Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[C:16]2=[O:22])[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[Cl:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][C:34]=1[F:35])[CH:27]=[CH:28][C:29](O)=[O:30].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:23][C:24]1[CH:25]=[C:26](/[CH:27]=[CH:28]/[C:29]([N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:6][CH2:7]4)[C@H:4]([OH:3])[CH2:11]3)[C:16](=[O:22])[CH:17]2[CH3:21])=[O:30])[CH:32]=[CH:33][C:34]=1[F:35]
Reactant: O=C(O)C=Cc1ccc(F)c(Cl)c1
Reactant: CC1NCCN(CCCN2CCC3(CC3)[C@H](O)C2)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1C(=O)N(CCCN2CCC3(CC3)[C@H](O)C2)CCN1C(=O)/C=C/c1ccc(F)c(Cl)c1
Reaction time: 1 h

Procedure:
To a solution of crude 1-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride (example 38; 0.03 g, 0.1 mmol) in N,N-dimethylformamide (0.8 ml) was added 3-chloro-4-fluorocinnamic acid (0.02 g, 0.1 mmol), triethylamine (0.05 ml, 0.4 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (0.04 g, 0.1 mmol) and the reaction shaken for 1 h, after which time the reaction mixture was directly purified by preparative HPLC. This afforded the titled product as a colorless gum MS (ISP)=464.3 (M+H)+.
Reaction SMILES: C([O:3][C:4]([N:6]1[CH2:12][CH2:11][N:10]([O:13][CH3:14])[CH2:9][CH2:8][N:7]1[C:15](=[O:26])[CH2:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[CH3:25])=O)C.CC(C)([O-])C.[K+]>CN(C)C=O>[CH3:14][O:13][N:10]1[CH2:9][CH2:8][N:7]2[C:15](=[O:26])[CH:16]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:4](=[O:3])[N:6]2[CH2:12][CH2:11]1
Reactant: CCOC(=O)N1CCN(OC)CCN1C(=O)Cc1c(C)cc(C)cc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CON1CCN2C(=O)C(c3c(C)cc(C)cc3C)C(=O)N2CC1
Reaction time: 1.5 h
Yield: 12.2 %

Procedure:
To a solution of 5-methoxy-2-[2-(2,4,6-trimethyl-phenyl)-acetyl]-[1,2,5]triazepane-1-carboxylic acid ethyl ester (1.035 g, 2.85 mmol) in absolute dimethylformamide (12 ml) at room temperature in a flame-dried flask under argon was added potassium tert-butoxide (479 mg, 4.27 mmol; weighed under argon atmosphere) in three portions. The reaction mixture was stirred for 1.5 hours, poured on ice, the aqueous layer extracted twice with ethyl acetate and the combined organic layers discarded. The aqueous alkaline phase was acidified with cooling to pH 2-3 by addition of a 1N HCl solution and the product thoroughly extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Yield: 500 mg of 3-methoxy-8-(2,4,6-trimethyl-phenyl)-tetrahydro-pyrazolo[1,2-a][1,2,5]triazepine-7,9-dione (compound P2.1) as a solid with a purity of 91% by LC-MS. This material (120 mg) was triturated in diethyl ether, filtered and dried to afford 110 mg of clean product, mp 229-230° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][N:17](COCC[Si](C)(C)C)[C:11]=3[CH:10]=2)[CH:6]=[N:5]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:27][C:2]([F:1])([F:26])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][NH:17][C:11]=3[CH:10]=2)[CH:6]=[N:5]1
Reactant: C[Si](C)(C)CCOCn1ncc2cnc(-c3cnn(CC(F)(F)F)c3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)Cn1cc(-c2cc3[nH]ncc3cn2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.9 %

Procedure:
A mixture of 6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-pyrazolo[4,3-c]pyridine (800 mg, 2.02 mmol) and TFA (5 mL) in DCM (10 mL) was stirred at ambient temperature for 20 hours. The reaction mixture was concentrated under reduced pressure to afford 6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]-pyridine as a yellow oil (539 mg, 100%). MS (ESI) m/z: 268 [M+H]+.
Reaction SMILES: [Cl:1]/[C:2](/[C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13])=[C:3](\Cl)/[C:4]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5].C([O-])(=O)C.[NH4+:23]>CN(C)C=O>[NH2:23]/[C:3](/[C:4]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5])=[C:2](\[Cl:1])/[C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13]
Reactant: [NH4+]
Reactant: CC(C)COC(=O)/C(Cl)=C(/Cl)C(=O)OCC(C)C
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CC(C)COC(=O)/C(N)=C(/Cl)C(=O)OCC(C)C
Yield: 80.3 %

