Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@:4]1([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[CH3:11])[C:6](=O)[CH2:5]1)[CH:2]=[CH2:3].Br[C:36]1[CH:37]=[CH:38][C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1.C([O-])([O-])=[O:45].[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O>[CH2:1]([C@:4]1([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:13]=[CH:14][C:15]([C:36]3[CH:37]=[CH:38][C:39](=[O:43])[N:40]([CH3:42])[CH:41]=3)=[CH:16][CH:17]=2)[CH3:11])[C:6](=[O:45])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)C1
Reactant: Cn1cc(Br)ccc1=O
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(=O)n(C)c3)cc2)C(=O)C1
Yield: 39 %

Procedure:
A mixture of (S)-4-allyl-4-(4-fluorophenyl)-1-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)piperidin-2-one (120 mg, 0.260 mmol), 5-bromo-1-methylpyridin-2(1H)-one (80 mg, 0.31 mmol), PdCl2(Ph3P)2 (12 mg) □ Cs2CO3 (0.4 mL, 0.8 mmol□ in 1,4-dioxane (3 mL) was heated to reflux for 2 h. The mixture was diluted with EtOAc, and washed with water. The organic phase was separated, and concentrated to give the product, which was purified by TLC to afford 5-(4-((S)-1-((S)-4-allyl-4-(4-fluorophenyl)-2-oxopiperidin-1-yl)ethyl)phenyl)-1-methylpyridin-2(1H)-one (45 mg, 39%). 1H NMR (CDCl3): δ 1.42 (t, 3H), 1.91 (m, 1H), 2.03 (m, 1H), 2.24 (m, 2H), 2.39 (m, 1H), 2.49 (d, 1H), 2.96 (m, 2H), 3.49 (s, 3H), 4.92 (m, 2H), 5.38 (m, 1H), 5.99 (m, 1H), 6.11 (m, 1H) □ 6.52 (m, 1H) □ 6.62 (m, 1H), 6.89 (m, 4H), 7.11 (m, 3H), 7.23 (m, 2H), 7.32 (m, 1H), 7.49 (m, 1H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>>[O:13]1[CH2:14][CH2:15][N:10]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:11][CH2:12]1
Reactant: C1COCCN1
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1ccccc1N1CCOCC1
Temperature: 125 °C
Yield: 63 %

Procedure:
A mixture of 2-fluorobenzaldehyde (0.5 mL, 4.8 mmol), morpholine (0.6 mL, 1.5 eq) and potassium carbonate (1.3 g, 2 eq) was heated in the microwave at 125° C. for 2.5 h. After evaporation, the residue was partitioned between water and DCM, the aqueous phase extracted with DCM. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford 2-morpholinobenzaldehyde (0.57 g, 63%).
Reaction SMILES: [Na].[OH:2][C:3]1[C:8]([CH2:9][CH2:10][CH3:11])=[C:7]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[NH:24][N:23]=[N:22][N:21]=3)=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]=1[C:25](=[O:27])[CH3:26].[Br:28][CH2:29][CH2:30][CH2:31]Br.CCC(C)=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[C:25]([C:4]1[CH:5]=[CH:6][C:7]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[N:22][N:23]([CH2:31][CH2:30][CH2:29][Br:28])[N:24]=3)=[CH:16][CH:15]=2)=[C:8]([CH2:9][CH2:10][CH3:11])[C:3]=1[OH:2])(=[O:27])[CH3:26]
Reactant: CCCc1c(COc2ccc(-c3nnn[nH]3)cc2)ccc(C(C)=O)c1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(COc2ccc(-c3nnn(CCCBr)n3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
1-[2-Hydroxy-3-propyl-4-((4-(1H-tetrazol-5-yl)phenoxy)methyl)phenyl]ethanone sodium salt (5 g, 0.013 mol), 1,3-dibromopropane (3.5 g, 0.18 mol), and MEK (50 ml) were combined potassium carbonate (4.15 g, 0.025 mol) potassium was added and the reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. The volume of the concentrate was doubled by the addition of water and the resultant solution was extracted with ethyl acetate (3×). The ethylacetate layers were combined, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed by HPLC (preparatory-scale, silica gel column, eluted with a mixture of 9:1 toluene:ethyl acetate) to yield 5.0 g, 82% yield of the title product: n.m.r. (300 MHz CDCl3) δ: 1.0 (t, 3H); 1.6 (m, 2H); 2.6 (s and t, 5H); 2.7 (t, 2H); 3.5 (t, 2 H); 4.8 (t, 2H); 5.15 (s, 2H); 7.1 (d, 2H); d, 1H); 7.6 (d, 1H); 8.1 (d, 2H); 12.7 (s, 1H).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.C(O)(=O)C.[Br:13][C:14]1[C:20]([CH3:21])=[CH:19][C:17]([NH2:18])=[C:16]([O:22][CH3:23])[C:15]=1[F:24]>[Cl-].[Na+].O>[Br:13][C:14]1[C:20]([CH3:21])=[C:19]([I:1])[C:17]([NH2:18])=[C:16]([O:22][CH3:23])[C:15]=1[F:24]
Reactant: COc1c(N)cc(C)c(Br)c1F
Reactant: O=C1CCC(=O)N1I
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1c(N)c(I)c(C)c(Br)c1F
Temperature: 25 °C
Reaction time: 67 h

