Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[N:11][N:10]=[C:9]1[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:17][CH:18]=1.C1C(=O)N([Br:32])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[Br:32][C:12]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[C:9]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:17][CH:18]=2)=[N:10][N:11]=1
Reactant: Brc1ccccc1-n1cnnc1-c1ccc(-c2ccccc2)nc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1ccccc1-n1c(Br)nnc1-c1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Yield: 69 %

Procedure:
5-[4-(2-Bromophenyl)-4H-1,2,4-triazol-3-yl]-2-phenylpyridine prepared in the Production Example 2 was dissolved in a mixture solvent of carbon tetrachloride (100 ml) and acetic acid (100 ml), followed by addition of n-bromosuccinimide (5.90 g), and refluxed under heating for 3 hours. After the reaction solution was cooled to ambient temperature, the solution was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and extracted with chloroform. Subsequently, the organic layer was dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1), to afford the entitled compound as yellow solid (6.96 g, 69%). The physico-chemical values are as follows.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3].C(OCC)C.C(O[CH:25](OCC)[N:26]([CH3:28])[CH3:27])C>>[CH3:25][N:26]([CH3:28])[CH:27]=[N:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:8]2[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=2)[CH:11]=1
Reactant: N=C(N)Nc1nc(-c2cccc(N)c2)cs1
Reactant: CCOC(OCC)N(C)C
Solvent: CCOCC
Product: CN(C)C=Nc1cccc(-c2csc(NC(=N)N)n2)c1
Yield: 77.7 %

Procedure:
A solution of 2.5 gm of 2-guanidino-4-(3-amino-phenyl)-thiazole in 7.5 gm of N,N-dimethylformamide diethylacetal was stirred at room temperature for 2 days. Addition of diethyl ether precipitated a solid which was filtered off and dried, yielding 2.4 gm of the title compound.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][OH:10].[Cl:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1F>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: OCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccn2)c(Cl)c1
Temperature: 0 °C
Reaction time: 36 h
Yield: 100 %

Procedure:
Sodium hydride (95%, 0.935 g, 37 mmol) is suspended in dry DMF (20 ml) under a nitrogen atmosphere and the resulting mixture is cooled in ice water. To above suspension is added dropwise over 15 minutes pyridin-2-yl-methanol (3.42 g, 31.3 mmol) in dry DMF (20 mL). Next, to the cold reaction mixture is added dropwise over 20 minutes a solution of 2-Chloro-1-fluoro-4-nitro-benzene (5 g, 28.5 mmol) in dry DMF (20 ml). Upon the end of addition the cold bath is removed and the reaction mixture is stirred for another 36 hours. Water (80 mL) was added slowly to the reaction mixture, and a yellow precipitate resulted. The resultant solid is isolated by suction filtration, washed with water (80 ml), and air dried to yield 7.52 g (28.5 mmol, 100%) of the clean desired material as a yellow powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@H:10]2[CH2:14][C@H:13]([F:15])[CH2:12][N:11]2[C:16]2[CH:21]=[CH:20][N:19]3[N:22]=[CH:23][C:24]([C:25]([N:27](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)=[O:26])=[C:18]3[CH:17]=2)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C@H:10]2[CH2:14][C@H:13]([F:15])[CH2:12][N:11]2[C:16]2[CH:21]=[CH:20][N:19]3[N:22]=[CH:23][C:24]([C:25]([NH2:27])=[O:26])=[C:18]3[CH:17]=2)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(N4C[C@@H](F)C[C@@H]4c4cc(F)cc(C#N)c4)cc23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(F)cc([C@H]2C[C@H](F)CN2c2ccn3ncc(C(N)=O)c3c2)c1
Temperature: 50 °C

Procedure:
A solution of 5-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-53) (10 mg, 0.02 mmol) in DCM (0.5 mL) was added TFA (0.5 mL) and heated to 50° C. for 12 hours. The reaction was reduced to dryness and purified by column chromatography on silica gel with DCM/MeOH gradient as eluant to yield 5-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (X-10). 1H NMR (400 MHz, CD3OD) δ 8.28 (d, J=8.0 Hz, 1 H), 8.23 (s, 1 H), 7.61 (m, 1 H), 7.48-7.42 (m, 1 H), 7.03 (d, J=2.4 Hz, 1 H), 6.52 (dd, J=2.8, 7.6 Hz, 1 H), 5.42 (d, J=52.4 Hz, 1 H), 5.14 (dd, J=7.2, 9.6 Hz, 1 H), 4.21 (ddd, J=3.2, 12.0, 36.8 Hz, 1 H), 3.94 (ddd, J=2.0, 12.4, 23.6 Hz, 1 H), 2.98-2.85 (m, 1 H), 2.16 (dddd, J=3.6, 9.6, 14.0, 40.4 Hz, 1 H). MS m/z 368.1 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[I:15]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>O>[Cl:1][C:2]1[N:7]=[C:6]([I:15])[C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: II
Reactant: Oc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Cl)nc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
6-chloropyridin-3-ol (5.0 g, 38.6 mmol) was dissolved in water (50 mL) and placed under an N2 atmosphere. Na2CO3 (8.2 g, 77.4 mmol) was added followed by iodine (9.8 g, 38.8 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into 1M Na2S2O3 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated to provide the product of 6-chloro-2-iodopyridin-3-ol (7.0 g, yield: 70.9%). 1H-NMR (CDCl3, 400 MHz) δ 7.17 (d, J=8.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H). MS (M+H)+: 256/258.
Reaction SMILES: CC(C)=O.[CH3:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([OH:34])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[NH:33][C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]=12.[C:35]([OH:43])(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>COC(C)(C)C>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([OH:34])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[NH:33][C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]=12.[C:35]([O-:43])(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(O)c1ccccc1
Agent: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Product: O=C([O-])c1ccccc1

Procedure:
A suitable reactor is charged with acetone. The solution is sequentially charged with carvedilol (4.1 grams, 0.1 moles), and benzoic acid solution. Upon addition of the benzoic acid (1.4 grams, 0.011 moles) solution, all material dissolves into the solution. To the stirred solution is added tert-butyl methyl ether (60 ml). The precipitate formed is stirred for a period of time, filtered and the collected cake is washed with water. The cake is dried under vacuum to a constant weight and stored in a polyethylene container.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1I.[CH3:13][N:14]1[C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=[N:15]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:18]1[N:14]([CH3:13])[N:15]=[CH:16][CH:17]=1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: FC(F)(F)c1ccc(Br)c(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1Br
Yield: 57.1 %

Procedure:
A 75-mL pressure vessel was charged with 1-bromo-2-iodo-4-(trifluoromethyl)benzene (2.015 g, 5.74 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Aldrich, St. Louis, Mo., 1.374 g, 6.60 mmol), potassium phosphate (2.438 g, 11.48 mmol), and PdCl2(dppf)-CH2Cl2 adduct (Strem Chemicals Inc., Newburyport, Mass., 0.469 g, 0.574 mmol). The vessel was flushed with Ar (g), then DMF (19.14 ml) was added. The vial was sealed and placed in an 80° C. oil bath for 2 hours. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on an 80 g silica gel column to give 5-(2-bromo-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazole (1.001 g, 3.28 mmol) as a yellow solid. [M+H]+=307.0.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[C:25]([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=[O:27])[CH3:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>[Cu]I.O.O1CCOCC1>[C:25]([N:28]1[CH2:32][CH2:31][N:30]([C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])[C:29]1=[O:33])(=[O:27])[CH3:26]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3Br)CC2)c(C)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C)cc3C)CC2)C1=O
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a mixture of (2-bromo-4-chlorophenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (817 mg) described in Preparation Example 167, 1-acetylimidazolidin-2-one (384 mg), tripotassium phosphate (849 mg) and copper(I) iodide (191 mg) were added dioxane (4 mL) and N,N′-dimethylethylenediamine (215 μL), and the mixture was stirred at 8 hr under refluxing. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was evaporated, and the residue was purified by column chromatography (ethyl acetate:methanol) to give the title compound (639 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9]O.P(Br)(Br)[Br:12].C(=O)(O)[O-].[Na+]>ClCCl>[Br:12][CH2:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: OCc1cc(F)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(Cl)c(CBr)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
To a solution of (2-chloro-5-fluoro-phenyl)-methanol (5.0 g, 31.1 mmol) in dichloromethane (40 mL) was added drop wise phosphorus tribromide (87 g, 31.1 mmol). The mixture was stirred at room temperature for 16 h. The reaction was poured onto ice/water. The aqueous phase was made basic with sodium bicarbonate. The aqueous phase was extracted with dichloromethane. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with (hexanes/ethyl acetate 90:10) to give the title compound (5.75 g, 82.5%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:19]([N-]C(C)C)(C)[CH3:20].[Li+].ICC.[Cl-].[NH4+]>C1COCC1>[CH2:19]([C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:8][CH2:7]1)[CH3:20]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
0.2 g (0.78 mmol) of tert-butyl 4-ethoxycarbonylpiperidine-1-carboxylate is dissolved in 4 mL of THF at −10° C. 0.8 mL (1.56 mmol) of lithium diisopropylamide is added dropwise. After 15 minutes, 0.09 mL (1.2 mmol) of iodoethane is added and the mixture is warmed to room temperature. It is stirred for 30 minutes and then poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried and then concentrated to dryness. The oil obtained is chromatographed on silica gel (eluent: 95/5 heptane/ethyl acetate). 183 mg of tert-butyl 4-ethyl-4-ethoxycarbonylpiperidine-1-carboxylate in the form of a yellow oil are obtained in a yield of 82%.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH:14]=[C:13]([C:27]([F:30])([F:29])[F:28])[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][CH:48]=1)(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCCCCCC>C1(C)C=CC=CC=1>[C:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=4)[CH:14]=[C:13]([C:27]([F:29])([F:28])[F:30])[N:12]=3)[CH:10]=2)=[N:49][CH:48]=1)(=[O:45])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (Example G.12) (0.570 g, 0.88 mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (Example H.1) (0.265 g, 0.99 mmol), tetrakis(triphenyl-phosphine)palladium (0.061 g, 0.046 mmol) in toluene (6 mL) was heated under reflux conditions for 16 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (220 mg, 43%). MS (ISP) 576.3 [(M+H)+]; mp 252° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[CH:10]=[N:9][CH:8]=[N:7]1.C(N(CC)CC)C.[NH:18]1[CH:26]=[C:24]([CH3:25])[C:22](=O)[NH:21][C:19]1=[O:20]>C(#N)C.O>[CH3:25][C:24]1[C:26]([N:6]2[CH:10]=[N:9][CH:8]=[N:7]2)=[N:18][C:19](=[O:20])[NH:21][CH:22]=1
Reactant: c1nc[nH]n1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c[nH]c(=O)nc1-n1cncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.5 %

Procedure:
50.6 g (0.33 mol) of phosphoryl trichloride are added under a protecting gas (nitrogen) to a suspension of 69 g (1 mol) of 1,2,4-triazole in 800 ml of dry acetonitrile at an internal temperature of 0°-50° C. During a period of 1 hour, 101.2 g (1 mol) of triethylamine are then added dropwise. After stirring for a further 40 minutes at room temperature, 18.9 g (0.15 mol) of thymine are added. The suspension is stirred for 24 hours at room temperature, 25 ml of water are added and the mixture is stirred for a further 10 minutes and then filtered. The yellow residue is suspended in 400 ml of water, stirred and filtered off by suction after 1 hour. 1.72 g of 5-methyl-4-(1,2,4-triazol-1-yl)-pyrimidin-2-(1H)-one are obtained as a yellow powder with melting point 258°-264° C. The acetonitrile solution is concentrated, the residue is suspended in 400 ml of water, stirred and filtered off by suction. In this manner, a further 7.21 g of the compound are obtained. The title compound can be recrystallized from dimethylformamide and then melts at 275°-280° C. 1H NMR (60 MHz, d6 -DMSO), δ[ppm]: approx. 12.0 (s, broad, 1H), 9.33 (s, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 2.3 (s, 3H).
Reaction SMILES: O.O.O.O.[N+]([O-])([O-])=O.[Ca+2:9].[N+]([O-])([O-])=O.[P:14]([OH:18])([O-:17])([O-:16])=[O:15].[NH4+].[NH4+].N>O>[P:14]([O-:18])([O-:17])([O-:16])=[O:15].[Ca+2:9].[P:14]([O-:18])([O-:17])([O-:16])=[O:15].[Ca+2:9].[Ca+2:9]
Reactant: O=P([O-])([O-])O
Agent: N
Agent: O=[N+]([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: O=P([O-])([O-])[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
118.1 g of calcium nitrate tetrahydrate were dissolved in 200 ml of water and heated to 80° C., a solution of 33 g of diammonium phosphate in 100 ml of water was added and the mixture was rendered basic with ammonia and was aged for 30 minutes. After cooling, filtration and washing, the precipitate was dried at 120° C. and calcined for 2 hours at 600° C. The powder obtained was converted into a novel molding according to catalyst preparation a).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[S:9](=O)(=[O:12])([OH:11])[OH:10]>O>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([S:9]([OH:12])(=[O:11])=[O:10])=[C:2]([Cl:1])[CH:3]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=S(=O)(O)O
Solvent: O
Product: Nc1ccc(S(=O)(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.4 mL of 3-chloroaniline was slowly added to 4 mL of a fuming sulfuric acid and stirred at room temperature overnight. Cooling it down to 0° C., the reaction solution was poured in water, and a precipitated solid substance was taken by filtration. The solid substance was dissolved in an aqueous solution of 2N sodium hydroxide. Then, a concentrated hydrochloric acid wad added thereto to make the liquid acidic. The precipitated solid substance was filtered out to obtain a crude product of 4-amino-2-chlorobenzenesulfonic acid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11]C)=[CH:7][CH:6]=1)=[O:4].BrB(Br)Br>C(Cl)Cl>[F:1][C:2]([F:13])([F:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[O:4]
Reactant: COc1ccc(C(=O)C(F)(F)F)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a cooled (−78° C.) solution of 2,2,2-trifluoro-4′-methoxyacetophenone (15 ml, 73 mmol) in DCM was added 1.0 M tribromoborane (73 ml, 73 mmol) drop wise. After the addition was completed, the reaction was slowly warmed to RT and stirred for overnight (15 h). At this point, reaction was completed by TLC. The product mixture was poured into ice water. The organic layer was washed with 10% aq Na2CO3, water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel column (5-40% EtOAc/hexane) to afford the title compound as a white crystalline solid. The major side product was a colorless oil with MS+=379.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]([CH3:20])[C:7](=[CH:21]O)[C:6]2=[O:23].C([O-])(=O)C.[NH4+:28]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]([CH3:20])[C:7](=[CH:21][NH2:28])[C:6]2=[O:23]
Reactant: [NH4+]
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CO)C1C
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CN)C1C
Yield: 46 %

Procedure:
The less polar diasteriomer from the reaction of racemic ethyl 6,7-dimethoxy-3-hydroxymethylene-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline-1-carboxylate with d-1-(1-naphthyl)ethylamine (see Example 18) was treated with ammonium acetate, according to the procedure of Example 19. This afforded a 46% yield of the title compound, m.p. 92°-95° C., [α]D25 = -91.52° (0.2% in CHCl3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:2].[CH3:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:13])[CH:19]=2)=[CH:7][CH:6]=1)=[O:12])[CH3:2]
Reactant: Cc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2cccc(C)c2)cc1
Temperature: 100 °C
Yield: 87.3 %

Procedure:
A mixture of 4-bromo benzoic acid ethyl ester (2.7 mL, 16.5 mmol), 3-methyl phenylboronic acid (2.2 g, 16.2 mmol) and sodium carbonate (7.5 g, 70.8 mmol) in toluene:ethanol:water (75 mL:37 mL:37 mL), was flushed with nitrogen for 1 hour. After addition of the tetrakis(triphenylphosphine) palladium(0) catalyst (0.94 g, 0.81 mmol), the reaction was heated at 100° C. overnight. After cooling, the mixture was filtered through Celite which was then washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification of the residue by flash chromatography with a solvent gradient from 25% to 50% of dichloromethane in hexane provided the title compound (3.4 g, 87.3%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[O:12].[Cl:13][CH2:14][CH2:15][CH2:16]Br.O>CN(C)C=O>[Cl:13][CH2:14][CH2:15][CH2:16][N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:3][C:4]1=[O:12]
Reactant: O=c1[nH]c2ccccc2o1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1oc2ccccc2n1CCCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of sodium hydride (7.8 g, 0.16 mol, ether-washed) in dimethylformamide (75 ml) was added dropwise under nitrogen, 2-benzoxazolinone (20.0 g, 0.15 mol) dissolved in dimethylformamide (150 ml). After complete addition the reaction was stirred at ambient temperature for 30 min. and then it was cooled to −5° C. with an ice-acetone bath. A solution of 3-chloro-1-bromopropane (46.6 g, 0.30 mol) in dimethylformamide (50 ml) was added dropwise (temperature never exceeded 0° C.). The reaction was allowed to reach ambient temperature and was stirred for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed with water, dried (MgSO4), and the extract concentrated from toluene-hexane to afford N-(3-chloropropyl)-2-benzoxazolinone as large needles, 15.6 g, m.p.=264°-266° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1>O.CO.[Pd]>[N:11]1([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:24])([F:23])[F:25])=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Temperature: 75 °C
Yield: 86.2 %

Procedure:
NH4COOH (15.5 g, 247 mmol) and 10% Pd/C (1.8 g) in water (2 mL) were added to a stirred solution of (4-benzyl-piperazin-1-yl)-(2-trifluoromethyl-phenyl)-methanone (8.6 g, 24.7 mmol) in MeOH (40 mL) and the resulting mixture was heated to reflux at 75° C. for 4 hrs. The reaction mixture was then filtered over celite and the filtrate evaporated. The resulting residue was dissolved in ethyl acetate, washed with 10% NaOH solution then brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford 5.5 g (86%) of piperazin-1-yl-(2-trifluoromethyl-phenyl)-methanone. 1H NMR: (DMSO-d6): δ 7.8 (d, 1H), 7.7 (t, 1H), 7.6 (t, 1H), 7.4 (d, 1H), 3.5 (m, 2H), 3.0 (m, 2H), 2.7 (m, 5H).