.22 g, 115 mmol) was added in three portions within a period of 15 min. After addition, the suspension was allowed to warm to room temperature and stirred for 2 days. The resulting black solids were filtered through a plug of celite and washed with dichloromethane (500 mL) and methanol (1.0 L). The combined solvents were removed under the vacuum and the crude residue was diluted with water (250 mL) and ethyl acetate (250 mL). The two layers were separated and the aqueous layer was extracted with dichloromethane (2×250 mL). The two organic extracts were washed separately with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude yellow solid. This solid was dissolved in acetonitrile (˜100 mL) at hot condition and then stored in the refrigerator overnight. The solids were collected by filtration and washed with cold acetonitrile. After drying in air, 12.99 g (50% yield) of 2-(2-hydroxy-1-(R)-phenyl-ethylamino)-thiazol-4-one was isolated as a white amorphous solid: EI-HRMS m/e calcd for C11H12N2O2S (M-H2O) 218.0514, found 218.0511.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])=[N:2]1.[F:14][CH:15]([F:26])[O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.N1C=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:14][CH:15]([F:26])[O:16][C:17]1[CH:22]=[CH:21][C:20]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=3)[C:9]#[N:10])=[N:2]2)=[CH:19][CH:18]=1
Reactant: N#Cc1cccc(-c2cc[nH]n2)c1
Reactant: OB(O)c1ccc(OC(F)F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2ccn(-c3ccc(OC(F)F)cc3)n2)c1
Temperature: 35 °C
Yield: 27.2 %

Procedure:
A solution of 3-(1H-pyrazol-3-yl)-benzonitrile (400 mg, 2.36 mmol) and 4-difluoromethoxybenzeneboronic acid (1.02 g, 5.44 mmol) in dimethylformamide (20 mL) is treated with copper (II) acetate (472 mg), pyridine (0.36 mL), and powdered, activated 4 Å molecular sieves (1 g). The resulting mixture is heated to 35° C. for 3 h, cooled and partially evaporated. The residue is partitioned between 1 M aq. HCl and ethyl acetate (200 mL each), and the extract is washed with brine (100 mL), dried over MgSO4, filtered and evaporated. The residue is separated by column chromatography (silica gel, 1:1 CH2Cl2-hexane) to afford 3-[1-(4-difluoromethoxy-phenyl)-1H-pyrazol-3-yl]-benzonitrile (200 mg, 23%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[OH:8][C:4]1[CH:3]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Oc1cccc(I)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Oc1cccc(-c2ccccc2)c1
Temperature: 100 °C
Yield: 84.2 %

Procedure:
A stirred mixture of 660 mg (3 mmol) of 3-iodophenol, 439 mg (3.6 mmol) phenylboronic acid, and 173 mg (0.15 mmol) tetrakistriphenylphosphine in 10 mL of toluene, 5 mL ethanol, and 6 mL 2M sodium carbonate (aqueous) was heated at 100° C. in an inert atmosphere of nitrogen for 15 minutes. The cooled mixture was partitioned between EtOAc, ice, and brine and the organic phase was separated, washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by plate layer chromatography (PLC) using CH2Cl2 as the eluant to give 430 mg of the title product.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:3]=1.[C:19]1([C:25]2[C:29](B(O)O)=[CH:28][N:27]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:19]1([C:25]2[C:29]([C:2]3[C:7](=[O:8])[CH:6]=[CH:5][N:4]([C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=4)[N:3]=3)=[CH:28][N:27]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1Br
Reactant: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1-c1ccccc1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
A mixture of 3-bromo-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (319 mg, 1.0 mmol), (3-phenyl-1-trityl-1H-pyrazol-4-yl)boronic acid (645 mg, 1.5 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol), Na2CO3 (318 mg, 3.0 mmol), DME (7.5 mL), and H2O (1.5 mL) was refluxed overnight under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane/AcOEt (1/1) and crystallized from MeOH to give the title compound (418 mg, 67% yield) as a white solid: mp 216-218° C.; 1H NMR (300 MHz, CDCl3): δ ppm 6.58 (1H, d, J=7.9 Hz), 7.08 (1H, dd, J=2.3, 7.9 Hz), 7.23-7.39 (20H, m), 7.47-7.54 (3H, m), 8.17 (1H, d, J=7.9 Hz), 8.67 (1H, s). LC-MS (ESI) m/z 625 [M+H]+. Anal. Calcd for C39H27F3N4O: C, 74.99; H, 4.36; N, 8.97. Found: C, 74.84; H, 4.39; N, 9.01.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:12]([O:14]C)=O.O.[NH2:17][NH2:18]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:12]([NH:17][NH2:18])=[O:14]
Reactant: COC(=O)c1ncnc2ccc(Br)cc12
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)c1ncnc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 961 mg methyl 6-bromoquinazoline-4-carboxylate (compound in Production Example 413), 0.9 mL hydrazine monohydrate and 70 mL methanol was stirred at room temperature for 30 minutes, and the precipitated crystals were collected by filtration. The filtrate was evaporated to give additional crystals. The title compound, 838 mg in total, was obtained as pale yellow crystals.
Reaction SMILES: O1CCCCC1[N:7]1[C@@H:10]([CH:11]([CH3:20])[CH2:12][O:13]C2CCCCO2)[C@H:9]([CH2:21][CH2:22][O:23][O:24][C:25]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[O:26])[C:8]1=[O:37].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.P([O-])([O-])([O-])=O>CO>[N+:34]([C:31]1[CH:30]=[CH:29][C:28]([CH2:27][C:25]([O:24][O:23][CH2:22][CH2:21][C@H:9]2[C@H:10]([CH:11]([CH3:20])[CH2:12][OH:13])[NH:7][C:8]2=[O:37])=[O:26])=[CH:33][CH:32]=1)([O-:36])=[O:35]
Reactant: CC(COC1CCCCO1)[C@H]1[C@H](CCOOC(=O)Cc2ccc([N+](=O)[O-])cc2)C(=O)N1C1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: CC(CO)[C@@H]1NC(=O)[C@H]1CCOOC(=O)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
A solution of trans-1-(2-tetrahydropyranyl)-3-(1-p-nitrobenzylcarbonyldioxyethyl)-4-[1-methyl-2-(2-tetrahydropyranyl)oxyethyl]-2-azetidinone in methanol at 25° C. is treated with 0.1 molar equivalent of p-toluenesulfonic acid monohydrate. The solution is stirred for a period of 2 hours and then neutralized with 1 M pH 7 phosphate buffer. The product is extracted into ethyl acetate. The ethyl acetate solution is washed with brine, dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure to give trans-3-(1-p-nitrobenzylcarbonyldioxyethyl)-4-(1-methyl-2-hydroxyethyl)-2-azetidinone. The cis diastereoisomers are obtained in an analogous manner.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[C:12]([O:17][CH3:18])(=[O:16])[C:13](C)=[CH2:14]>C(O)(C)(C)C>[CH3:18][O:17][C:12](=[O:16])[CH2:13][CH2:14][C:9]([C:10]#[N:11])([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:14][CH2:13][C:12]([O:17][CH3:18])=[O:16]
Reactant: C=C(C)C(=O)OC
Reactant: COc1ccc(CC#N)cc1
Solvent: CC(C)(C)O
Product: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC)cc1
Yield: 70.2 %

Procedure:
A mixture of 36.75 g. (0.25 mole) of the known compound (p-methoxyphenyl)acetonitrile and 116 ml. of methyl methacrylate in 120 ml. of t-butyl alcohol is heated to reflux. The heat is removed and 38 ml. of 40% methanolic Triton B in 56 ml. of t-butyl alcohol quickly added. After about 4 hours of heating at reflux the mixture is allowed to cool and taken up in water and benzene. The organic layer is washed successively with 2.5 N hydrochloric acid, water and brine and then evaporated to dryness. The residue is distilled under vacuum, first at 40 mm. of mercury to remove excess methyl acrylate and then at 0.6 to 0.75 mm. to give 55.9 g. (70.2% yield) of dimethyl-4-cyano-4-(4-methoxyphenyl)pimelate, having a boiling point of 205° to 210°C. The NMR spectrum of the compound confirms its expected structure.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([Br:13])[CH:10]=[C:9]([Br:14])[CH:8]=1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1>CCCCCC.CCOCC>[Br:14][C:9]1[CH:8]=[C:7]([CH:20]([C:19]2[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=2)[OH:21])[CH:12]=[C:11]([Br:13])[CH:10]=1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: O=Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OC(c1ccc(F)cc1)c1cc(Br)cc(Br)c1
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
A 2.5M solution of n-butyllithium in hexane (44.0 ml) was added dropwise to a stirred suspension of 1,3,5-tribromobenzene (31.5 g) in dry ether (1000 ml) at -78° C. under an atmosphere of dry nitrogen. The resulting mixture was stirred at this temperature for 30 minutes and the 4-fluorobenzaldehyde (13.65 g) was added dropwise. Stirring at -78° C. was continued for a further 30 minutes and then the reaction was quenched by the addition of water. The temperature was allowed to reach room temperature and the organic layer was separated and dried (MgSO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. The column was eluted with dichloromethane/hexane (1:5), gradually increasing the ratio of solvents to 2:3. The product fractions were combined, evaporated and the residue was triturated with hexane to give the title compound (31.42 g), m.p. 92°-93° C. Found: C,43.75; H,2.43. C13H9Br2OF requires C,43.37; H,2.52%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:27][C:11]([C:10]2[CH:9]=[CH:8][C:7]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:16])=[CH:15][CH:14]=2)=[O:13])(=[O:25])=[O:26])=[CH:22][CH:23]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(C(=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A 5-liter, 3-necked, round-bottomed flask was equipped with a mechanical stirrer and nitrogen inlet. dichloromethane (2 liters) was placed in the reaction flask and terephthalic acid mono-t-butyl ester (127.5 g), 4-dimethylaminopyridine (70.06 g), and 4-chlorobenzenesulfonamide (110.04 g) were added in that order using dichloromethane (400 ml) to wash down the solids. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (110.10 g) was added in portions over 10 min using dichloromethane (100 ml) to wash down the solid. After the reaction mixture was stirred overnight at room temperature, it was evaporated. The residue was partitioned between ethyl acetate and water. The organic solution was washed (20% (w/v) aqueous citric acid, saturated aqueous NaHCO3, brine), dried (Na2SO4), and evaporated to a white solid. After drying in a vacuum oven at 50° C., the ester (227 g, 100%) was obtained in a sufficiently pure state to be used directly for the next step; TLC, Rf =0.43, methanol:chloroform (15:85). (Further purification was possible by recrystallization from ethanol:water; mp above 300° C.).
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([N:23]([CH3:25])[CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)C=CC=CC=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1>O1CCOCC1>[CH3:24][N:23]([CH3:25])[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:8]([N:40]2[CH2:39][CH:38]=[C:37]([C:31]3[C:30]4[C:34](=[CH:35][CH:36]=[C:28]([F:27])[CH:29]=4)[NH:33][CH:32]=3)[CH2:42][CH2:41]2)=[O:7])[CH2:12][CH2:13]1
Reactant: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccccc2)CC1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)N2CC=C(c3c[nH]c4ccc(F)cc34)CC2)CC1
Yield: 15.1 %

Procedure:
The diastereoisomer mixture of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid phenyl ester (700 mg, 1.98 mmole) was added to a solution of 5-fluoro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (428.2 mg, 1.98 mmole) in dioxane (10 ml). The reaction mixture was then boiled under reflux for 12 hours. The reaction mixture was slightly cloudy at RT. The reaction mixture was worked up by distilling off the solvent. The residue contained, apart from phenol, also the two diastereoisomers of 4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide. The diastereoisomers were separated and purified by flash chromatography on silica gel (50 g). Methanol/EE (1:1; 1000 ml) was used as eluent. The non-polar diastereoisomer of 4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexyl-methyl)-amide (300 mg, pale yellow, m.p. 105°-109° C., 32%) and the polar diastereoisomer of 4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (142 mg, 15%) were thereby obtained in pure form.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24]([CH3:25])=[CH:23][C:12]([CH2:13][C@@H:14]([CH2:19][C:20]([O-])=[O:21])[C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=1[O:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:40][CH2:39][C:38]3[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=3[NH:36][C:35]2=[O:45])[CH2:30][CH2:29]1.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(#N)C.C1COCC1>[CH2:1]([O:8][C:9]1[C:24]([CH3:25])=[CH:23][C:12]([CH2:13][C@@H:14]([CH2:19][C:20](=[O:21])[N:28]2[CH2:29][CH2:30][CH:31]([N:34]3[CH2:40][CH2:39][C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[NH:36][C:35]3=[O:45])[CH2:32][CH2:33]2)[C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=1[O:26][CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CC(=O)[O-])Cc1cc(C)c(OCc2ccccc2)c(OC)c1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)Cc1cc(C)c(OCc2ccccc2)c(OC)c1

Procedure:
Prepared analogously to Example 12d from 5.80 g (15.6 mmol) 1-methyl (S)-2-(4-benzyloxy-3-methoxy-5-methyl-benzyl)-succinate and 4.20 g (17.13 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, using 3.43 g (17.9 mmol) (3-dimethylamino-propyl)-ethyl-carbodiimide and 2.38 g (19.5 mmol) 4-dimethylamino-pyridine for the coupling and 130 mL acetonitrile and 50 mL THF as solvent.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2Cl)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1nccnc1C1CCNCC1
Yield: 245.6 %

Procedure:
To a well stirred solution of tert-butyl 4-(3-chloropyrazin-2-yl)piperidine-1-carboxylate (92 g, 0.309 mol, 1 eq.) in dichloromethane (1 L) was added trifluoroacetic acid (119 mL, 1.545 mol, 5 eq.). The resulting mixture was heated to reflux overnight (16 h). The mixture was concentrated and the resulting TFA salt was dried with toluene (500 mL) azetropically to give 150 g 2-chloro-3-(piperidin-4-yl)pyrazine. This was used in the next step without further purification.
Reaction SMILES: [O:1](C)[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].CC1CN2CCN1CC2.C(O)C.[O-:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24].[O-]S(C(F)(F)F)(=O)=O.[CH3:38][N+:39]12[CH2:46][CH2:45][N+:42]([CH3:47])([CH2:43][CH2:44]1)[CH2:41][CH:40]2C>C(#N)C>[O-:4][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:3])=[O:1].[CH3:38][N+:39]12[CH2:46][CH2:45][N+:42]([CH3:47])([CH2:43][CH2:44]1)[CH2:41][CH2:40]2.[O-:25][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:24])=[O:22]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CC1C[N+]2(C)CC[N+]1(C)CC2
Agent: CC1CN2CCN1CC2
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCO
Solvent: CC#N
Product: C[N+]12CC[N+](C)(CC1)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl triflate (3.2 g, 19.5 mmol) was added dropwise to a cold (0 ° C) stirred solution of 2-methyl-1,4-diazabicyclo [2,2,2]octane (2.5 g, 20.0 mmol) in dry acetonitrile under an atmosphere of dry nitrogen. The mixture was stirred at 0° C. for 1 hour and then at 20° C. overnight. The orange solution obtained was treated dropwise with ethanol until precipitation of a white solid ceased; this solid was recovered by filtration, washed with ethanol, dried in vacuo at room temperature and shown by n.m.r. spectroscopy (1H and 19F) to be 1,2,4-trimethyl-1,4-diazoniabicyclo[2,2,2]octane ditriflate (0.45 g, 0.99 mmol, 5%). Removal of acetonitrile from the filtrate in vacuo left an orange oil (3.6 g, 12.4 mmol, 64%), shown by n.m.r. spectroscopy (1H and 19F) to be methyl-N-methyl-1,4-diazabicyclo [2,2,2]octane triflate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[O:21])=[CH:13][CH:12]=2)=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].[C:33]([CH2:41][CH2:42][C:43](O)=O)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:9][C:5]1[N:4]=[C:3]2[N:10]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]([NH:22][S:23]([C:26]4[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=4)(=[O:25])=[O:24])=[O:21])=[CH:13][CH:12]=3)[C:43]([CH2:42][CH2:41][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:1][C:2]2=[C:7]([CH3:8])[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(Nc3nc(C)cc(C)c3N)cc2)cc1
Reactant: O=C(O)CCC(=O)c1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3c(CCC(=O)c4ccccc4)nc4c(C)cc(C)nc43)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 241 from N-{[(2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (step 4 of Example 162) and 3-benzoylpropionic acid.