Procedure:
29.7 g (0.1 mol) of diisobutyl dichloromaleate, 19.27 g (0.25 mol) of ammonium acetate and 40 ml of dimethylformamide were reacted under the same conditions as described in Example 1. A reddish oil was obtained which crystallized on trituration. After the crystal slurry had been washed with hexane, 22.3 g (80%) of diisobutyl aminochloromaleate were obtained as cubic crystals (m.p. 80° C.-81° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]23[CH2:26][CH2:25][CH:24]([O:27][CH2:28][CH2:29][NH2:30])[CH2:23][CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[O:39](S(C(F)(F)F)(=O)=O)[S:40]([C:43]([F:46])([F:45])[F:44])(=O)=[O:41]>C(Cl)Cl.[NH4+].[Cl-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]23[CH2:26][CH2:25][CH:24]([O:27][CH2:28][CH2:29][NH:30][S:40]([C:43]([F:46])([F:45])[F:44])(=[O:41])=[O:39])[CH2:23][CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: NCCOC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=S(=O)(NCCOC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h
Yield: 29.3 %

Procedure:
A solution of 2-[10a-(4-chloro-benzene sulfonyl)-1,4-difluoro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-8-yloxy]-ethylamine (71 mg, 0.168 mmol) in CH2Cl2 (5 mL) at −78° C. was treated with 2,6-lutidine (33 μL, 0.284 mmol), Tf2O (45 μL, 0.948 mmol) and warmed slowly to ambient temperature. After 17 h, the reaction mixture was diluted with saturated aqueous NH4Cl and extracted with CH2Cl2 (2×). The combined organic extracts were washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated in vacuo. The residue was purified by preparative-chromatography over silica gel (eluted in hexanes/EtOAc 1:1) to afford the title compound (29 mg, 30%): 1H NMR (CDCl3 400 MHz) δ 7.61 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H), 7.08 (m, 1H), 6.44 (m, 1H), 5.22 (dd, J=11.7, 2.9 Hz, 1H), 4.12 (d, J=11.7 Hz, 1H), 3.57 (m, 3H), 3.01 (m, 1H), 2.56 (m, 1H), 2.33 (m, 1H), 1.91 (m, 2H), 1.56 (m, 1H), 1.15 (m, 2H).
Reaction SMILES: [C:1]1([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]([CH:29]=1)=[N:25][C:26](=[O:28])[N:27]=2.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(CC(C)C)=O>[C:1]1([N:11]2[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]4[C:24]([CH:29]=3)=[N:25][C:26](=[O:28])[N:27]=4)[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: O=C1N=c2ccc(CCBr)cc2=N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=C1N=c2ccc(CCN3CCN(c4cccc5ccccc45)CC3)cc2=N1
Yield: 14 %

Procedure:
To a 100 ml round-bottomed flask equipped with magnetic stirrer, condenser, and N2 inlet were added 2.64 g (12.4 mmol) of N-(1-naphthyl)-piperazine, 3.0 g (12.4 mmol) of 6-(2-bromoethyl)-benzimidazolone, 1.31 g (12.4 mmol) sodium carbonate, 50 ml methylisobutylketone, and a catalytic amount of sodium iodide. The reaction was refluxed for 3 days, cooled, and evaporated to a brown gum. The gum was partitioned between 50 ml water and 75 ml ethyl acetate, and the ethyl acetate layer washed with brine, dried over sodium sulfate, and evaporated, then chromatographed on silica gel. Fractions containing the product were combined and evaporated, the residue taken up in tetrahydrofuran, treated with HCl gas, and the resulting hydrochloride salt of the product filtered off to give a white solid, m.p. 260°-262° C., 716 mg (14% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N:10]=[C:11]=S.[NH:13]([C:15](=[O:38])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH:31]([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)=[O:17])[NH2:14].CCN=C=NCCCN(C)C.O>CC(N(C)C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11]1[O:38][C:15]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C@H:25]3[CH2:30][CH2:29][C@H:28]([CH:31]([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)=[O:17])=[N:13][N:14]=1
Reactant: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Reactant: Fc1cc(F)c(N=C=S)cc1F
Agent: CCN=C=NCCCN(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,4,5-Trifluorophenyl isothiocyanate (252 mg, 1.33 mmol) was added in one portion to a suspension of trans-ethyl 2-[4-(4-{[hydrazino(oxo)acetyl]amino}phenyl)cyclo-hexyl]propanoate (Intermediate 99, 400 mg, 1.11 mmol) in DMA (6 mL) and the reaction mixture was stirred at room temperature for 2 h. EDCI (319 mg, 1.66 mmol) was added in one portion and the reaction mixture was heated to 90° C. for 10 mins in the microwave. The mixture was then cooled to room temperature and H2O (20 mL) was added. The mixture was filtered to leave a solid, which was washed with H2O (10 mL) to give the title compound (550 mg, 95%) as a solid; 1H NMR δ 1.1 (3H, d), 1.12-1.28 (2H, m), 1.2 (3H, t), 1.35-1.51 (2H, m), 1.52-1.64 (1H, m), 1.65-1.75 (1H, m), 1.77-1.9 (3H, m), 2.22-2.32 (1H, m), 2.38-2.51 (1H, m), 4.01-4.16 (2H, m), 7.2 (2H, d), 7.65-7.78 (1H, m), 7.69 (2H, d), 8.1-8.25 (1H, m), 10.95 (1H, s), 11.05 (1H, s); MS m/e MH+ 517.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=Cc1cccc(Br)c1
Reactant: C#CCCCCCCCCC
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCC#Cc1cccc(C=O)c1
Temperature: 55 °C
Reaction time: 4 h
Yield: 13.2 %

