Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15](OCC)=[O:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[NH2:22][NH2:23]>CCO>[F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:22][NH2:23])=[O:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)CN1CCN(C(=O)c2ccc(F)cc2)CC1
Solvent: CCO
Product: NNC(=O)CN1CCN(C(=O)c2ccc(F)cc2)CC1
Yield: 64 %

Procedure:
Synthesized according to General Procedure C: 51g (3.73 g, 12.7 mmol, 1.0 equiv.), anhydrous hydrazine (1.6 mL, 50.8 mmol, 4.0 equiv.), EtOH (25 mL, 0.5 M). 46g (2.28 g, 64.1%) was obtained as a white solid after extraction without further purification. 1H-NMR (500 MHz, CDCl3) δ 1H-NMR (500 MHz, CDCl3) δ 8.09 (br s, 1H), 7.37-7.33 (m, 2H), 7.06-7.02 (m, 2H), 3.85 (br s, 2H), 3.70 (br s, 2H), 3.42 (br s, 2H), 3.06 (s, 2H), 2.48 (br s, 4H). 13C-NMR (125 MHz, CDCl3) δ 169.8, 169.5, 163.5 (d, JC-F=249.1 Hz), 131.5 (d, JC-F=2.8 Hz), 129.4 (d, JC-F=9.1 Hz), 115.7 (d, JC-F=22.0 Hz), 60.6, 53.5 (br), 47.7 (br), 42.3 (br). 19F-NMR (470 MHz, CDCl3) δ −113.1. HRMS (ESI): 281.1409 (M+1); calcd. for C13H1sFN4O2: 281.1414.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:11].[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N(CC)CC)C>>[Br:10][C:8]1[CH:7]=[C:4]2[C:3](=[C:2]([Br:1])[CH:9]=1)[O:11][C:12](=[O:14])[CH:13]=[CH:5]2
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1cc(Br)cc(Br)c1O
Solvent: CCN(CC)CC
Product: O=c1ccc2cc(Br)cc(Br)c2o1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
To a suspension of 3,5-dibromosalicylaldehyde (100 g, 357 mmol) in acetic anhydride (164.8 mL, 1.8 mol) was added triethylamine (45 mL, 375 mmol). The reaction solution was heated overnight at reflux under argon. The solution was cooled to room temperature and a solid mass formed. The dark brown reaction mixture was washed with hot hexanes (3×300 mL) and aqueous saturated sodium bicarbonate. The resulting solid was dissolved in EtOAc (2 L) and washed with water. The organic layer was dried (sodium sulfate) and concentrated to give a brown solid that was collected by filtration. The solid was dried in vacuo to give substantially pure 6,8-dibromocoumarin (94.2 g, 87% yield).
Reaction SMILES: CC#N.C(=O)=O.[CH2:7]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:8]#[CH:9].C([Mg]Cl)(C)C.CON(C)[C:24](=[O:26])[CH3:25]>C1COCC1>[N:10]1([CH2:7][C:8]#[C:9][C:24](=[O:26])[CH3:25])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: CON(C)C(C)=O
Reactant: C#CCN1CCOCC1
Agent: CC(C)[Mg]Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(=O)C#CCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a cooled (˜40° C., CH3CN/CO2) solution of 4-(2-propyn-1-yl)morpholine (2.2 g, 17.58 mmol) in THF (5 mL) was added dropwise via. syringe under N2 a solution of 2 M isopropylmagnesium chloride in THF (10 mL, 20.00 mmol). The reaction was stirred for 1 hr then a solution of N-methoxy-N-methylacetamide (2.2 mL, 20.69 mmol) in THF (5 mL) was added in one portion. The reaction was stirred for 2 hr (allowed to slowly warm to RT), quenched with aq. NH4Cl, extracted with EtOAc, washed with brine, dried (Na2SO4), filtered and evaporated to dryness under vacuum. The remaining was purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 80% EtOAc in hexanes). The pure fractions were combined and evaporated to dryness to give the product 5-(4-morpholinyl)-3-pentyn-2-one (2.09 g, 12.50 mmol, 71.1% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 3.62-3.57 (m, 4H), 3.56 (s, 2H), 2.49-2.43 (m, 4H), 2.34 (s, 3H). MS(ES)+m/e 168.0 [M+H]+.
Reaction SMILES: [N:1](=[C:3]([C:9]([CH3:11])=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])O.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH2:16]>C(#N)C>[CH2:7]([O:6][C:4]([C:3]1[N:1]=[C:15]([C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[Cl:12])[NH:16][C:9]=1[CH3:11])=[O:5])[CH3:8]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: NCc1ccccc1Cl
Solvent: CC#N
Product: CCOC(=O)c1nc(-c2ccccc2Cl)[nH]c1C
Temperature: 25 °C

Procedure:
To a solution of 8.5 g of ethyl 2-oximinoacetoacetate in acetonitrile (100 ml) was added 7.5 ml of 2-chlorobenzylamine. The reaction mixture was then refluxed for 4 hours under argon atmosphere. After such time the reaction mixture was then concentrated in vacuo and the residue was triturated with warm ethylacetate for 10 minutes. After allowing to cool down to room temperature the solid was filtered and dried in vacuo to yield 11.3 g of a white powder, MS (ISP) 265.1 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([CH2:17]O)[CH:13]=[N:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:21])=O>>[Cl:21][CH2:17][C:12]1[CH:13]=[N:14][C:15]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:16]=2
Reactant: O=S(Cl)Cl
Reactant: OCc1cnc2cc(-c3ccccc3)ccc2c1
Product: ClCc1cnc2cc(-c3ccccc3)ccc2c1
Yield: 96 %

Procedure:
In substantially the same manner as in Reference Example 73, 7-phenyl-3-quinolylmethanol was reacted with thionyl chloride to obtain 3-chloromethyl-7-phenylquinoline. The yield was 96%. Recrystallization from ethyl acetate-hexane gave colorless prisms, 105-106° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20].CN(C1C=CC=CN=1)C>CCOC(C)=O.C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cccc(NC(=O)Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To THF (15 mL) was added 3-tert-butylaniline (447 mg, 3 mmol), potassium carbonate (828 mg, 6 mmol), phenyl chloroformate (1.13 mL, 9 mmol), and dimethylaminopyridine (36 mg, 0.30 mmol) and the reaction stirred at room temperature overnight. The mixture was diluted with EtOAc, filtered, concentrated in vacuo, and purified by silica gel column chromatography (5-15% EtOAc/hexanes) to give phenyl 3-tert-butylphenylcarbamate (458 mg, 1.70 mmol, 57%). 1H NMR (300 MHz, DMSO-d6) δ 10.14 (s, 1H), 7.59 (s, 1H), 7.49-7.10 (m, 7H), 7.08 (d, 1H), 1.25 (s, 9H); LC-MS (ESI) m/z 270 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:19][N:18]([C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[C:23]#[N:24])[C:17](=[O:28])[CH2:16]2)=[CH:11][C:10]=1[O:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)C1C=CC=CC=1>CCO.CCOC(C)=O.[Pd]>[CH:30]1([O:29][C:10]2[CH:11]=[C:12]([CH:15]3[CH2:19][N:18]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[C:17](=[O:28])[CH2:16]3)[CH:13]=[CH:14][C:9]=2[OH:8])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: N#Cc1cccc(N2CC(c3ccc(OCc4ccccc4)c(OC4CCCC4)c3)CC2=O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1cccc(N2CC(c3ccc(O)c(OC4CCCC4)c3)CC2=O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 25.4 %

Procedure:
200 mg of Pd—C was added to 3-[4-(4-benzyloxy-3-cyclopentyloxyphenyl)-2-oxo-pyrrolidin-1-yl]-benzonitrile (1.7 g. 3.8 mmol) in EtOH/EtOAc and flushed with H2 three times. The mixture was then stirred under H2 at r.t. for 72 h. The mixture was filtered through celite and then concentrated under reduced pressure. The residue was then dissolved in EtOAc and washed with 2N HCl, sat. NaHCO3, and sat. NaCl. Purification by silica gel gave 350 mg of the desired product. Yield: 26%.
Reaction SMILES: C[N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.N[C:15]1[CH:19]=C[NH:17][N:16]=1>C(O)(=O)C>[C:7]1([C:5]2[N:17]3[N:16]=[CH:15][CH:19]=[C:13]3[N:2]=[CH:3][CH:4]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=CC(=O)c1ccccc1
Reactant: Nc1cc[nH]n1
Solvent: CC(=O)O
Product: c1ccc(-c2ccnc3ccnn23)cc1

Procedure:
A reaction mixture of 5.25 g. of 3-dimethylaminoacrylophenone [von H. Meerwein et al., Annalen der Chemie, Band 641, 1-39, (1961)] and 2.50 g. of 3-aminopyrazole in 25 ml. of glacial acetic acid is refluxed for 3.5 hours, cooled overnight and evaporated to a thick yellow oil. This oil is dissolved in methylene chloride, washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate and then passed through a sintered glass funnel or a chromatographic column packed in vacuo with hydrous magnesium silicate. Additional methylene chloride is passed through the funnel (column). The effluent is refluxed on a steam bath. The gradual addition of hexane produces crystals. The crystallization from methylene chloride with hexane is repeated giving the desired product, m.p. 72°-73° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4]O1.[CH2:8]([O:10][C:11](=[O:13])[CH3:12])[CH3:9]>O1CCCC1>[CH2:8]([O:10][C:11](=[O:13])[CH:12]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:2][OH:1])[CH3:9]
Reactant: CCOC(C)=O
Reactant: OC1CCCCO1
Solvent: C1CCOC1
Product: CCOC(=O)C=CCCCCO
Temperature: 25 °C

Procedure:
A solution of 2-hydroxytetrahydropyran (59.2 g, 0.58 mol) and triphenyl-λ5-phosphanylidene)-acetic acid ethyl ester (201.3 g, 0.58 mol) in tetrahydrofuran (1.2 L) was heated at reflux for 14 h. The mixture was cooled to room temperature to afford 7-hydroxy-hept-2-enoic acid ethyl ester in tetrahydrofuran and was then used directly in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)[CH:6]=[CH:7][C:8]=1[S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])#[N:2].[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH:33][CH3:34])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][N:33]([CH3:34])[C:15]([NH:14][C:5]2[CH:6]=[CH:7][C:8]([S:9]([CH2:12][CH3:13])(=[O:10])=[O:11])=[C:3]([C:1]#[N:2])[CH:4]=2)=[O:23])=[CH:29][CH:30]=1
Reactant: CNCCc1ccc(Br)cc1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(NC(=O)N(C)CCc2ccc(Br)cc2)cc1C#N
Yield: 91.7 %

Procedure:
A solution of 25A (750 mg, 2.3 mmol) and 23B (486 mg, 4.5 mmol) with potassium carbonate (627 mg, 2.3 mmol) in DMF (6 mL) were heated at 50° C. for 15 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The organics were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (0% to 100% EtOAc in hexanes) to yield give 25B (950 mg, 93%) as a colorless oil. MS (ESI) m/z 449.89/451.91 (M+H)+.
Reaction SMILES: [CH:1]1[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3][CH:2]=1.[CH2:9]=[CH:10]CCCC>CO.[Ru]>[CH3:9][CH2:10][CH2:1][CH2:8][CH:7]=[CH:6][CH2:5][CH2:4][CH2:3][CH3:2]
Reactant: C1=CCCC=CCC1
Reactant: C=CCCCC
Agent: [Ru]
Solvent: CO
Product: CCCCC=CCCCC
Yield: 20 %

Procedure:
In contrast to the “classical” ruthenium metathesis catalysts mentioned above, which react only with highly-strained olefins, alkylidenes 6 and 7 of Example 6 also promote the ROMP of less-strained monomers such as 1,5-cyclooctadiene, and are active in the metathesis of acyclic olefins in protic solvents. For example, 6 will dimerize 1-hexene in methanol to give 5-decene in 20% yield (Equation 3). In these systems, separation of catalyst from product is facilitated through addition of water to the reaction mixture. Olefins collected from the resulting two-phase system contain very low levels of detectable ruthenium.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:32])[O:13][CH2:14][C@@H:15]([N:18]([CH3:31])[C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[Cl:30])=[O:20])[CH2:16][NH2:17])[N:2]=1.FC(F)(F)S(O[CH2:39][CH:40]([F:42])[F:41])(=O)=O.CCN(C(C)C)C(C)C>C1COCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:32])[O:13][CH2:14][C@@H:15]([N:18]([CH3:31])[C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[Cl:30])=[O:20])[CH2:16][NH:17][CH2:39][CH:40]([F:42])[F:41])[N:2]=1
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CN)COC(=O)Nc1cc2ccccc2cn1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CNCC(F)F)COC(=O)Nc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
To a solution of (S)-3-amino-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)propyl isoquinolin-3-ylcarbamate (200 mg, 0.44 mmol) in THF (2.0 mL) were added 2,2-difluoroethyl trifluoromethanesulfonate (94 mg, 0.44 mmol) and DIEA (0.15 mL, 0.88 mmol) at RT The reaction mixture was stirred at RT for 30 min. The solvent was removed. The resulting residue was dissolved in MeOH and mixture was purified on RP-HPLC using a mixture of acetonitrile and water to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-3-(2,2-difluoroethylamino)propyl isoquinolin-3-ylcarbamate (130 mg, 56% for two steps). LRMS (M+H+) m/z 524.2.
Reaction SMILES: [NH:1]1[CH2:3][CH:2]1[C:4]([NH2:6])=[O:5].Cl[C:8]([O:10][CH3:11])=[O:9]>>[C:4]([CH:2]1[CH2:3][N:1]1[C:8]([O:10][CH3:11])=[O:9])(=[O:5])[NH2:6]
Reactant: COC(=O)Cl
Reactant: NC(=O)C1CN1
Product: COC(=O)N1CC1C(N)=O

