Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Ni+2:2].[OH-].[C:4]([O-:7])(=[O:6])[CH3:5].[Ni+2].[C:9]([O-:12])(=[O:11])[CH3:10]>C(O)(=O)C>[OH2:6].[OH2:11].[OH2:1].[OH2:6].[C:4]([O-:7])(=[O:6])[CH3:5].[Ni+2:2].[C:9]([O-:12])(=[O:11])[CH3:10]
Reactant: [OH-]
Agent: [Ni+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O

Procedure:
The nickel hydroxide (line 50) is transferred to the nickel acetate production system tank (n) where it is dissolved in acetic acid (line 49, 1:1 ratio to dry nickel solids) and 100% wt acetic acid (line 51) are added to produce the final product nickel acetate tetrahydrate (line 52). The reaction is shown below: 2H2O+Ni(OH)2+2CH3COOH→Ni(CH3COO)2.4H2O
Reaction SMILES: C(OC([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([Cl:22])=[C:14]([CH3:23])[CH:13]=3)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:22][C:15]1[N:16]=[C:17]2[C:12](=[CH:13][C:14]=1[CH3:23])[CH2:11][C@H:10]1[N:18]2[C@H:19]([CH3:21])[CH2:20][NH:8][CH2:9]1
Reactant: Cc1cc2c(nc1Cl)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(nc1Cl)N1[C@@H](CNC[C@H]1C)C2
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a solution of 0.20 g (0.59 mmol) (4R,9aR)-6-chloro-4,7-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 2 mL dichloromethane was added 0.91 mL (1.35 g, 11.8 mmol) trifluoroacetic acid. After 30 min., all volatile components were removed at a rotary evaporator and the residue was purified by column chromatography on silica gel with dichloromethane:methanol:ammonia (19:1:0.1) as eluant to give the desired compound as a colourless oil (95.9%).
Reaction SMILES: Cl.[C:2]([CH:10]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[S:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:27]C1C=CC=C(C(OO)=[O:35])C=1>C(Cl)(Cl)Cl>[ClH:27].[C:2]([CH:10]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[S:11]1=[O:35])(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(C)CCCN1C(=O)C(C(=O)c2ccccc2)Sc2ccccc21
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN(C)CCCN1C(=O)C(C(=O)c2ccccc2)S(=O)c2ccccc21
Reaction time: 2 h

Procedure:
By treating the product from Example 2 (B) with a chloroform solution containing 1 equivalent of m-chloroperbenzoic acid and allowing the mixture to stand for about two hours at room temperature, the title product is obtained.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19])=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[Br:20][C:21]1[CH:27]=[C:26]([CH3:28])[C:24]([NH2:25])=[C:23]([O:29][CH3:30])[CH:22]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Br:20][C:21]1[CH:27]=[C:26]([CH3:28])[C:24]([NH:25][C:2]2[N:6]([CH3:7])[C:5]3[C:8]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[CH2:18][CH3:19])=[CH:9][CH:10]=[CH:11][C:4]=3[N:3]=2)=[C:23]([O:29][CH3:30])[CH:22]=1
Reactant: CCc1ccccc1-c1cccc2nc(Cl)n(C)c12
Reactant: COc1cc(Br)cc(C)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCc1ccccc1-c1cccc2nc(Nc3c(C)cc(Br)cc3OC)n(C)c12
Temperature: 120 °C
Reaction time: 15 h
Yield: 54.2 %

Procedure:
A mixture of 100 mg (0.369 mmol) of 2-chloro-7-(2-ethylphenyl)-1-methyl-1H-benzimidazole and 239 mg (1.11 mmol) of 4-bromo-2-methoxy-6-methylaniline was stirred at 120° C. for 15 hours. After cooling, the reaction mixture was neutralized by saturated aqueous sodium hydrogen carbonate, followed by addition of ethyl acetate. The resulting crystals were collected by filtration and washed with water and ethyl acetate, and suspended in hot ethyl acetate. After cooling to room temperature, the crystals were collected by filtration and washed with ethyl acetate and a 50% dimethylsulfoxide/methanol mixture to give 90 mg (54%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH2:15](N(CC)CC)C>O1CCOCC1>[CH3:15][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[Cl:1]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccnc1Cl
Yield: 85.4 %