Procedure:
N-iodosuccinimide (1.91 g, 8.5 mmol) was added to an acetic acid (40 ml) solution of 4-bromo-3-fluoro-2-methoxy-5-methylaniline (I-43) (1.90 g, 8.1 mmol), followed by stirring at room temperature for 67 hours. Saturated brine was added to the reaction liquid, followed by extraction twice with ethyl acetate, the organic layer was washed three times with saturated brine, dried over anhydrous magnesium sulfate.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[N:4]=1.Cl.[C:18]([Cl:26])(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[ClH:26].[CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]1[N:4]=[C:5]([NH:9][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CN1CCC(N(C)c2cccc(N)n2)CC1
Agent: Cl
Solvent: c1ccncc1
Product: CN1CCC(N(C)c2cccc(NC(=O)c3ccncc3)n2)CC1
Yield: 86 %

Procedure:
Prepare according to procedure in Example 69 starting with N-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34) (175 mg, 0.794 mmol), isonicotinoyl chloride hydrochloride (212 mg, 1.19 mmol), and pyridine (15 mL) to yield 247 mg (86%) of the title compound: mass spectrum (ion spray): m/z=326.1 (M+1); Analysis Calcd for C18H24N5OCl.0.5H2O: C, 58.29; H, 6.79; N, 18.88. Found: C, 58.49; H, 6.79; N, 19.22. mp 274–7° C.
Reaction SMILES: ClC1[C:3]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:4]=2[S:5][C:6]=1[C:7]#[N:8].[CH3:14][NH:15][NH2:16].[CH3:17]S(C)=O>>[Cl:13][C:9]1[C:4]2[S:5][C:6]3[C:7]([NH2:8])=[N:16][N:15]([CH3:17])[C:14]=3[C:3]=2[CH:12]=[CH:11][CH:10]=1
Reactant: N#Cc1sc2c(Cl)cccc2c1Cl
Reactant: CS(C)=O
Reactant: CNN
Product: Cn1nc(N)c2sc3c(Cl)cccc3c21

Procedure:
By substituting this amide for the amide employed in Example 1, the corresponding 3,7-dichlorobenzo[b]thiophene-2-carbonitrile, m.p. 124°-128° C., was obtained. Treatment of this nitrile was methylhydrazine in dimethyl sulfoxide gave 5-chloro-1-methyl-1H-(1)-benzothieno[3,2-c]pyrazol-3-amine, m.p. 239°-241° C. Reaction of this amine with isobutyryl chloride followed by work up as described in Example 1 gave 2-methyl-N-(5-chloro-1-methyl-1H-(1)benzothieno[3,2-c]pyrazol-3-yl)-propanamide, m.p. 218°-219° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=2)[NH:3]1.[O:15]=[C:16]1[C:21]2=[CH:22][NH:23][C:24]([CH:25]=O)=[C:20]2[CH2:19][CH2:18][NH:17]1.N1CCCCC1>C(O)C>[O:1]=[C:2]1[C:10](=[CH:25][C:24]2[NH:23][CH:22]=[C:21]3[C:20]=2[CH2:19][CH2:18][NH:17][C:16]3=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]([NH2:14])(=[O:12])=[O:13])[CH:8]=2)[NH:3]1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: NS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCNC3=O)C(=O)N2
Temperature: 80 °C
Yield: 82.8 %