Procedure:
A mixture of 3-bromobenzaldehyde (51.8 g), 1-undecyne (48.6 g), bis(triphenylphosphine)palladium(II)chloride (3.37 g), copper iodide (457 mg), and triethylamine (196 ml) in dry tetrahydrofuran (300 ml) was stirred for 4 hrs at 55° C. The reaction mixture was filtered, the filtrate was diluted with ethyl acetate, and the solution was washed with water and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed on 300 g of silica gel (1:4-ethyl acetate:hexane). The appropriate fractions were collected and evaporated. Distillation of a 40-g sample of the residue (81.3 g) gave 9.5 g (13%) of the product, bp 172°-174° C. (0.5 mm mercury).
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH3:4].[CH2:6]([C:13]#[N:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[O-].[Na+]>>[CH3:1][C:2]([CH2:3][CH3:4])=[C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:13]#[N:14]
Reactant: N#CCc1ccccc1
Reactant: CCC(C)=O
Agent: C[O-]
Agent: [Na+]
Product: CCC(C)=C(C#N)c1ccccc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 22.2 %

Procedure:
Butanone (45.0 g, 0.63 mol) is added to the mixture of benzyl cyanide (58.5 g, 0.50 mol) and sodium methoxide (30% in MeOH, 34.3 ml, 0.185 mol) and the resulting suspension is heated to 60° C. (oilbath) and stirred for 6 h at this temperature. The product is extracted with cyclohexane, washed with dilute NaHCO3-solution and brine. The organic layer is dried over MgSO4, the solvent removed under reduced pressure and the residue distilled over a short-path apparatus at 0.05 mbar. The fraction distilling at 90° C. is collected (45 g) and subjected to a fine distillation over a Widmer-column to yield olfactorily pure 3-methyl-2-phenyl-pent-2-ene nitrile (19 g, 22%) as a colourless oil (b.p. 102° C./0.05 mbar). (E/Z) ratio about 55:45.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:9]2[CH2:10][CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][C:8]2=[N:7][N:6]=1)([CH3:4])[CH3:3].[ClH:21].C(OCC)C.O1CCOCC1>C(Cl)Cl>[ClH:21].[ClH:21].[N:7]1[N:6]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[N:9]2[CH2:10][CH2:11][NH:12][CH2:13][C:8]=12
Reactant: CC(C)(C)OC(=O)N1CCn2c(nnc2C(C)(C)O)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)(O)c1nnc2n1CCNC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 103 %

Procedure:
To a solution of tert-butyl 3-(2-hydroxypropan-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (0.40 g, 1.417 mmol) in DCM (10 mL) at 0° C., was added 2 M HCl in diethyl ether (3.54 mL, 7.08 mmol) dropwise. The reaction was stirred overnight at RT. After 16 hours, the white precipitate was collected by vacuum filtration, washed with ether, and dried in vacuo. The residue was resuspended in 1,4-dioxane (10 mL) and 4 M HCl in dioxane (1.78 mL, 7.08 mmol) was added. The mixture was heated to 60° C. and stirred vigorously overnight. After 16 hours, the suspension was concentrated to a white powder and dried in vacuo to generate 2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)propan-2-ol dihydrochloride (0.373 g, 103% yield).
Reaction SMILES: [OH:1][CH:2]([CH2:5][OH:6])[CH2:3][NH2:4].[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]>>[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([NH:4][CH2:3][CH:2]([OH:1])[CH2:5][OH:6])[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: NCC(O)CO
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCC(O)CO)n4)cc3)cc12

