Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([N:10]1[CH2:15][CH2:14][C:13]([C:17]#[CH:18])([OH:16])[CH2:12][CH2:11]1)(=[O:9])[CH3:8].[F:19][C:20]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=1[CH2:22]Cl>CN(C=O)C>[C:7]([N:10]1[CH2:15][CH2:14][C:13]([C:17]#[CH:18])([O:16][CH2:22][C:21]2[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:20]=2[F:19])[CH2:12][CH2:11]1)(=[O:9])[CH3:8]
Reactant: C#CC1(O)CCN(C(C)=O)CC1
Reactant: Fc1ccc(F)c(CCl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CC1(OCc2cc(F)ccc2F)CCN(C(C)=O)CC1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
A solution of 7.04 g of potassium t-butoxide (62.9 mmole) in 20 ml of dry DMF was added dropwise to a chilled solution of 10 g of 1-acetyl-4-ethynyl-4-hydroxypiperidine (59.9 mmole) in 75 ml of dry DMF, at such a rate as to maintain the temperature at 10° C. The mixture was allowed to equilibrate at 10° C. for 15 min. after which time it was cooled to -20° C. To this solution was added 9.73 g of 2,5-difluorobenzylchloride (59.9 mmole) at such a rate as to maintain the temperature around -20° C. After complete addition, the reaction mixture was warmed to 0° C. and allowed to react for 1 hr. The reaction appeared to be complete by GLC and was quenched with ice and water. The products were extracted into ether and dried over K2CO3. After filtration, the solvent was removed under vacuum. The crystalline product was recrystallized from cyclohexane and dried, affording 10.5 g of 1-acetyl-4-ethynyl-4-(2,5-difluorophenylmethoxy)piperidine (35.8 mmole, 59.83%). This material appeared pure by GLC (99% on OV225, temperature program: 200° C. (2 min), rate=25° C./min, 250° C. (15 min), flow=30 ml/min tR =4.00 min) and by TLC on silica gel in hexane:ethylacetate (1:1), Rf =0.2. MS (ci MH+ =294), NMR-CDCl3 and IR-CHCl3 were consistent with the structure; m.p.=90°-93° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]3[CH3:26])[C:11]3[CH2:17][CH2:16][N:15]([CH:18]=[O:19])[CH2:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[O:27]1[CH2:32]COCC1.C(N(CC)CC)C.C(Cl)(Cl)=O.[F:44][C:45]([F:49])([F:48])[CH2:46][NH2:47]>C1(C)C=CC=CC=1>[CH:18]([N:15]1[CH2:16][CH2:17][C:11]2[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]3[CH3:26])=[N:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:32]([NH:47][CH2:46][C:45]([F:49])([F:48])[F:44])=[O:27])=[CH:7][CH:6]=3)=[N:13][C:12]=2[CH2:14]1)=[O:19]
Reactant: NCC(F)(F)F
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2)nc2c1CCN(C=O)C2
Reactant: C1COCCO1
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCC(F)(F)F)cc2)nc2c1CCN(C=O)C2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Step 3—Synthesis of compound uv: (S)-2-(4-aminophenyl)-4-(3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carbaldehyde (0.100 g, 0.000283 mol) in dry 1,4-Dioxane (2.00 mL, 0.0256 mol) was added Triethylamine (0.0434 mL, 0.000311 mol) followed by 20% Phosgene in toluene (1:4, Phosgene:Toluene, 0.170 mL). The reaction mixture was heated at 50° C. for 1 hour. The reaction mixture was cooled to room temperature and then added 2,2,2-trifluoroethylamine (0.1340 mL, 0.001703 mol). The reaction mixture was stirred overnight. The reaction mixture was concentrated and purified by HPLC. 1H NMR (500 MHz, DMSO) δ 9.01 (s, 1H), 8.27-8.17 (m, 3H), 7.52 (d, J=8.8, 2H), 6.81 (d, J=6.5, 1H), 4.66-4.39 (m, 2H), 4.08 (s, 1H), 3.93 (ddd, J=31.8, 19.1, 10.1, 3H), 3.78-3.53 (m, 6H), 3.50-3.40 (m, 2H), 2.73 (s, 1H), 2.64 (s, 1H), 1.25 (t, J=7.4, 3H). LC/MS-m/z+479.2 (M+H)+