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid amide (63 mg, 0.3 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (50 mg, 0.3 mmol) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give 89 mg (82%) of the title compound.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[C:9]#[N:10].[CH2:18]([OH:23])[C:19]([CH3:22])([CH3:21])[CH3:20].[H-].[Na+]>O>[N+:15]([C:12]1[CH:13]=[CH:14][C:7]([O:23][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:8]([CH:11]=1)[C:9]#[N:10])([O-:17])=[O:16]
Reactant: CC(C)(C)CO
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)COc1ccc([N+](=O)[O-])cc1C#N
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To dimethylformamide solution (364 ml) containing 2-chloro-5-nitrobenzonitrile (91 g) and neopentyl alcohol (52 g) was added sodium hydride (60% content, 27.8 g) under ice-cooling and the mixture was stirred for 1 h. The reaction mixture was poured into water and extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give 5-nitro-2-neopentyloxybenzonitrile (105 g), melting point: 90–91° C.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][N:13]([C:16]2[N:17]=[C:18]([C:26]3[C:27](=[O:56])[N:28]([CH2:42][O:43][P:44]([O:51]C(C)(C)C)([O:46]C(C)(C)C)=[O:45])[C:29](=[O:41])[C:30]=3[C:31]3[C:39]4[C:34](=[C:35]([CH3:40])[CH:36]=[CH:37][CH:38]=4)[NH:33][CH:32]=3)[C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][C:9]21[CH2:11][CH2:10]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCCl.CO>[CH2:10]1[C:9]2([CH2:12][N:13]([C:16]3[N:17]=[C:18]([C:26]4[C:27](=[O:56])[N:28]([CH2:42][O:43][P:44](=[O:45])([OH:51])[OH:46])[C:29](=[O:41])[C:30]=4[C:31]4[C:39]5[C:34](=[C:35]([CH3:40])[CH:36]=[CH:37][CH:38]=5)[NH:33][CH:32]=4)[C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:14][CH2:15][NH:8]2)[CH2:11]1
Reactant: Cc1cccc2c(C3=C(c4nc(N5CCN(C(=O)OC(C)(C)C)C6(CC6)C5)cc5ccccc45)C(=O)N(COP(=O)(OC(C)(C)C)OC(C)(C)C)C3=O)c[nH]c12
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1cccc2c(C3=C(c4nc(N5CCNC6(CC6)C5)cc5ccccc45)C(=O)N(COP(=O)(O)O)C3=O)c[nH]c12
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
To a solution of 7-{1-[1-(di-tert-butoxy-phosphoryloxymethyl)-4-(7-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-isoquinolin-3-yl}-4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester (1.90 g, 2.42 mmol) in 1,2-dichloroethane (50 mL) was added TFA (8.27 g, 72.5 mmol) under argon at 0° C. The reaction mixture was stirred for 3.5 h under argon at 0° C. until UPLC-MS indicated that full conversion of the starting material had occurred. The reaction mixture was diluted with 1,2-dichloroethane (50 mL) and concentrated at reduced pressure to afford the crude product as a red solid. The crude reaction product was dissolved in MeOH and slowly concentrated at reduced pressure until crystallization started to occur. Pentane was added and the solids were filtered off and washed with Et2O. Further purification was achieved by suspending the crude product in DMSO, followed by sonication for 30 min. The solids were filtered off, washed with Et2O and dried at high vacuum (<1 mm Hg) to afford the title compound as a dark red solid. 1H-NMR (400 MHz, DMSO-d6): 12.10 (s, 1H), 8.08 (d, 1H), 7.65-7.61 (m, 2H), 7.44 (t, 1H), 7.20 (s, 1H), 7.06 (t, 1H), 6.74 (d, 1H), 6.43 (t, 1H), 6.00 (d, 1H), 5.29 (d, 2H), 3.87-3.01 (m, 6H), 2.37 (s, 3H), 0.97-0.62 (m, 4H). 31P-NMR (162 MHz, DMSO-d6): −6.0. LCMS: [M+1]+=574.0, Rt(1)=1.77 min., Rt(2)=0.71 min.
Reaction SMILES: [CH2:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1)CC=C.[CH:16]([OH:19])([CH3:18])[CH3:17].CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:41]C)C=C4)N(CC2)C1>O>[C:10]1([C:7]2[CH:6]=[C:5]([CH2:1][CH2:17][C@H:16]([OH:19])[CH2:18][OH:41])[NH:9][N:8]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C=CCCc1cc(-c2ccccc2)n[nH]1
Reactant: CC(C)O
Solvent: O
Product: OC[C@@H](O)CCc1cc(-c2ccccc2)n[nH]1
Reaction time: 48 h