Procedure:
Using 2,3-dihydroxy-propylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 457 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26].[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH3:34][O:33][C:29]1[CH:28]=[C:24]([CH:23]=[C:22]([O:21][CH3:20])[C:30]=1[O:31][CH3:32])[C:25]([C:10]1[C:11]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:12]=2[S:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:26]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Yield: 125.4 %

Procedure:
2-(4'-methoxyphenyl)-6-methoxybenzo[b]thiophene 5 was prepared according to the procedure of Kost et al. To a well-stirred solution of 5 (0.500 g, 1.85 mmol) and 3,4,5-trimethoxybenzoyl chloride (0.640 g, 2.77 mmol) in CH2Cl2 (20 ml), was added AlCl3 (0.123 g, 0.925 mmol) portion-wise over a 15 minute period. After 5 hours (total reaction time), water was added, and the product was isolated initially by extraction with CH2Cl2 and subsequently by extraction with ethyl acetate (EtOAc). The organic layers were separately washed with brine and then combined and dried over MgSO4. Purification by flash chromatography (silica gel, 60:40 EtOAc/hexane) afforded 3-(3',4',5'-trimethoxybenzoyl)-2-(4'-methoxyphenyl)-6-methoxybenzo [b]thiophene (0.537 g, 1.16 mmol, 63%) as an off-white solid. Recrystallization (hexane/ethanol) afforded a highly pure crystalline sample of the compound with mp 131°-133° C. 1H-NMR (CDCl3, 360 Mhz): δ=7.66 (d,J=8.9 Hz, 1H, ArH)7.32 (d,J=2.4 Hz, 1H, ArH), 7.31 (d,J=8.8 Hz, 2H, ArH), 7.07 (s,2H, ArH), 7.01 (dd,J=8.9,2.4 Hz, 1H, ArH), 6.75 (D,J=8.8 Hz, 2H, ArH), 3.89 (s,3H, --OCH3), 3.83 (s,3H, --OCH3), 3.74 (s,3H, --OCH3), 3.73 (s, 6H, --OCH3); 13C-NMR (CDCl3, 90 Mhz): δ=192.9, 159.9, 157.7, 152.7, 143.7, 142.6, 140.1, 133.9, 132.3, 130.3, 129.9, 126.1, 124.2, 114.9, 114.1, 107.5, 104.4, 60.8, 56.1, 55.6, 55.2 HRMS (EI) M+ calcd for C26H24O6S 464.1294. and Anal. Calcd for C 26H24O6S: C, 67.23; H, 5.21; S, 6.90. Found: C, 67.20; H, 5.26; S, 6.88.
Reaction SMILES: [S:1]1[C:5]2[C:6]([CH:10]=O)=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].Cl>N1C=CC=CC=1>[S:1]1[C:5]2[C:6]([CH:10]=[CH:13][C:14]([OH:16])=[O:15])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=Cc1cccc2nnsc12
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cccc2nnsc12
Temperature: 0 °C
Yield: 447.6 %

Procedure:
A mixture of 1.96 g of benzo-1,2,3-thiadiazole-7-carbaldehyde, 1.24 g of malonic acid and 6 ml of pyridine are heated for 26 hours at 120° C., with 2 further additions of 0.6 g portions of malonic acid after 4 and 7 hours. The mixture is then cooled, poured into ice-water and acidified with concentrated hydrochloric acid. The precipitate which has formed is filtered off and dissolved in dilute sodium hydroxide solution, the mixture is washed three times with methylene chloride, and the aqueous phase is subsequently acidified once more, using hydrochloric acid. The precipitate obtained is filtered off, washed with water and dried in vacuo, resulting in 11 g of the title compound of m.p. 199°-202° C.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:4]=2[CH2:3]1.[CH2:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:20]#[CH:21]>>[CH3:18][C:15]1[CH:16]=[CH:17][C:4]2[CH2:3][CH:2]([N:25]3[CH2:26][CH2:27][N:22]([CH2:19][C:20]#[CH:21])[CH2:23][CH2:24]3)[C:8]3[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[S:6][C:5]=2[CH:14]=1
Reactant: Cc1ccc2c(c1)Sc1ccc(F)cc1C(Cl)C2
Reactant: C#CCN1CCNCC1
Product: C#CCN1CCN(C2Cc3ccc(C)cc3Sc3ccc(F)cc32)CC1