Procedure:
To a mixture of 2-chloronicotinic acid (Aldrich, 100.0 g, 0.63 mol) in 1,4-dioxane (500 mL) was added thionyl chloride (70 mL, 0.96 mol). The suspension was heated under reflux for 22 h with a gas trap to absorb hydrogen chloride gas. After evaporation of the solvent, the residue was dissolved in methanol (300 mL). To the solution was added dropwise triethylamine (TEA, 120 mL, 1.26 mol) at 0° C. over 2 h. The solvents were evaporated and the residue was suspended in ethyl acetate. The precipitate was removed by filtration. The filtrate was concentrated to afford the ester 18 (92.3 g, 86%) as an oil:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][O:8][C:9]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:10]=3[CH2:11][C:4]=2[CH:3]=1.[Br:19]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:19][CH:11]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:18]=[CH:17][C:5]=2[O:6][CH2:7][O:8][C:9]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:10]1=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccc2c(c1)Cc1cc(Cl)ccc1OCO2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc2c(c1)C(Br)c1cc(Cl)ccc1OCO2
Temperature: 80 °C
Yield: 27 %

Procedure:
To a solution of 2,10-dichloro-12H-dibenzo[d,g][1,3]-dioxocin (21.4 g, 76.1 mmol) and N-bromosuccinimide (13.5 g, 76.1 mmol) in tetrachloromethane (275 mL) was added azobisisobutyronitrile (200 mg, 1.2 mmol). The mixture was heated at 80° C. for 24 h. Another 3 x azobisisobutyronitrile (200 mg, 1.2 mmol) was added within the 24 h. The mixture was filtrated and the solution phase concentrated in vacuo. The residue was added dichloromethane (30 mL) and ether (100 mL). The mixture was filtered and the solution phase concentraded in vacuo. The residue was submitted to flash chromatography eluting with heptane/ethyl acetate (3:1) to give 7.4 g (27%) of 12-bromo-2,10-dichloro-12H-5,7-dioxadibenzo[a,d]cyclooctene.
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH3:11])[N:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].O>C(O)C>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])[N:4]([CH3:11])[N:3]=1
Reactant: CC(C)(C)N
Reactant: Cn1nc(Br)c([N+](=O)[O-])c1Br
Solvent: O
Solvent: CCO
Product: Cn1nc(Br)c([N+](=O)[O-])c1NC(C)(C)C
Yield: 78 %

Procedure:
1.5 g (5.26 mmoles) of 3,5-dibromo-1-methyl-4-nitropyrazole are heated in a solution of 20 ml tert-butylamine in 30 ml ethanol for 20 hours at boiling temperature. After cooling, the reaction mixture is poured on 150 ml water, the separated product is filtered and washed with 100 ml water. After vacuum drying, 1.14 g (78 percent of theory) of 3-bromo-5-tert-butylamino-1-methyl-4-nitropyrazole are obtained in the form of pale yellow flakes with a melting point of 75° to 77° C.
Reaction SMILES: C(=O)([S:3][CH2:4][C:5]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])([CH3:7])[CH3:6])C.[OH-].[Na+].C(OCC)(=O)C>CO>[SH:3][CH2:4][C:5]([NH:8][C:9](=[O:10])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:7])[CH3:6]
Reactant: CC(=O)SCC(C)(C)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(CS)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of S-2-(Benzyloxycarbonylamino)-2-methylpropyl ethanethioate (4.75 g, 16.9 mmol) in methanol (35 mL) was mixed with a 5 N sodium hydroxide solution (3 equiv, 50 mL, 50.7 mmol) and stirred at RT for 15 min. TLC (20% ethyl acetate in hexanes) analysis of reaction mixture indicated all the starting material was consumed. The organic solvent was removed under reduced pressure and the resulting aqueous solution was made acidic (˜pH 3) with 6 N HCl (9 mL) while cooled in an ice bath. The aqueous suspension was extracted with ethyl acetate (3×100 mL) and the combined organic layer dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give benzyl 1-mercapto-2-methylpropan-2-ylcarbamate as a pale yellow oil, 4.6 g. This material was used without any further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([OH:14])[CH:8]=1)[CH3:2].C([O-])(O)=O.[Na+].[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:23](=[O:24])[CH2:22][Cl:21])=[C:9]([OH:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(N)c(O)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C=Cc1ccc(NC(=O)CCl)c(O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 10-3 (3.38 g, 16.3 mmol) in CHCl3 (80 mL) was added saturated NaHCO3 (50 mL) and it was then chilled to 0° C. A solution of chloroacetyl chloride (1.94 mL, 24.4 mmol) in CHCl3 (30 mL) was added dropwise to the chilled biphase. Upon addition completion, the reaction was stirred at 0° C. for 1 h. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give 10-4 which was used without further purification in the next step.
Reaction SMILES: [O:1]=[C:2]([CH3:8])/[CH:3]=[CH:4]/[C:5](Cl)=[O:6].[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10]>CCOCC>[CH2:9]([N:11]([CH2:12][CH3:13])[C:5](=[O:6])/[CH:4]=[CH:3]/[C:2](=[O:1])[CH3:8])[CH3:10]
Reactant: CC(=O)/C=C/C(=O)Cl
Reactant: CCNCC
Solvent: CCOCC
Product: CCN(CC)C(=O)/C=C/C(C)=O
Temperature: -15 °C
Reaction time: 2 h