Procedure:
To a solution of 5-(but-3-enyl)-3-phenyl-1H-pyrazole (1 g, 5.04 mmol) in H2O (25 mL), and isopropanol (25 mL) was added AD-mix-β (5 g, 5.04 mmol) at room temperature. The reaction was stirred for 48 h, quenched with Na2SO3 and extracted with ethyl acetate. The organic extract was dried over MgSO4 and concentrated under reduced pressure to give the title compound (1.02 g) without further purification. LCMS m/z=232.9 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[CH:8]=O>ClCCl>[CH2:12]([O:11][C:7](=[O:10])[CH:8]=[N:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])[CH3:13]
Reactant: CCOC(=O)C=O
Reactant: CC(C)(N)CO
Solvent: ClCCl
Product: CCOC(=O)C=NC(C)(C)CO
Reaction time: 16 h
Yield: 98.1 %

Procedure:
2-Amino-2-methyl-1-propanol (9.54 ml, 0.10 mol) was added to a stirred solution of ethyl glyoxylate (50% soln. in toluene, 21 ml, 0.10 mol) in dichloromethane (100 ml) in the presence of 4Å molecular sieves. The reaction was stirred under nitrogen for 16 h whereupon the system was filtered through Dicalite® and washed with more dichloromethane. Evaporation of the solvent in vacuo gave (1,1-dimethyl-2-hydroxy-ethylimino)-acetic acid ethyl ester (17.0 g) as an oil (EIMS: m/z=174 [M+H]+). 2-Fluorobenzoyl chloride (0.60 ml, 5.00 mmol) and then pyridine (0.96 ml, 12.0 mmol) were added to a stirred solution of the above described ethyl ester (0.87 g, 5.00 mmol) in dichloromethane (8 ml) cooled to ˜5° C. and under nitrogen. After 1.5 h water (20 ml) was added, the layers separated and the aqueous phase washed with more dichloromethane (30 ml). The combined organic phase was then washed with 1N hydrochloric acid (25 ml) before being dried (MgSO4), filtered and solvent removed in vacuo. The crude residue was purified by chromatography on silica using dichloromethane as eluant, to give 3-(2-fluorobenzoyl)4,4-dimethyl-oxazolidine-2-carboxylic acid ethyl ester (0.64 g) as an oil, EIMS: m/z=296 [M+H]+
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][S:27][CH3:28])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.FC(F)(F)C(O)=[O:42]>>[CH:10]1[CH:11]=[C:12]2[C:4]([CH2:3][CH:2]([NH2:1])[C:13]([OH:14])=[O:42])=[CH:5][NH:6][C:7]2=[CH:8][CH:9]=1.[NH2:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][S:27][CH3:28])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(N)=O
Reactant: O=C(O)C(F)(F)F
Product: CSCC[C@H](NC(=O)[C@@H](N)CC(C)C)C(N)=O
Product: NC(Cc1c[nH]c2ccccc12)C(=O)O
Yield: 81 %