Procedure:
In a manner analogous to that described in Example 1, from 10-chloro-10,11-dihydro-3-methyl-8-fluoro-dibenzo[b,f]thiepin and N-(2-propynyl)-piperazine there is obtained 1-[10,11-dihydro-3-methyl-8-fluoro-dibenzo[b,f]thiepin-10-yl]-4-(2-propynyl)-piperazine, the dimethanesulfonate of which melts at 168°-174° C.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:34]([NH:36][CH2:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:35])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:34]([NH:36][CH2:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:35])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C(=O)NCC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(C(=O)NCC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'[(2-n-butyl-6-cyclohexylmethylaminocarbonyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28]([C:29]5[CH:30]=[N:31][C:32]([NH2:39])=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=5)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:40][CH3:41])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:42].O1CCOCC1>C(Cl)Cl>[CH3:41][O:40][C:16]1[CH:17]=[C:18]([C:21]2[S:25][C:24]3=[N:26][CH:27]=[C:28]([C:29]4[CH:34]=[C:33]([C:35]([F:37])([F:36])[F:38])[C:32]([NH2:39])=[N:31][CH:30]=4)[N:23]3[N:22]=2)[CH:19]=[CH:20][C:15]=1[O:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1.[ClH:42]
Reactant: COc1cc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)cnc3s2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)cnc3s2)ccc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{4-[5-(6-Amino-5-trifluoromethyl-pyridin-3-yl) -imidazo[2,1-b][1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester (23 mg; 0.039 mmol; 1 eq) was suspended in anhydrous DCM (3 ml) and 4M HCl in 1,4-dioxane (0.097 ml, 0.39 mmol, 10 eq) was added. The reaction mixture was stirred at RT overnight. The solvents were removed and the residue was co-evaporated with DCM (×3). The residue was triturated in CH3CN and filtered to give the desired product as HCl salt (19 mg, 92%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=3.25 min, [M+H]+ m/z 491.2; 1H NMR (300 MHz, DMSO) δ 9.10 (s, 2H), 8.88 (s, 1H), 8.49 (d, J=1.6 Hz, 1H), 7.87 (s, 1H), 7.53 (m, 2H), 7.31 (d, J=9.1 Hz, 1H), 4.76 (s, 1H), 3.91 (s, 3H), 3.17 (m, 2H), 3.09 (m, 2H), 2.12 (m, 2H), 1.90 (m, 2H).
Reaction SMILES: Cl[CH2:2][C@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:2][C@H:3]2[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4]2)=[CH:13][C:12]=1[C:18]([F:19])([F:20])[F:21]
Reactant: CC1(C)OC[C@H](CCl)O1
Reactant: Oc1ccc(Br)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COc2ccc(Br)c(C(F)(F)F)c2)O1
Temperature: 60 °C
Reaction time: 6 h
Yield: 56.3 %

Procedure:
(S)-4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane (63; 3.3 g, 20.5 mmol) was added to a mixture containing 4-bromo-3-(trifluoromethyl)phenol (126; 5 g, 20 mmol) and K2CO3 (8.30 g, 60 mmol) in 20 mL of DMF. The resulting reaction mixture was stirred at 60° C. for 6 h. Upon cooling to room temperature, the mixture was poured into water and extracted by EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ether:EtOAc=50:1) to afford (S)-4-((4-bromo-3-(trifluoromethyl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxolane (4 g, 56%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[N:5]=[C:4]([C:11]([OH:13])=O)[CH:3]=1.NC1C(C#N)=C(OCC)N=C(C(O)=O)C=1.[C:29]1([C:35]2[CH:39]=[C:38]([CH2:40][N:41]3[CH2:46][CH2:45][CH:44]([CH2:47][NH2:48])[CH2:43][CH2:42]3)[O:37][N:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[N:5]=[C:4]([C:11]([NH:48][CH2:47][CH:44]2[CH2:43][CH2:42][N:41]([CH2:40][C:38]3[O:37][N:36]=[C:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:39]=3)[CH2:46][CH2:45]2)=[O:13])[CH:3]=1
Reactant: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Reactant: CCOc1cc(N)cc(C(=O)O)n1
Agent: CCOc1nc(C(=O)O)cc(N)c1C#N
Product: CCOc1cc(N)cc(C(=O)NCC2CCN(Cc3cc(-c4ccccc4)no3)CC2)n1

Procedure:
According to the same procedure described in example 225, using 4-amino-6-ethoxypicolinic acid (prepared according to the reported preparation in J. Med. Chem. 2006, 49(15), 4455-4458), instead of 4-amino-5-cyano-6-ethoxypicolinic acid, and the compound prepared in Example 9 instead of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, the title compound having the following physical data was obtained.