Procedure:
To flame dried flask containing (E)-4-oxo-2-pentenoyl chloride (1.16 g, 8.76 mmol) in ether cooled to -15° C. is added diethylamine (1.41 g, 19.28 mmol) in ether (5 ml) and stirred for 2 hours while being warmed to ambient temperature. The solvents are removed in vacuo, and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with hexane/ethyl acetate (75/25). The appropriate fractions are combined (Rf =0.31, TLC, hexane/ethyl acetate, 25/75) and concentrated in vacuo to give the title compound, NMR (CDCl3) 7.15, 7.04, 3.45, 3.40, 2.33, 1.20, 1.15.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[Cl:17][C:18]1[CH:19]=[C:20](/[CH:25]=[CH:26]/[C:27]#[N:28])[CH:21]=[CH:22][C:23]=1[Cl:24].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:5][CH:25]([C:20]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=2)[CH:26]([C:27]#[N:28])[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: N#C/C=C/c1ccc(Cl)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.9 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (10.25 g, 43 mmol) in CH2Cl2 (55 mL) was added dropwise, over a 30 minutes period, to a stirred solution of (E)-3-(3,4-dichloro-phenyl)-acrylnitrile (5.70 g, 29 mmol) and trifluoroacetic acid (0.22 mL, 3 mmol) in CH2Cl2 (10 mL) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, CH2Cl2) afforded the title compound (7.0 g, 73%) as a colorless oil. ES-MS m/e: 332.3 (M+H+).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([N:9]1[CH2:33][CH2:32][CH2:31][C@H:10]1[C:11]([NH:13][C@H:14]([C:20]([NH:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21])[CH2:15][CH2:16][C:17](=[O:19])[NH2:18])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]>CO.[Pd]>[NH2:1][C@H:2]([C:7]([N:9]1[CH2:33][CH2:32][CH2:31][C@H:10]1[C:11]([NH:13][C@H:14]([C:20]([NH:22][NH:23][C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])=[O:21])[CH2:15][CH2:16][C:17](=[O:19])[NH2:18])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)NNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)NNC(=O)OC(C)(C)C

Procedure:
3.50 Grams of Z-Leu-Pro-Gln-NHNHBoc was dissolved in 50 ml of methanol and was catalytically reduced by using palladium as the catalyst to obtain H-Leu-Pro-Gln-NHNHBoc.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH3:13]I.O>CN(C=O)C>[Cl:3][C:4]1[N:8]([CH3:13])[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1
Reactant: CI
Reactant: Clc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(Cl)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (contained by 60%, 0.288 g) was suspended in DMF (10 mL), and 2-chlorobenzimidazole (1 g) was added thereto. The mixture was stirred at room temperature for 30 min and methyl iodide (0.61 mL) was added thereto. After stirring at room temperature for 1 hr, water was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with brine and concentrated under reduced pressure to give 2-chloro-1-methylbenzimidazole (0.928 g) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:16][CH2:17][CH2:12][CH2:13][CH2:14][CH2:15][CH3:18])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N=Nc2ccc(-c3ccc(O)cc3)cc2)cc1
Solvent: CCO
Product: CCCCCCCOc1ccc(-c2ccc(N=Nc3ccc([N+](=O)[O-])cc3)cc2)cc1