Procedure:
Condensation of BocTrpOPFP (1.41 g.) and HLeu-Met-NH2 hydrochloride salt (Example 1, 0.89 g.) by the activated ester method gave BocTrp-Leu-MetNH2 in 81% yield. De-t-butoxycarbonylation of BocTrp-Leu-MetNH2 (1.06 g.) using trifluoroacetic acid containing 10% water gave Htrp-Leu-MetNH2 in 81% yield.
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:4]=2[S:5][CH:6]=1.[C:12](C(O[Na])=O)([F:15])([F:14])[F:13].CN1CCCC1=O>[Cu]I.O>[CH3:11][C:7]1[C:4]2[S:5][CH:6]=[C:2]([C:12]([F:15])([F:14])[F:13])[C:3]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O[Na])C(F)(F)F
Reactant: Cc1cccc2c(Br)csc12
Agent: [Cu]I
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cccc2c(C(F)(F)F)csc12
Reaction time: 1 h

Procedure:
A mixture of 2 g of 3-bromo-7-methylbenzo[b]thiophene, 4.8 g of CF3COONa, 3 g CuI and 20 ml of 1-methylpyrrolidone are vigorously stirred and heated at 160°. After a short while evolution of gas commences. Stirring is continued for one hour at 160° and a further hour at 180°. After cooling the reaction mixture is poured into water, extracted with ether/hexane (1/1) and the organic phase washed, dried and concentrated under vacuum. The raw product is chromatographed over silica gel (eluant: n-hexane) and the title compound obtained as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[CH3:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9])=[O:18]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCCCCC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (5.77 g, 40.0 mmol) and 4-dimethylaminopyridine (5.86 g, 44.0 mmol) in 100 ml of CH2Cl2 was added dropwise the solution of crude 5-methoxyvaleric chloride (6.00 g, 39.9 mmol) in 10 ml of CH2Cl2 at 0° C. The mixture was stirred at 0° C. for 1 hr then at room temperature for an additional 1 hr. The solution was washed with 1N aqueous HCl (100 ml) and brine (250 ml). After dried over Na2SO4 and evaporation of solvent, 5-(5-methoxypentanoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione was obtained as a light pink oil (9.20 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([C:29]([F:32])([F:31])[F:30])=[N:27][N:28]=2)[N:25]=1>>[Cl:1][C:2]1[C:3]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([C:20]3[CH:21]=[CH:22][C:23]4[N:24]([C:26]([C:29]([F:30])([F:32])[F:31])=[N:27][N:28]=4)[N:25]=3)[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: FC(F)(F)c1cnc(N2CCCNCC2)c(Cl)c1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: FC(F)(F)c1cnc(N2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c(Cl)c1

Procedure:
A mixture of 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-1,4-diazepane and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8](=[O:10])[CH3:9])=[CH:3][CH:2]=1.[N+:11]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O)([O-:13])=[O:12].C([O-])(=O)C.[NH2+]1CCCCC1>C1C=CC=CC=1>[N+:11]([C:14]1[CH:15]=[C:16]([CH:17]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[C:8](=[O:10])[CH3:9])[CH:19]=[CH:20][CH:21]=1)([O-:13])=[O:12]
Reactant: CC(=O)Cc1ccncc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)c1ccncc1

Procedure:
4.62 g (34 mmole) of 1-(4-pyridyl)-2-propanone and 5.14 g (34 mmol) of 3-nitrobenzaldehyde were dissolved in benzene. To this solution, 0.49 g (3.4 mmol) of piperidinium acetate was added, and the mixture was refluxed with application of heat for 6 hours for dehydration. The reaction mixture was washed with water, and dried over anhydrous sodium sulfate. The benzene contained in the reaction mixture was distilled off under reduced pressure and the remaining reaction product was chromatographed on a silica gel column, whereby the captioned compound was obtained. The yield was 7.695 g (87.3%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S:7]([OH:9])=[O:8])=[CH:3][CH:2]=1.[Li].[S:12]([CH2:16][CH2:17][NH:18][C:19](=[O:22])[CH2:20]Br)([OH:15])(=[O:14])=[O:13].O>C(O)C>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([S:7]([CH2:20][C:19]([NH:18][CH2:17][CH2:16][S:12]([OH:15])(=[O:14])=[O:13])=[O:22])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(CBr)NCCS(=O)(=O)O
Reactant: Cc1ccc(S(=O)O)cc1
Agent: [Li]
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)CC(=O)NCCS(=O)(=O)O)cc1
Reaction time: 4 h
Yield: 89 %