Reaction SMILES: Cl[CH2:2][CH:3]([OH:22])[CH2:4][NH:5][C@@H:6]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@H:6]([N:5]2[CH2:4][CH:3]([OH:22])[CH2:2]2)[C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])=[CH:16][CH:17]=1
Reactant: N#Cc1cccc([C@@H](NCC(O)CCl)c2ccc(Cl)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#Cc1cccc([C@H](c2ccc(Cl)cc2)N2CC(O)C2)c1
Temperature: 160 °C

Procedure:
A solution of 8.0 g (24.0 mmole) of 3-[(S)-[(3-chloro-2-hydroxypropyl)amino](4-chlorophenyl)methyl]benzonitrile and 11.7 g (36 mmole) of Cs2CO3 in 50 mL of dry CH3CN was divided between two 80 mL microwave tubes. The tubes were irradiated in a microwave oven (with cooling) at 160° C. for 8 h. The samples were filtered and the solids were washed with 20 mL of CH3CN and then 20 mL of CH2Cl2. The combined filtrates were concentrated and the residue was portioned between 300 mL ethyl acetate and 100 mL water. The layers were separated and the aqueous layer was washed with 100 mL ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography using 10-20% ethyl acetate in CH2Cl2 to afford the title compound as a clear oil; 1H-NMR(CDCl3) δ 1.6 (s, 2H, br), 5.24 (s, 1H), 7.24-7.78 (m, 8H) 2.89 (m, 2H), 3.54 (m, 2H), 4.39 (s, 1H), 4.52 (m, 1H), 7.27-7.8 (m, 8H).
Reaction SMILES: [NH4+].[N:2]#[C:3][S-:4].[CH3:5][CH:6]([CH3:10])[C:7](Cl)=[O:8].[NH2:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)=[O:16]>CC(C)=O>[C:27]([C:26]1[CH:25]=[CH:24][C:23]([CH:20]2[CH2:19][CH2:18][N:17]([C:15]([C:14]3[CH:31]=[CH:32][C:33]([CH3:34])=[C:12]([NH:11][C:3]([NH:2][C:7](=[O:8])[CH:6]([CH3:10])[CH3:5])=[S:4])[CH:13]=3)=[O:16])[CH2:22][CH2:21]2)=[CH:30][CH:29]=1)#[N:28]
Reactant: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1N
Reactant: N#C[S-]
Reactant: CC(C)C(=O)Cl
Agent: [NH4+]
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1NC(=S)NC(=O)C(C)C
Temperature: 40 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
Into around-bottom flask, was placed a solution of NH4SCN (72 mg, 0.95 mmol, 2.00 equiv) in acetone (10 mL). A solution of 2-methylpropanoyl chloride (50 mg, 0.47 mmol, 1.00 equiv) in acetone was added (5 mL) dropwise at 25° C. and the reaction was stirred overnight at 40° C. in an oil bath. To this was added 4-(1-(3-amino-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 121.1, 150 mg, 0.42 mmol, 1.00 equiv) at 25° C. The resulting solution was stiffed for 2 h at 25° C., then concentrated under reduced pressure. The residue was diluted with 100 mL of ethyl acetate. The organic layer was washed with 2×30 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with dichloromethane/methanol (20:1) as eluent to furnish 150 mg (64%) of the title compound as a brown oil.
Reaction SMILES: [N:1]#[C:2][Br:3].[CH2:4]([O:6][C:7](=[O:20])[CH2:8][NH:9][CH2:10][C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([Cl:18])[C:12]=1[Cl:19])[CH3:5]>C1(C)C=CC=CC=1>[CH3:5][CH2:4][O:6][C:7]([CH2:8][N:9]1[C:2]([NH2:1])=[N:17][C:16]2[CH:15]=[CH:14][C:13]([Cl:18])=[C:12]([Cl:19])[C:11]=2[CH2:10]1)=[O:20].[BrH:3]
Reactant: CCOC(=O)CNCc1c(N)ccc(Cl)c1Cl
Reactant: N#CBr
Solvent: Cc1ccccc1
Product: Br
Product: CCOC(=O)CN1Cc2c(ccc(Cl)c2Cl)N=C1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
A solution of cyanogen bromide (0.53 gm. 5 mmol) in toluene (10 ml.) was added to a solution of N-(6-amino-2,3-dichlorobenzyl)glycine ethyl ester (1.39 gm, 5 mmol) in toluene (10 ml.) and stirred at room temperature. There was an almost immediate precipitate. Stirring was continued for 30 minutes, and the reaction mixture was then heated to reflux and refluxed for 18 hours. After cooling, the solid was filtered off, washed with toluene and dried to give 1.81 gm (94.5%) of the title product. A portion of the product was recrystallized from ethanol, washed with ethanol and ether, and dried in vacuo at 78° to give an analytical sample as golden crystals.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([C:21]([OH:26])=[CH:22][C:23]=2[O:24][CH3:25])[CH:19]=[O:20])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH3:27]OS(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([C:21]([O:26][CH3:27])=[CH:22][C:23]=2[O:24][CH3:25])[CH:19]=[O:20])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: COS(=O)(=O)OC
Reactant: COc1cc(O)c(C=O)cc1-c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OC)c(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1C=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.1 %

Procedure:
To a solution of 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzaldehyde (1.04 g, 2.95 mmol) in acetone (20 mL) was added dimethylsulfate (0.37 mL, 3.84 mmol) and potassium carbonate (490 mg, 3.55 mmol). The reaction mixture was stirred at room temperature for 15 hours and extracted with ethyl acetate (2×50 mL). The organic extracts were successively washed with water (100 mL) and a saturated aqueous solution of NaCl (100 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzaldehyde (1.05 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.[F:16][C:17]([F:26])([F:25])[C@H:18]1[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(Cl)Cl.CCO>CN(C=O)C>[F:16][C:17]([F:25])([F:26])[C@H:18]1[CH2:19][CH2:20][C@H:21]([NH:24][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]([NH2:12])=[CH:11][C:3]=2[O:2][CH3:1])[CH2:22][CH2:23]1
Reactant: COc1cc(N)c([N+](=O)[O-])cc1C(=O)O
Reactant: N[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1cc(N)c([N+](=O)[O-])cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The sub-title compound was prepared from 2-methoxy-4-amino-5-nitro benzoic acid and trans-4-trifluoromethyl-cyclohexylamine with TBTU and TEA in DMF in analogy to example 3e._Yield: quantitative; TLC: silica gel, DCM/EtOH 9:1, Rf=0.68.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1.[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.O>C1(C)C=CC=CC=1>[C:12]1(=[O:17])[N:1]([CH2:2][CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4]2)[C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCC1Cc2ccccc2N1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CC1Cc2ccccc2N1
Yield: 105.1 %

Procedure:
A mixture of 2-aminomethylindoline (6.0 g, 40.48 mmol) and phthalic anhydride (6.30 g, 42.51 mmol) in toluene (600 mL) was refluxed for 4 h, while water generated during the reaction was removed by azeotropic distillation by using Dean-Stark apparatus. The mixture was concentrated to give a crude 2-phthalimidomethylindoline (11.84 g), which was used for the next step without further purification: 1H NMR (270 MHz, CDCl3) δ7.82 (m, 2H), 7.71 (m, 2H), 7.03 (d, 1H, J=7 Hz), 6.95 (dt, 1H, J=1,7 Hz), 6.61 (m, 2H), 4.19 (m, 1H), 3.86 (d, 2H, J=6 Hz), 3.18 (dd, 1H, J=16, 9 Hz), 2.93 (dd, 1H, J=16, 6 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([F:12])([F:11])[F:10])=[N:7][CH:8]=1.BrCC1CCCCO1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]>>[F:10][C:9]([F:12])([F:11])[C:6]1[N:7]=[CH:8][C:3]([CH2:2][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]3([C:41]4[C:32](=[CH:33][C:34]5[O:39][CH2:38][CH2:37][O:36][C:35]=5[CH:40]=4)[O:31][CH2:30]3)[C:22]2=[O:42])=[CH:4][CH:5]=1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc(C(F)(F)F)nc2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-chloromethyl-2-(trifluoromethyl)pyridine to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (90%) as a colorless solid: mp 204-207° C. (dichloromethane); 1H NMR (300 MHz, CDCl3) δ 8.74 (d, J=1.6 Hz, 1H), 7.82 (dd, J=8.1, 1.6 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.27-7.15 (m, 1H), 7.03-7.05 (m, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.18 (s, 1H), 5.11 (d, J=16.0 Hz, 1H), 4.92 (d, J=16.1 Hz, 1H), 4.91 (d, J=9.0 Hz, 1H), 4.64 (d, J=9.0 Hz, 1H), 4.22-4.07 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 177.7, 155.3, 149.0, 147.9 (q, J=139.5 Hz), 144.8, 141.2, 138.4, 136.5, 134.9, 132.1, 129.1, 124.4, 124.1, 121.4, 120.8 (q, J=10.8 Hz), 120.5, 111.4, 108.6, 99.6, 80.1, 64.5, 63.9, 58.0, 41.3; MS (ES+) m/z 429.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[SH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([S:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: Oc1ccc(S)cc1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a solution of 4-chloro-3-nitrobenzoic acid methyl ester (4.00 g, 18 mmol) and 4-mercaptophenol (2.37 g, 18 mmol) in acetone (60 mL) was added Cs2CO3 (5.93 g, 18 mmol) at room temperature, and then the mixture was refluxed for 30 minutes. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated. The residue was diluted with AcOEt (30 mL), washed with H2O (3 times) and brine, dried over MgSO4, and evaporated to give brown oil. The oily residue was separated by silica gel column chromatography (n-hexane/AcOEt=4/3) to give the title compound as yellow amorphous (5.60 g).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH:7]1([CH2:10][N:11]2[C:17](=[O:18])[C@@H:16]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH:32]=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[NH:30][C:29]4=[O:39])[CH2:24][CH2:23]3)=[O:21])[CH2:15][NH:14][C@H:13]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:12]2)[CH2:9][CH2:8]1.IC>CC(C)=O>[CH:7]1([CH2:10][N:11]2[C:17](=[O:18])[C@H:16]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH:32]=[C:31]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[NH:30][C:29]4=[O:39])[CH2:24][CH2:23]3)=[O:21])[CH2:15][N:14]([CH3:1])[C@@H:13]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:12]2)[CH2:9][CH2:8]1
Reactant: O=C(N[C@H]1CN[C@H](c2ccccc2)CN(CC2CC2)C1=O)N1CCC(n2cc(-c3ccccc3)[nH]c2=O)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN1C[C@@H](NC(=O)N2CCC(n3cc(-c4ccccc4)[nH]c3=O)CC2)C(=O)N(CC2CC2)C[C@@H]1c1ccccc1
Reaction time: 18 h
Yield: 35.1 %

Procedure:
Potassium carbonate (5.8 mg, 0.040 mmol) was added to a solution of N-[(3R,6S)-1-(cyclopropylmethyl)-7-oxo-3-phenyl-1,4-diazepan-6-yl]-4-(2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)piperidine-1-carboxamide (11.0 mg, 0.021 mmol) and iodomethane (3 □L, 0.040 mmol) in acetone (0.5 mL). After 18 h, the mixture was concentrated. Purification by silica gel chromatography (1% methanol/dichloromethane→5% methanol/dichloromethane) gave the title compound (4 mg). MS 543.3 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@@H:8]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([C:21]2[CH:26]=[N:25][C:24](Cl)=[CH:23][N:22]=2)=[O:20])[C:13]=1[F:28])[CH:9]1[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1.C(N(CC)CC)C.CN(C)C=O>C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:29])[NH:7][C@@H:8]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([C:21]2[CH:26]=[N:25][C:24]([NH:37][CH2:36][C:35]3[CH:38]=[CH:39][C:32]([O:31][CH3:30])=[CH:33][CH:34]=3)=[CH:23][N:22]=2)=[O:20])[C:13]=1[F:28])[CH:9]1[CH2:10][CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(CN)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccc(Cl)c(C(=O)c2cnc(Cl)cn2)c1F)C1CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2cnc(C(=O)c3c(Cl)ccc([C@H](NC(=O)OC(C)(C)C)C4CC4)c3F)cn2)cc1
Yield: 58.8 %

Procedure:
Step 2 {(R)-[4-Chloro-3-(5-chloro-pyrazine-2-carbonyl)-2-fluoro-phenyl]-cyclopropyl-methyl}-carbamic acid tert-butyl ester (709 mg, 1.61 mmol), 4-methoxybenzylamine (0.232 ml, 1.77 mmol), triethylamine (0.448 ml, 3.22 mmol) and dimethylformamide (5 ml) was heated to 80 deg C for 3 hours. The reaction was allowed to cool, ethyl acetate was added, and the mixture was washed with 10% aqueous lithium chloride solution and brine. The organic liquors were dried (MgSO4) and concentrated. The residue was purified by column chromatography eluting with 10-50% ethyl acetate/petroleum ether furnishing ((R)-{4-Chloro-2-fluoro-3-[5-(4-methoxy-benzylamino)-pyrazine-2-carbonyl]-phenyl}-cyclopropyl-methyl)-carbamic acid tert-butyl ester (512 mg) as a yellow oil. [M+H]+ 541
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23](F)=[CH:22][C:21]=2[O:27][CH2:28][CH2:29][O:30][CH3:31])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[CH3:33][N:34]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([N:37]3[CH2:38][CH2:39][CH2:40][N:34]([CH3:33])[CH2:35][CH2:36]3)=[CH:22][C:21]=2[O:27][CH2:28][CH2:29][O:30][CH3:31])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: CN1CCCNCC1
Reactant: COCCOc1cc(F)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Product: COCCOc1cc(N2CCCN(C)CC2)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1

Procedure:
Prepared from 5-fluoro-2-[4-fluoro-2-(2-methoxyethoxy)-benzoylamino]-N-(5-chloropyridin-2-yl)-benzamide and 1-methyl-hexahydro-1,4-diazepine to afford 91 mg (72%).
Reaction SMILES: CS[C:3]1[S:4][CH2:5][CH2:6][N:7]=1.C(O)(=O)C.[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[C:16](/[CH:20]=[CH:21]/[S:22]([N:25]2[CH2:41][CH2:40][C:28]3([C:32](=[O:33])[NH:31][C:30]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[N:29]3)[CH2:27][CH2:26]2)(=[O:24])=[O:23])=[C:15]([CH3:42])[CH:14]=1>CCO.C(OCC)(=O)C>[CH:34]1([C:30]2[NH:31][C:32](=[O:33])[C:28]3([CH2:27][CH2:26][N:25]([S:22](/[CH:21]=[CH:20]/[C:16]4[C:17]([CH3:19])=[CH:18][C:13]([NH:12][C:3]5[S:4][CH2:5][CH2:6][N:7]=5)=[CH:14][C:15]=4[CH3:42])(=[O:23])=[O:24])[CH2:41][CH2:40]3)[N:29]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CSC1=NCCS1
Reactant: Cc1cc(N)cc(C)c1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(C1CCCCC1)NC2=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(NC2=NCCS2)cc(C)c1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(C1CCCCC1)NC2=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
2-(Methylthio)-2-thiazoline (19 μL, 0.17 mmol) and acetic acid (1.2 ml) were added to a solution of 8-[(E)-2-(4-amino-2,6-dimethyl-phenyl)vinyl]sulfonyl-3-cyclohexyl-2,4,8-triazaspiro[4.5]dec-3-en-1-one (74 mg, 0.16 mmol) in EtOH (2.5 ml) at room temperature, and the mixture was heated with stirring at 80° C. for 16 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was then sequentially washed with water and saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 2-cyclohexyl-8-{(E)-2-[4-(4,5-dihydro-thiazol-2-ylamino)-2,6-dimethyl-phenyl]-ethenesulfonyl}-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (46.1 mg, 52%).
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][C:8]([CH3:30])=[CH:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:31][C:32]([F:42])([F:41])[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=O.O>CCCCCC.O1CCCC1>[F:31][C:32]([F:42])([F:41])[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[CH:10][CH:9]=[C:8]([CH3:30])[CH3:7]
Reactant: CC(C)=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)=CC=C(c1ccccc1)C(F)(F)F
Yield: 56.6 %

Procedure:
65 ml of 15% strength solution of n-butyl-lithium in hexane were added dropwise to a suspension of 41.1 g (0.1 mol) of dry 3,3-dimethylallyl-triphenyl-phosphonium bromide in 300 ml of anhydrous tetrahydrofuran at 0° C. under nitrogen, while stirring. The deep red solution thus obtained was stirred at 0° C. for a further 15 minutes and 17.4 g (0.1 mol) of ≃,≃,≃-trifluoroacetophenone were then added dropwise at 0°-10° C. The mixture was subsequently stirred at room temperature until it was decolorized (about 12 hours). 600 ml of water were then added and the reaction mixture was extracted 5 times with 200 ml of petroleum ether each time. The petroleum ether phases were dried over magnesium sulphate and the solvent was then stripped off in a rotary evaporator under a waterpump vacuum. 150 ml of n-hexane were added to the residue and residual triphenyl-phosphine oxide was filtered off. The solvent was subsequently distilled off from the filtrate under normal pressure and the oily residue was then distilled in vacuo. 12.8 g (56.6% of theory) of 1,1,1-trifluoro-2-phenyl-5-methyl-hexa-2,4-diene were obtained as a slightly reddish liquid with a boiling point of 80°-85° C. under 3 mbar.
Reaction SMILES: [Mg].I[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[C:11]([C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH:14]=1)#N.S(=O)(=O)(O)[OH:23]>O.CCOCC>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:11]([C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH:14]=2)=[O:23])=[CH:4][CH:5]=1
Reactant: N#Cc1coc2ccccc12
Reactant: COc1ccc(I)cc1
Reactant: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(C(=O)c2coc3ccccc23)cc1
Reaction time: 17 h

Procedure:
To a solution of the Grignard reagent prepared from 4.27 g. (0.14 g.-atom) of magnesium turnings and 31.0 g. (0.13 mol.) of 4-iodoanisole in 50 ml. of ether was added dropwise a solution of 10.0 g. (0.07 mol.) of 3-cyanobenzofuran in 150 ml. of ether. The reaction mixture was stirred at 25° for 17 hours, then 30 ml. of water was added followed by a mixture of 20 ml. of sulfuric acid and 40 ml. of water. Additional amounts of the acid solution were added to dissolve the precipitate that formed in the reaction mixture. The mixture was poured into 500 ml. of water and the aqueous solution was extracted with chloroform. The extracts were dried (MgSO4) and concentrated in vacuo to give 3-(4'-methoxybenzoyl)benzofuran which was purified by chromatography on alumina with chloroform, m.p. 89°-90° (hexane-benzene).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12](=[O:21])[NH:11][N:10]=1.[H-].[Na+].[CH2:25](I)[CH3:26]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12](=[O:21])[N:11]([CH2:25][CH3:26])[N:10]=1
Reactant: CCI
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)n[nH]c(=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(Cc2c(Cl)cncc2Cl)c2ccc(OC)cc2c1=O
Yield: 77.9 %

Procedure:
A suspension of 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-2H-phthalazin-1-one (0.52 g, 1.55 mmoles), prepared as described in example 38, in DMF (10 ml) was added with NaH (0.057 g, 1.55 mmoles) and, after 1 hour, with ethyl iodide (0.125 ml, 1.55 mmoles). After 1 night the mixture was diluted with water (10 volumes) and extracted twice with ethyl acetate. The organic phase was anhydrified and concentrated to give a solid which was purified by flash chromatography (eluent: ethyl acetate/petrolatum 3:7). There was thus obtained 0.44 g of the title compound (yield: 78%). m.p.: 150.2-151.2° C.