Procedure:
In an analogous manner, by reacting 2-aziridine-carboxamide with methyl chloroformate, there is obtained methyl 2-carbamoyl-1-aziridine-carboxylate which, after recrystallization from toluene, melts at 117°-120° C.
Reaction SMILES: [C:1](=[NH:21])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([F:20])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:22]([CH:24]([CH2:29][C:30]1[CH:31]=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=1)[C:25](OC)=O)=[O:23].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[F:20][C:15]1[CH:14]=[C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:25]=[C:24]([CH2:29][C:30]4[CH:31]=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=4)[C:22](=[O:23])[N:21]=3)=[CH:11][CH:10]=2)[CH:18]=[CH:17][C:16]=1[CH3:19]
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Reactant: Cc1ccc(Oc2ccc(CCOC(=N)N)cc2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(C)c(F)c4)cc3)nc2=O)cn1
Temperature: 115 °C
Yield: 6.2 %

Procedure:
To the solution of 2-{4-[(3-fluoro-4-methylphenyl)oxy]phenyl}ethyl imidocarbamate (100 mg, 0.347 mmol) and methyl 2-formyl-3-[2-(methyloxy)-5-pyrimidinyl]propanoate (93 mg, 0.416 mmol) in NMP (1.5 mL), was added K2CO3 (192 mg, 1.387 mmol). The mixture was heated with a microwave reactor at 115° C. for 2 h. Purification via MDAP then afforded the title compound (10 mg, 6.23% yield). LCMS: rt=3.30 min, [M+H+]=463
Reaction SMILES: [ClH:1].Cl.[C@H]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][C@@H:55]([N:57]2[CH2:62][CH2:61][CH:60]([OH:63])[CH2:59][CH2:58]2)C)CC1>>[ClH:43].[ClH:1].[OH:63][CH:60]1[CH2:61][CH2:62][N:57]([C@@H:55]([CH3:54])[CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[CH2:58][CH2:59]1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Agent: Cl
Product: C[C@@H](CN1CCC(NC(=O)c2cc3c(OCc4coc5ccc(Cl)cc45)cccc3[nH]2)CC1)N1CCC(O)CC1

Procedure:
This compound is synthesized from 4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (97, see example 42) and amine 50 analogously to the method described in example 1.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C([O-])([O-])=O.[K+].[K+]>C1(C)C(C)=CC=CC=1.CCOC(C)=O>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][N:10]1[CH2:11][CH2:12][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH:9]1[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: COC(=O)C1CCNC(CCc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CCC(C(=O)OC)CC1CCc1ccccc1

Procedure:
To a suspension of methyl 2-(2-phenylethyl)piperidine-4-carboxylate in xylene were added ethyl bromoacetate and K2CO3, followed by heating under reflux for 8 hours. The reaction mixture was diluted with EtOAc, the organic layer was washed with water and brine in this order, dried over MgSO4, and then filtered. The filtrate was concentrated under reduced pressure. To the residue was added hexane, and the insolubles were removed by filtration, followed by concentration under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to obtain methyl 1-(2-ethoxy-2-oxoethyl)-2-(2-phenylethyl)piperidine-4-carboxylate as a pale brown oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:4]=1[NH:14][NH2:15].CN(C)[CH:18]=[C:19]([S:23][C:24]([F:27])([F:26])[F:25])[C:20](=O)[CH3:21]>C(O)C>[Cl:2][C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:6]=[C:5]([Cl:13])[C:4]=1[N:14]1[C:20]([CH3:21])=[C:19]([S:23][C:24]([F:27])([F:26])[F:25])[CH:18]=[N:15]1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CC(=O)C(=CN(C)C)SC(F)(F)F
Agent: Cl
Solvent: CCO
Product: Cc1c(SC(F)(F)F)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 16 h
Yield: 65.8 %

Procedure:
A mixture of 29 g (0.1 mol) of 2,6-dichloro-4-trifluoromethylphenylhydrazine hydrochloride and 21 g (0.1 mol) of 1-dimethylamino-2-trifluoromethylthio-but-1-en-3-one in 150 ml of ethanol is stirred for 16 hours at 70° C. to 75° C. The mixture is worked up by concentrating in vacuo, the residue is taken up in chloroform, washed with water, dried over sodium sulphate and concentrated in vacuo, and the residue is distilled in a high vacuum. 26 g (61% of theory) of 1-(2,6-dichloro-4-trifluoromethyl-phenyl)-5-methyl-4-trifluoromethylthiopyrazole of boiling point 140° C. at 0.02 mbar and of melting point 54° C.-56° C. are obtained.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]([F:35])([F:34])[C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>CN(C)C=O.O>[N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[N:10]([C:26]([C:25]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:24]=3[C:23]([F:35])([F:22])[F:34])=[O:27])[CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1C(F)(F)F)N1Cc2cccnc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Example 1, Step B (10.6 g, 53.8 mmol) in dimethylformamide (125 mL) under nitrogen was added potassium carbonate (22.4 g, 162 mmol). The mixture was cooled and treated dropwise with a solution of crude 2-trifluoromethyl-4-fluorobenzoyl chloride of Step A (81 mmol) in dimethylformamide (25 mL). After stirring at room temperature for 2 hours, the mixture was diluted with water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate and evaporated to dryness. The crude material was dissolved in dichloromethane and purified by flash chromatography (on silica Merck-60, hexane-ethyl acetate 80:20) to provide the pure title compound (6.9 g) which was crystallized by sonication from ethanol-hexane, m.p. 183-185° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:50][C:51]([F:67])([F:66])[O:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([NH2:65])[CH:60]=1>CN(C=O)C>[F:50][C:51]([F:66])([F:67])[O:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([NH:65][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])[CH:60]=1
Reactant: Nc1cccc(-c2ccccc2OC(F)(F)F)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccccc4OC(F)(F)F)c3)c(=O)oc12
Temperature: 25 °C
Yield: 78.2 %

Procedure:
DIEA (0.011 mL, 0.065 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.013 g, 0.059 mmol) and HATU (0.025 g, 0.065 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′-trifluoromethoxy-biphenyl-3-ylamine (0.015 g, 0.059 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.021 g of product in 76% yield: LCMS (ESI) m/z 456 (MH+).
Reaction SMILES: S([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-])(=O)=O.[C-:12]#[N:13].[K+].O>CS(C)=O>[CH3:9][C:8]([CH3:10])=[CH:7][CH2:6][CH2:5][C:5]1[CH2:11][CH2:10][CH:8]([CH2:9][C:12]#[N:13])[CH2:7][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)=CCCC1=CCC(CC#N)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of tosylate 1H (R=4-Methyl-3-pentenyl) (20 g) in dimethylsulfoxide (178 mL) is added potassium cyanide (19.4 g). The reaction mixture is heated to 100° C., and the reaction mixture is stirred at that temperature for three hours. The reaction mixture is cooled to room temperature, added to water (300 mL), and extracted with hexane. The combined organic layers are dried over magnesium sulfate and the solution is concentrated in vacuo.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:10][C:11]2[O:12][C:13]3[C:19]([CH2:20][CH:21]=[CH2:22])=[CH:18][C:17]([Cl:23])=[CH:16][C:14]=3[N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:10][C:11]2[O:12][C:13]3[C:19]([CH2:20][CH2:21][CH3:22])=[CH:18][C:17]([Cl:23])=[CH:16][C:14]=3[N:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C=CCc1cc(Cl)cc2nc(Cc3ccc(OC)c(OC4CCCC4)c3)oc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1cc(Cl)cc2nc(Cc3ccc(OC)c(OC4CCCC4)c3)oc12
Yield: 45.8 %

Procedure:
A solution of 2-(3-cyclopentyloxy-4-methoxybenzyl)-5-chloro-7-allylbenzoxazole (1.2 g, 3.0 mmol) in ethyl acetate (50 ml) was hydrogenated over 0.104 g of 10% Pd on carbon catalyst in a Parr apparatus at 23 psi until hydrogen uptake ceased. The catalyst was filtered and the solvent was evaporated. The residue was recrystallized from hexane to give the title compound (0.55 g, 46%), mp 54-55° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][NH:5][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: COCCN
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 2-methoxyethylamine (0.58 ml) in dichloromethane (10 ml) was added triethylamine (1.0 ml) and methanesulphonyl chloride (0.51 ml). The mixture was stirred at room temperature overnight. The solvents were removed in vacuo to give a crude product which was purified by flash chromatography to give N-(2-Methoxy-ethyl)-methanesulfonamide (0.74 g).