Procedure:
To a 5-liter flask equipped with a mechanical stirrer and reflux condenser was added p-toluenesulfinic acid, lithium salt (309 g), N-(2-sulfoethyl)-2-bromoacetamide, lithium salt (527 g), water (180 ml), and ethyl alcohol (3380 ml). The resulting suspension was heated to reflux. After about an hour of reflux, nearly all of the reactants had dissolved. Reflux was continued another four hours, and the solution was filtered hot through a Celite pad to remove some haziness. The solution was cooled overnight to room temperature. The solid that formed was collected and washed with 1 liter of 95% ethyl alcohol/water. The white solid was air dried and then dried at high vacuum, providing 554 g (89% yield) of 2-(4-methylphenyl)sulfonyl-N-(2-sulfoethyl)acetamide, lithium salt (Intermediate 1). HPLC analysis showed no detectable impurities. Ion chromatography indicated 0.035 weight % bromide and 1.8 weight % lithium. The material exhibited an acceptable proton spectrum.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[ClH:12].[N:13]1([CH2:18][CH2:19][CH2:20][C:21](=[S:23])[NH2:22])[CH:17]=[CH:16][N:15]=[CH:14]1>>[ClH:12].[ClH:12].[N:13]1([CH2:18][CH2:19][CH2:20][C:21]2[S:23][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:22]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: O=C1c2ccccc2CC1Br
Reactant: NC(=S)CCCn1ccnc1
Agent: Cl
Product: c1ccc2c(c1)Cc1sc(CCCn3ccnc3)nc1-2

Procedure:
Starting compounds: 2-bromo-1-indanone, 4-(1-imidazolyl)butanethioamide hydrochloride
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:18]=[C:17]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])[C:16]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)=[CH:15][C:11]=2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[N:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][N:43]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:18]=[C:17]([C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[O:20])[C:16]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)=[CH:15][C:11]=2[C:12]([NH:48][C:45]2[CH:46]=[CH:47][N:42]=[N:43][CH:44]=2)=[O:14])=[CH:4][CH:3]=1
Reactant: Cn1cc(-c2cc(C(=O)O)c(OCc3ccc(F)cc3)cc2C(=O)N2CCOCC2)cn1
Reactant: Nc1ccnnc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cc(C(=O)Nc3ccnnc3)c(OCc3ccc(F)cc3)cc2C(=O)N2CCOCC2)cn1
Reaction time: 2 h

Procedure:
To a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-morpholinylcarbonyl)benzoic acid (may be prepared as described in Description 29; 95 mg, 0.22 mmol) in N,N-dimethylformamide (3 ml) was added diisopropylethylamine (0.08 ml, 0.43 mmol), 4-pyridazinamine (24.67 mg, 0.26 mmol), 1-hydroxy-7-azabenzotriazole (35.3 mg, 0.26 mmol) and EDC (62.2 mg, 0.32 mmol). The mixture was stirred for 2 hours, the solvent removed in vacuo and the residue was purified by MDAP to yield the title compound as a white solid. 50 mg.
Reaction SMILES: C1COCC1.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]#[CH:19])[C:10](Cl)=[O:11].[CH:20]1([CH2:26][NH2:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(CC)CC)C>C(OCC)(=O)C>[CH:20]1([CH2:26][NH:27][C:10](=[O:11])[C:9]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]#[CH:19])=[C:7]([F:6])[CH:8]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NCC1CCCCC1
Reactant: C#CCOc1ccc(C(=O)Cl)cc1F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C#CCOc1ccc(C(=O)NCC2CCCCC2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To a mixture of 10 ml of THF and 0.40 g of 3-fluoro-4-(2-propynyloxy)benzoyl chloride were added 0.45 g of cyclohexylmethylamine and 0.50 g of triethylamine in order at room temperature. The mixture obtained was stirred at room temperature for 1 hour. Then, ethyl acetate was added to the reaction mixture and the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.35 g of N-cyclohexylmethyl-3-fluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 22 of the present invention) represented by the formula: