Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][CH:24]([OH:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(O)(=O)C.C(OCC)(=O)C.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][CH:24]([O:31][S:40]([CH3:39])(=[O:42])=[O:41])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CC(O)COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)CC(COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1)OS(C)(=O)=O
Reaction time: 2 h

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-[{3-(ethoxycarbonyl)-2-hydroxypropyl}oxymethyl]-4-methanesulfonyloxypyrrolidine (9.5 g) in acetic acid (150 ml) were added triethylamine (15 ml) and methanesulfonyl chloride (2 ml) at -40° C. and the mixture was stirred at the same temperature for 2 hours under nitrogen atmosphere. Resulting precipitate was filtered off and the filtrate was concentrated in vacuo to give a residue, which was dissolved in a mixture of ethyl acetate (100 ml) and water (50 ml). The organic layer was separated, washed with brine (50 ml) and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (300 ml) eluting with a mixture of hexane and ethyl acetate (1:1 V/V) to give (2S,4R)-1-benzyloxycarbonyl-2-[{3-(ethoxycarbonyl)-2-methanesulfonyloxypropyl}oxymethyl]-4-methanesulfonyloxypyrrolidine (3.74 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:4][C:3]=1[CH3:20].[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:19][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:4][C:3]=1[CH3:20]
Reactant: O=C(O)c1ccccc1
Reactant: COCCOc1ncc(N)cc1-c1ccc(Cl)c(C)c1
Product: COCCOc1ncc(NC(=O)c2ccccc2)cc1-c1ccc(Cl)c(C)c1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-3-methyl-phenyl)-6-(2-methoxy-ethoxy)-pyridin-3-ylamine (example 69 c) and benzoic acid as starting materials; LC-MS (UV peak area/ESI) 100%, 397.1307 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[NH:8][CH2:9][CH2:10][S:11][CH:12]([C:13]3[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=3[CH3:22])[C:6]=2[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[N:4]1)[CH3:2].S(Cl)([Cl:31])=O.CN(C=O)C>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2[NH:8][CH2:9][CH2:10][S:11][CH:12]([C:13]3[CH:21]=[CH:20][C:16]([C:17]([Cl:31])=[O:18])=[CH:15][C:14]=3[CH3:22])[C:6]=2[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[N:4]1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCn1nc(-c2ccccn2)c2c1NCCSC2c1ccc(C(=O)O)cc1C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCn1nc(-c2ccccn2)c2c1NCCSC2c1ccc(C(=O)Cl)cc1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To a mixture of 4-(1-ethyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methylbenzoic acid (2.0 g, 5.07 mmol, Preparation #V.1) and thionyl chloride (1.8 mL, 25.3 mmol) in DCM (20 mL) was added DMF (0.04 mL, 0.51 mmol) and stirred at about 50° C. for about 2 h. The reaction was cooled to ambient temperature and the solvent was removed under reduced pressure to give 4-(1-ethyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methylbenzoyl chloride (2.1 g, 5.09 mmol, 100%) as a brown solid. LC-MS (Table 1, Method k) Rt=1.97 min, m/z 409 (M+H)+ for MeOH quench.
Reaction SMILES: [N:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[S:3][C:2]=1[NH:10][C:11]([C:13]1[C:18]2[NH:19][C:20]([NH:22][C:23]([C:25]3[N:26]=[CH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:24])=[N:21][C:17]=2[CH:16]=[CH:15][CH:14]=1)=[O:12].N1C=CC=CC=1.[C:41](Cl)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(Cl)Cl.C(OCC)(=O)C>[C:41]([N:6]1[CH2:7][CH2:8][C:9]2[N:1]=[C:2]([NH:10][C:11]([C:13]3[C:18]4[N:19]=[C:20]([NH:22][C:23]([C:25]5[N:26]=[CH:27][C:28]6[C:33]([CH:34]=5)=[CH:32][CH:31]=[CH:30][CH:29]=6)=[O:24])[NH:21][C:17]=4[CH:16]=[CH:15][CH:14]=3)=[O:12])[S:3][C:4]=2[CH2:5]1)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(Nc1nc2cccc(C(=O)Nc3nc4c(s3)CNCC4)c2[nH]1)c1cc2ccccc2cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1nc2c(C(=O)Nc3nc4c(s3)CN(C(=O)c3ccccc3)CC4)cccc2[nH]1)c1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a solution of 30 mg (0.063 mmol) of isoquinoline-3-carboxylic acid [7-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide (Example 198) in DCM (2 mL) was added pyridine (0.5 mL) and benzoyl chloride (0.05 mL). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (20 mL), the organic phase was washed with sat. aq. Na2CO3 solution, dried over Na2SO4, and concentrated under reduced pressure. The crude product was dissolved in DCM (0.5 mL), hexane was added (4 mL), and the resulting precipitate was filtered and dried to provide 17 mg (47%) of isoquinoline-3-carboxylic acid [4-(5-benzoyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 574 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:20][CH:19]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C.[Cl:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH:40]=O>CO>[Cl:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH2:40][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]5[CH2:28][CH2:29][CH2:30][CH2:31]5)=[CH:20][CH:19]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cc1
Reactant: O=Cc1cccc(Cl)c1
Solvent: CO
Solvent: CC(=O)O
Product: Clc1cccc(CNc2ccc(-c3cccc4nc(Nc5ccc(OCCN6CCCC6)cc5)nn34)cc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of [5-(4-amino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.05 g, 0.121 mmol) and MP-CNBH3 (180 mg, 0.360 mmol) in methanol (1 ml) was added acetic acid (6 μl, 0.121 mmol) followed by 3-chlorobenzaldehyde (15 μl, 0.133 mmol). The mixture was stirred for 18 hours at room temperature, then filtered and concentrated in vacuo. The product was purified by preparatory HPLC to yield the desired product. RT: 3.09 min, MI: 539, Method: 2; 1H NMR (DMSO, 300 MHz): 8.47 (s, 1H), 7.90 (2H, d), 7.50-7.27 (m, 8H), 6.92 (d, 1H), 6.84 (d, 2H), 6.74 (d, 2H), 4.42 (s, 2H), 4.30 (t, 2H), 3.37 (t, 2H), 3.26 (s, 4H), 2.03 (s, 4H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]([C:14]2([CH3:19])[O:18][CH2:17][CH2:16][O:15]2)[CH:11]=[CH:10][C:6]=1[C:7]([O-:9])=O.[Li+].C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([NH:40][C:41](=[O:49])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[NH2:48])=[N:38][CH:39]=1>C(Cl)Cl.CN(C=O)C>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([NH:40][C:41](=[O:49])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[NH:48][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:12]([C:14]3([CH3:19])[O:18][CH2:17][CH2:16][O:15]3)=[CH:13][C:5]=2[O:4][CH2:3][O:2][CH3:1])=[N:38][CH:39]=1
Reactant: COCOc1cc(C2(C)OCCO2)ccc1C(=O)[O-]
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCOc1cc(C2(C)OCCO2)ccc1C(=O)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a suspension of lithium 2-(methoxymethoxy)-4-(2-methyl-1,3-dioxolan-2-yl)-benzoate (0.08 g, 0.29 mmol) in CH2Cl2 (2 mL) at 0° C. was added DMF (2 drops) followed by oxalyl chloride (0.025 mL, 0.29 mmol). Vigorous bubbling occurred. The reaction was stirred at room temperature for 30 min and then the solvent was removed under reduced pressure. The residue was suspended in CH2Cl2 (10 mL) and cooled to 0° C. Pyridine (0.07 mL, 0.87 mmol) and N-(5-chloropyridiri-2-yl)-2-aminobenzamide (0.072 g, 0.29 mmol) were added and the reaction was stirred at room temperature for 6 h. The reaction was quenched with H2O:EtOAc (10 mL each) and extracted with EtOAc (3×30 mL). The organic solution was washed with 2 NHC (cold), H2O (10 mL), 2 N NaOH (cold) and H2O (10 mL), dried (Na2 SO4), and concentrated. The resulting residue was purified by silica gel flash chromatography (n-hexanes through 30% EtOAc/n-hexanes) to obtain the desired product (0.110 g, 76%); TLC Rf: 0.42 (40% EtOAc/n-hexanes).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]([NH:19][C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])=[S:18])[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C>C(O)C.Cl.O>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]([NH:19][C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])=[S:18])[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cc(C)c(NC(=S)Nc2cccc(CO[Si](C)(C)C(C)(C)C)c2)c(C)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(NC(=S)Nc2cccc(CO)c2)c(C)c1
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To 0.56 g (0.1.4 mmol) of 1-[3-(tert-butyldimethylsilyloxymethyl)phenyl]-3-mesitylthiourea in 10 mL of ethanol was added 10 drops of concentrated hydrochloric acid. After 30 min, the reaction was diluted with water and the precipitate that formed was collected to give 0.35 g (86%) of the title compound as a white powder.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[NH:14][C:10]=3[CH:9]=2)[C:5]2[CH:18]=[C:19]([C:22]([O:24]C)=[O:23])[CH:20]=[CH:21][C:4]=2[O:3]1.Cl>O>[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[NH:14][C:10]=3[CH:9]=2)[C:5]2[CH:18]=[C:19]([C:22]([OH:24])=[O:23])[CH:20]=[CH:21][C:4]=2[O:3]1
Reactant: COC(=O)c1ccc2oc(=O)n(Cc3ccc4[nH]c(=O)[nH]c4c3)c2c1
Agent: Cl
Solvent: O
Product: O=C(O)c1ccc2oc(=O)n(Cc3ccc4[nH]c(=O)[nH]c4c3)c2c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
1.1 g (3.24 mmol) of methyl 2-oxo-3-(2-oxo-2,3-dihydro-1H-benzimidazol-5-ylmethyl)-2,3-dihydrobenzoxazole-5-carboxylate are suspended in 20 ml of water, 30 ml of conc. hydrochloric acid are added, and the mixture is stirred at a bath temperature of 100° C. for 24 h. A further 20 ml of conc. HCl are added, and the reaction mixture is stirred at a bath temperature of 130° C. for 3 days. The suspension is filtered and washed with water, and the residue is dried at 50° C. in a drying cabinet; product: 996 mg; m.p. 230-231° C.; ESI 326; HPLC: Rt=4.24 min (method A).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.OC1C=CC=C2C=1N=CC=C2.C(=O)([O-])[O-].[Cs+].[Cs+].[F:24][C:25]([F:35])([F:34])[O:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1>CCOC(C)=O.[Cu]I.O.CN(C=O)C>[Br:1][C:2]1[N:3]=[CH:4][N:5]([C:30]2[CH:29]=[CH:28][C:27]([O:26][C:25]([F:24])([F:34])[F:35])=[CH:32][CH:31]=2)[CH:6]=1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: Brc1c[nH]cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)Oc1ccc(-n2cnc(Br)c2)cc1
Temperature: 130 °C
Yield: 51.3 %

Procedure:
A round bottom flask was charged with 4-bromoimidazole (1.15 g, 7.81 mmol), CuI (0.07 g, 0.36 mmol), 8-hydroxyquinoline (0.05 g, 0.36 mmol), cesium carbonate (3.39 g, 10.4 mmol) and 4-trifluoromethoxyiodobenzene (1.50 g, 5.21 mmol). A 10:1 mixture of DMF (15 mL) and H2O (1.5 mL) was added to the reaction mixture, and the solution was heated to 130° C. for 4 h. The reaction mixture was then diluted with EtOAc and washed sequentially with water, ammonium chloride (saturated), water and sodium bicarbonate. The organics were dried over MgSO4, filtered and purified on a reverse phase column to give the imidazole (820 mg) as a white solid: mp 139-141° C.; ESIMS m/z 308.0 (M+H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.C([O-])(O)=O.[Na+].[C:16]([C:18]1[CH:19]=[N:20][C:21]([NH2:25])=[CH:22][C:23]=1[NH2:24])#[N:17].O>CO>[NH2:24][C:23]1[C:18]([C:16]#[N:17])=[CH:19][N:20]2[CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:25]=[C:21]2[CH:22]=1
Reactant: N#Cc1cnc(N)cc1N
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1cn2cc(-c3ccccc3)nc2cc1N

Procedure:
2-Bromoacetophenone (1.11 g, 5.6 mmol) and NaHCO3 (470 mg) were added to a solution of 3-cyano-4,6-diaminopyridine (500 mg, 3.7 mmol) in methanol (7.5 ml), and the mixture was heated to reflux overnight. Upon cooling, water (4 ml) was added and the precipitate was filtered and dried under vacuum to give a first crop of the desired product. The filtrate was evaporated, the residue was taken up in ethyl acetate (20 ml) and washed (water, brine). The organic layer was dried (Na2SO4) and evaporated. The residue was purified by column chromatography (silica gel, heptane:ethyl acetate=100:0-50:50) to give a second crop of the desired product. The combined crops gave the title compound (350 mg, 40%). MS (m/e)=235.1 [M+H+].
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([NH:8][C:9](=[O:18])[C:10]([CH3:17])([CH3:16])[CH:11]([OH:15])[CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1.I[CH3:22]>CN(C)C(=O)C.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:8][C:9](=[O:18])[C:10]([CH3:16])([CH3:17])[CH:11]([O:15][CH3:22])[CH:12]([CH3:13])[CH3:14])=[CH:19][CH:20]=1
Reactant: CI
Reactant: CC(C)C(O)C(C)(C)C(=O)Nc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(C(C)C)C(C)(C)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 44.7 %

Procedure:
To a stirred suspension of sodium hydride (0.25 g of a 60% dispersion in mineral oil, 5.1 mmol) in N,N-dimethylacetamide is added dropwise a solution of 4′-chloro-3-hydroxy-2,2,4-trimethylvaleranilide (1.5 g, 5.6 mmol) in N,N-dimethylacetamide. After stirring for 40 minutes at room temperature, iodomethane (1.58 g, 11.1 mmol) is added. The reaction mixture is stirred at room temperature for 18 hours, diluted with water, and extracted with ether. The combined organic extracts are washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a semisolid. Flash column chromatography of the semi-solid using silica gel and an ethyl acetate/hexanes solution (1:10) gives the title product as a white solid (0.71 g, mp 103-107° C.) which is identified by 1H NMR spectral analysis.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[CH:7][N:6]([CH2:21][CH3:22])[CH:5]=1)(=[O:3])C.ClN1C(=O)CCC1=O.[CH:31]([Cl:34])(Cl)[Cl:32]>>[Cl:32][CH:31]([Cl:34])[C:1]([C:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)=[CH:7][N:6]([CH2:21][CH3:22])[CH:5]=1)=[O:3]
Reactant: ClC(Cl)Cl
Reactant: CCn1cc(C(C)=O)c(=O)c(-c2cccc(C(F)(F)F)c2)c1
Agent: O=C1CCC(=O)N1Cl
Product: CCn1cc(C(=O)C(Cl)Cl)c(=O)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
A 0.9 g. portion of 3-acetyl-1-ethyl-5-(3-trifluoromethylphenyl)-4(1H)-pyridinone was combined with 0.8 g. of N-chlorosuccinimide in 125 ml. of chloroform. The mixture was stirred at reflux overnight, and was then cooled, washed with 1 N sodium hydroxide solution and then with saturated sodium chloride solution, and evaporated under vacuum to obtain 0.9 g. of an orange glass. The residue was chromatographed on a 350 g. silica gel column with 1:10 ethyl acetate:chloroform as the eluting solvent. The product-containing fractions were combined and evaporated under vacuum. The residue was then triturated under hexane to obtain 0.25 g. of the desired product, m.p. 108°-110°. Nmr analysis in DMSOd6 showed peaks at δ7.6-8.4 (m, 7H, aromatic and CHCl2); 4.0-4.4 (q, 2H, N--CH2); 1.4-1.6 (t, 3H, CH2CH3).
Reaction SMILES: CC1(C)[O:7][C:6](=[O:8])[C:5]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[C:4](=[O:29])[O:3]1.C1COCC1.[Li+].[OH-]>O>[N+:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:5]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)([C:4]([OH:29])=[O:3])[C:6]([OH:8])=[O:7])=[CH:15][CH:14]=1)([O-:18])=[O:17]
Reactant: CC1(C)OC(=O)C(Cc2ccc([N+](=O)[O-])cc2)(Cc2ccc([N+](=O)[O-])cc2)C(=O)O1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(Cc1ccc([N+](=O)[O-])cc1)(Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reaction time: 17 h
Yield: 87.2 %

Procedure:
An adaptation of the procedure described by Tiefenbacher and Rebek (2012) was followed. To a suspension of 5.33 g (12.9 mmol) of 2,2-dimethyl-5,5-di(4-nitrobenzyl)-1,3-dioxane-4,6-dione in 60 mL of a 9:1 mixture of THF to water was added 1.11 g (46.3 mmol) LiOH. This suspension was stirred for ˜17 h. After stirring, 100 mL of water was added to the suspension. The aqueous solution was washed twice with 50 mL of diethyl ether. The aqueous solution was then acidified to pH=1. The product was extracted with ethyl acetate. The ethyl acetate solution was washed once with 100 ml of water and once with 100 mL of brine. The ethyl acetate solution was dried with MgSO4 and the solvent was removed in vacuo to yield 4.21 g (87%) of the desired material. IR, 1HNMR, 13CNMR in addition to TLC were used to confirm identity of the product.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[O:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][O:9][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:18]I>CN(C)C=O>[CH3:18][O:1][C:2]1[CH:15]=[CH:14][C:5]2[O:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][O:9][C:4]=2[CH:3]=1
Reactant: CI
Reactant: COC(=O)C1=COc2cc(O)ccc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1=COc2cc(OC)ccc2O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
Stir for 15 minutes at room temperature, under argon, a solution of 0.48 mmol of methyl 6-hydroxy -1,4-benzodioxin-2-carboxylate in 5 cm3 of N,N-dimethylformamide in the presence of 0.57 mmol of 60% sodium hydride suspended in oil, and then add 0.72 mmol of methyl iodide. After being stirred for 4 hours at room temperature, the reaction mixture is concentrated under reduced pressure and then extracted with methylene chloride. After the methylene chloride phases have been concentrated to dryness, the crude product is purified by chromatography on a silica column (eluant:petroleum ether/ethyl acetate, 80:20). Methyl 6-methoxy -1,4-benzodioxin-2-carboxylate is thereby obtained in a yield of 78%.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1)[CH3:9])(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:8]([NH2:7])[CH3:9])=[N:11][CH:12]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H](N)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a solution of (S)-tert-butyl-1-(5-bromopyridin-2-yl)ethylcarbamate (Method 27; 2.0 g, 6.6 mmol) in DCM (15 ml) was added HCl/dioxane (17 ml, 4 N, 68 mmol). The reaction was stirred at room temperature for 1 hour. The solvent was removed and 10 ml of saturated sodium bicarbonate was added. The resulting aqueous solution was extracted with ether (6×100 ml), dried over sodium sulfate and concentrated to give the title compound (0.98 g, 73%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J=1.2 Hz, 1H), 7.76 (dd, J=2.0 and 8.4 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 4.13 (q, J=6.8 Hz, 1H), 1.73 (b, 2H), 1.41 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([CH3:24])=[C:21]([CH:23]=3)[NH2:22])=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH:25]1[CH:29]=[C:28]([CH2:30][C:31](Cl)=[O:32])[S:27][CH:26]=1.C(O)C(N)(CO)CO>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([CH3:24])=[C:21]([NH:22][C:31](=[O:32])[CH2:30][C:28]4[S:27][CH:26]=[CH:25][CH:29]=4)[CH:23]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1N
Reactant: O=C(Cl)Cc1cccs1
Agent: NC(CO)(CO)CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)Cc1cccs1
Reaction time: 16 h
Yield: 96.3 %

Procedure:
To a solution of 5-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-methylaniline (856 mg, 2.55 mmol) in THF (25 mL) was added thiophene-2-acetyl chloride (0.33 mL, 2.68 mmol). When TLC showed the reaction to be complete, PS-trisamine was added. After 16 h, TEA was added and the mixture was filtered. The filtrate was diluted with DCM and washed with water. The organic phase was dried over MgSO4 and concentrated onto silica gel. The crude material was purified by column chromatography to give of the desired product (1.13 g, 97%). 1H NMR (400 MHz, d6-DMSO) δ 9.63 (s, 1H), 8.87 (d, J=7.2 Hz, 1H), 8.43-8.39 (m, 2H), 7.70 (s, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.38-7.30 (m, 3H), 7.20 (m, 1H), 7.18 (d, J=6.8 Hz, 1H), 7.09-6.95 (m, 2H), 3.91 (s, 2H), 2.28 (s, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6](NC2C=CC(N)=CC=2OC)=[O:7])=[CH:4][CH:3]=1.COC1C=C([N+]([O-])=O)C=CC=1N.[Cl:32][C:33]1[CH:39]=[C:38]([N+:40]([O-])=O)[CH:37]=[C:36]([Cl:43])[C:34]=1[NH2:35]>>[NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:35][C:34]2[C:33]([Cl:32])=[CH:39][C:38]([NH2:40])=[CH:37][C:36]=2[Cl:43])=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Reactant: COc1cc(N)ccc1NC(=O)c1ccc(N)cc1
Agent: COc1cc([N+](=O)[O-])ccc1N
Product: Nc1ccc(C(=O)Nc2c(Cl)cc(N)cc2Cl)cc1

Procedure:
By operating as described under (a) above, but using instead of 202 parts of 2-methoxy-4-nitro-aniline, 248 parts of 2,6-dichloro-4-nitro-aniline, high yields of 4,4'-diamino-2'6'-dichloro-benzanilide were obtained.
Reaction SMILES: C[Li].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:27]=[CH:26][CH:25]=[CH:24][C:12]=1[NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:10].O1CCC[CH2:29]1>C1C=CC=CC=1.CCCCCC>[OH:10][C:9]([C:11]1[CH:27]=[CH:26][CH:25]=[CH:24][C:12]=1[NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1)[CH3:29]
Reactant: COc1ccc(C(=O)Nc2ccccc2C(=O)c2ccccn2)cc1
Reactant: C1CCOC1
Agent: [Li]C
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COc1ccc(C(=O)Nc2ccccc2C(C)(O)c2ccccn2)cc1
Reaction time: 0.5 h

Procedure:
Methyl lithium (0.24 mole, 142 ml. of 1.7 molar in ether) is added to 2'-(2-pyridinecarbonyl)-p-anisanilide (36.6 g., 0.11 mole) in 400 ml. of tetrahydrofuran in 15 min. with stirring at 10°-20°C. Stirring is continued for another 30 min., the reaction mixture hydrolyzed by addition of 300 ml. of water, concentrated under reduced pressure until the tetrahydrofuran solvent is substantially removed, and the mixture extracted with ethyl acetate. The ethyl acetate extract washed with water, brine, dried over sodium sulfate and concentrated affords a residual dark brown oil. The residue taken up in benzene and diluted with hexane affords 2'-[1-hydroxy-1-(2-pyridyl)ethyl]-p-anisanilide, m.p. 127°-128°C., from aqueous-methanol.