Procedure:
0.6 g of 4-nitro-4'-(4-hydroxyphenyl)azobenzene was suspended in 40 ml of hot ethanol, placed in a sulfonation flask and rinsed with 10 ml of ethanol. Then, 0.336 g of 1-bromoheptane, 0.260 g of potassium carbonate and a spatula tip of sodium iodide were added and the dark brown suspension was stirred under reflux for 16 hours. Since starting material was still present, on additional 0.342 g of 1-bromoheptane and 0.260 g of potassium carbonate were added and the mixture was boiled under reflux for an additional 4 hours. Subsequently, the mixture was concentrated to dryness in vacuo, suspended in 30 ml of toluene and chromatographed on silica gel with 1.0 l of toluene and 0.8 l of toluene/acetone (2%). There was thus obtained 0.276 of 4-nitro-4'-(4-heptyloxy-phenyl)azobenzene which was recrystallized from methylene chloride/hexane: m.p. 146.9°-148.2° C.; cl.p. 257.7°-258.1° C.; smectic-nematic conversion 238.2° C.; ε252 =15480, ε294 =13830, ε390 =28180.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[C:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:15]=2)=[N:11][CH:12]=1)[CH2:2][CH2:3][C:4]#[CH:5].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[N:28]=1.C(N(CC)CC)C>CS(C)=O.O>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[CH:20]=[C:21]2[CH2:26][CH2:25][N:24]([C:34]([NH:33][C:29]3[N:28]=[N:27][CH:32]=[CH:31][CH:30]=3)=[O:35])[CH2:23][CH2:22]2)=[N:11][CH:12]=1)[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C#CCCCOc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: C#CCCCOc1ccc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnn4)CC3)c2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.2 %

Procedure:
5-(Pent-4-ynyloxy)-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine (0.26 g, 0.746 mmol) and phenyl pyridazin-3-ylcarbamate (0.16 g, 0.746 mmol) were dissolved in DMSO (3 mL) and triethylamine (0.3 mL) was added dropwise. The reaction was stirred for 12 h at RT. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (acetone:hexane, 2:5) to give the title compound (0.225 g, 64%). 1H NMR (500 MHz, CDCl3): δ 8.77 (s, 1H), 8.40 (s, 1H), 7.89 (s, 1H), 7.46 (t, J=4.5 Hz, 1H), 7.29 (m, 2H), 6.98 (d, J=7.5 Hz, 1H), 6.92 (m, 2H), 6.87 (d, J=8.75 Hz, 1H), 6.40 (s, 1H), 4.08 (t, J=5.75 Hz, 2H), 3.70 (m, 2H), 3.59 (m, 2H), 2.60 (d, J=5.2 Hz, 2H), 2.47 (m, 2H), 2.40 (t, J=6.6 Hz, 2H), 1.99 (m, 3H); 13C NMR (125 MHz, CDCl3): δ157.48, 156.60, 155.19, 151.80, 138.72, 137.46, 133.67, 129.42, 128.15, 126.84, 124.96, 124.59, 120.58, 118.38, 112.52, 83.14, 69.12, 67.25, 45.66, 44.64, 35.76, 29.13, 28.08, 15.06; m/z (470.2 MH+); HPLC: 97.8%.
Reaction SMILES: [NH3:1].Cl[C:3]1[NH:4][SH:5](=[O:21])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1.O>C(O)C>[NH2:1][C:3]1[NH:4][SH:5](=[O:21])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1
Reactant: N
Reactant: O=[SH]1(c2ccccc2)C=C(c2ccccc2)N=C(Cl)N1
Solvent: O
Solvent: CCO
Product: NC1=NC(c2ccccc2)=C[SH](=O)(c2ccccc2)N1
Temperature: 100 °C
Yield: 93 %

Procedure:
To 75 ml of saturated a solution of ammonia in ethanol was added 3 g (0.01 mole) of 3-chloro-1,5-diphenyl-1H-1,2,4-thiadiazine-1-oxide and the mixture was heated in an autoclave at 100° C. for 3 hours. The mixture was cooled, poured into water and the product was filtered off, washed with water and dried to obtain 2.6 g (93%) of 3-amino-1,5-diphenyl-1H-1,2,4-thiadiazine-1-oxide melting at 169°-170° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][C@@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[CH3:12][C@@H:13]1[CH2:18][N:17]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:16][CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20]
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Product: C[C@@H]1CN(Cc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from 4-nitrobenzaldehyde and 1,1-dimethylethyl (2R)-2-methyl-1-piperazinecarboxylate using a method similar to that described for D21 in Description 21. MS (ES): [M-(CH2═CMe2)]H+ 280.2, [M—(CH2═CMe2)—CO2]H+ 236.3, no molecular ion.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH3:26])=[N:20][C:19]2=[O:27])=[CH:4][CH:3]=1.Cl[C:29]1C=CN(CC2N3C=CC=CC3=NC=2C2C=CC(Cl)=CC=2)[C:31](=O)[N:30]=1.CN(C)CCN>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH2:26][N:30]([CH3:31])[CH3:29])=[N:20][C:19]2=[O:27])=[CH:6][CH:7]=1
Reactant: CCNc1ccn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c(=O)n1
Reactant: O=c1nc(Cl)ccn1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: CN(C)CCN
Product: CN(C)CCNc1ccn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c(=O)n1

Procedure:
The title compound was prepared according to the experimental for compound 132 from 4-chloro-1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2(1H)-one and N1,N1-dimethylethane-1,2-diamine. M/e+ 423 for C22H24ClN6O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.42 (d, J=6.9 Hz, 1H), 7.68 (dd, J=8.4, 2.2 Hz, 2H), 7.64 (dd, J=9.1, 1.1 Hz, 1H), 7.47 (dd, J=8.4, 2.2 Hz, 2H), 7.28 (d, J=7.7 Hz, 1H), 6.86 (t, J=6.6 Hz, 1H), 6.65 (dd, J=7.3, 2.2 Hz, 1H), 6.49 (bs, 1H), 5.54 (d, J=1.8 Hz, 2H), 5.46 (dd, J=7.3, 1.8 Hz, 1H), 3.59 (m, 2H), 2.61 (m, 2H), 2.16 (s, 6H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:28][CH:29](F)[C:30](Cl)=[O:31]>>[F:28][CH2:29][C:30]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:31]
Reactant: O=C(Cl)C(F)F
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Product: C[C@H](NC(=O)CF)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 36 mg, 100 μmol) and difluoroacetyl chloride (29 mg, 300 μmol). Yield 40 mg (95%).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:7][C:6](=[O:12])[CH:5]=[CH:4][C:3]1=2.[H-].[Li+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CN(C)C=O>[CH2:16]([N:7]1[C:8]2[CH2:9][CH2:10][CH2:11][C:2](=[O:1])[C:3]=2[CH:4]=[CH:5][C:6]1=[O:12])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C1CCCc2[nH]c(=O)ccc21
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCCCCn1c2c(ccc1=O)C(=O)CCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5,6,7,8-tetrahydro-5-oxo-2(1H)-quinolinone (10.0 g), lithium hydride (0.78 g), and dimethylformamide (400 ml) was stirred for 3 hrs at 25° C., under nitrogen. 1-Bromohexane (10.6 g) was added and the mxture was stirred for an additional eighteen hrs. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The layers were separted and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by high performance liquid chromatography (silica gel, two columns, eluted with 50% ethyl acetate/hexane). The appropriate fractions were collected and evaporated to give 4.6 (31%) of 1-hexyl-5,6,7,8-tetrahydro-5-oxo-2(1H)-quinolinone.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+].Cl[C:7]1[S:8][C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:11]=1.[Cl-].[Na+]>CN(C)P(=O)(N(C)C)N(C)C>[CH2:1]([S:3][C:7]1[S:8][C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[N:11]=1)[CH3:2]
Reactant: CCS
Reactant: COc1ccc(-c2nc(Cl)sc2-c2ccc(OC)cc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCSc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1
Reaction time: 1 h

Procedure:
0.217 g of ethyl mercaptan is dissolved under nitrogen in 10 ml of hexamethylphosphoric acid triamide, the solution is cooled to 10° and, while stirring, 170 mg of 50% strength sodium hydride suspension (in mineral oil, de-oiled with hexane) are added in portions. The mixture is then stirred for 15 minutes at room temperature, 1.0 g of 2-chloro-4,5-bis-(p-methoxyphenyl)-thiazole is added and stirring is carried out at room temperature for 1 hour. The mixture is then poured into 300 ml of 10% strength sodium chloride solution, digested until crystallisation occurs and filtered with suction and the residue is then washed twice with water and sucked dry on a suction filter. The crude product is recrystallised from methanol. 2-Ethylthio-4,5-bis-(p-methoxyphenyl)-thiazole having a melting point of 73°-75° is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][C:14]1C=C[C:17](Cl)=[CH:16][CH:15]=1)=[C:5]2[Cl:21].[S:22]1C=CC=C1CC(C(O)=O)C(O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][C:14]1[S:22][CH:17]=[CH:16][CH:15]=1)=[C:5]2[Cl:21]
Reactant: Clc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Reactant: O=C(O)C(Cc1cccs1)C(=O)O
Product: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1cccs1

Procedure:
The title compound was prepared by substituting 2-(4-chlorobenzyl)malonic acid (Intermediate 3: step b) with 2-(thiophen-2-ylmethyl)malonic acid (Intermediate 9: step b) then following the procedure described for the preparation of 6-bromo-2,4-dichloro-3-(4-chlorobenzyl)quinoline (Intermediate 3: step c).