Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[C:23]([CH3:30])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl.NO.[CH3:34]CN=C=NCCCN(C)C.C1C=C[C:48]2[N:53]([OH:54])N=NC=2C=1.CCN(CC)CC>CCOC(C)=O.CN(C=O)C>[CH2:1]([C:3]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:53]([O:54][CH3:34])[CH3:48])=[O:27])=[C:23]([CH3:30])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:17])([CH3:16])[CH3:18])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(C(=O)O)c(C)c1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(C(=O)N(C)OC)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
To a mixture of enantiomer 1 of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid (1.11 g, 2.69 mmol) and DMF (5 mL) is added hydroxylamine hydrochloride (0.29 g, 2.96 mmol), EDCI (0.57 g, 2.96 mmol), HOBt (0.40 g, 2.96 mmol), and NEt3 (1.65 mL, 11.84 mmol). The mixture is stirred at ambient temperature overnight, diluted with EtOAc (40 mL), washed with 1M HCl (40 mL), water (40 mL), brine (40 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO (110%-40% EtOAc gradient) to furnish the title compound (1.0 g, 2.19 mmol, 81%).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[C:9]1([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[CH2:20][CH2:21][S:22][CH3:23]>C1CCCCC1.O1CCCC1>[CH3:23][S:22][CH2:21][CH2:20][CH:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:16]([O:18][CH3:1])=[O:17]
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(O)Cc1ccccc1
Reactant: CSCCCl
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)C(CCSC)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Lithium diisopropylamide (450 ml of a 1.5M solution in cyclohexane) was added to a stirred solution of phenylacetic acid (40.8 g) in tetrahydrofuran (300 ml) at between 0° and 5° C. The mixture was warmed to room temperature, stirred for 1.5 hours, treated with 2-chloroethylmethylsulphide (30 ml) in tetrahydrofuran 30 ml, refluxed for 2 hours, cooled and evaporated. To the residue in methanol (200 ml) was added concentrated sulphuric acid (50 ml) in methanol (250 ml), the mixture refluxed for 1.5 hours, and evaporated. The residue was partitioned between water and chloroform, the organic layer washed with aqueous 10% potassium carbonate, dried over sodium sulphate and evaporated to give a light brown oil (55 g). A portion of this (33 g) was distilled to give the title compound (24.5 g, 61%) as a clear liquid b.p. 128°-135° C. at 5 mm Hg.
Reaction SMILES: [Cu]([C:4]#[N:5])C#N.Br[C:7]1[CH:8]=[CH:9][C:10](/[C:15](/[C:34]2[CH:39]=[CH:38][C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:36][CH:35]=2)=[CH:16]/[C@@H:17]2[N:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH3:32])[C:20](=[O:33])[CH2:19][CH2:18]2)=[N:11][C:12]=1[O:13][CH3:14].O>CN(C)C=O>[C:40]([C:37]1[CH:36]=[CH:35][C:34](/[C:15](/[C:10]2[N:11]=[C:12]([O:13][CH3:14])[C:7]([C:4]#[N:5])=[CH:8][CH:9]=2)=[CH:16]\[C@H:17]2[CH2:18][CH2:19][C:20](=[O:33])[N:21]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])=[CH:39][CH:38]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(Br)c(OC)n2)c(OC)c1
Reactant: N#C[Cu]C#N
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(C#N)c(OC)n2)c(OC)c1
Temperature: 180 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
Copper cyanide (27 mg) was added to a solution of (5R)-5-[(E)-2-(5-bromo-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in Reference Example 4-42(1) (90 mg) in N,N-dimethylformamide (5 mL), and the mixture was stirred at an external temperature of 180° C. for two hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to give 6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridine-3-carbonitrile (32 mg, 40%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]([C:16]([F:19])([F:18])[F:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:4][C:3]=1[O:20][CH3:21].[N+:22]([O-])([OH:24])=[O:23]>C(O)(=O)C>[OH:1][C:2]1[C:7]([N+:22]([O-:24])=[O:23])=[CH:6][C:5]([C:8]([C:10]2[C:11]([C:16]([F:17])([F:18])[F:19])=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:4][C:3]=1[O:20][CH3:21]
Reactant: COc1cc(C(=O)c2cccnc2C(F)(F)F)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1cc(C(=O)c2cccnc2C(F)(F)F)cc([N+](=O)[O-])c1O

Procedure:
To a solution of (4-hydroxy-3-methoxyphenyl)(2-(trifluoromethyl)pyridin-3-yl)methanone (0.472 g, 1.59 mmol) in acetic acid (10 mL) at room temperature was added 60% nitric acid (0.14 mL, 1.75 mmol) dropwise. The resulting mixture was allowed to stir for thirty minutes then poured onto ice-water (100 mL) and the resulting precipitate was filtered off, washed with water and dried. Recrystallisation from ethanol afforded (4-hydroxy-3-methoxy-5-nitrophenyl)(2-(trifluoromethyl)pyridin-3-yl)methanone as a yellow solid, 0.315 g (58%).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].S(Cl)([Cl:12])=O>>[Cl-:12].[CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O-:9])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: Cc1sccc1C(=O)O
Product: Cc1sccc1C(=O)[O-]
Product: [Cl-]

Procedure:
2-Methyl-3-thiophenecarboxylic acid (54 g) was reacted with thionyl chloride (100 ml) at 60° C. for 1.5 hr. The reaction solution was evaporated, and to the resulting residue was added THF (100 mlx2), and then excess thionyl chloride was removed, to give 60.5 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.ClC1C=C(C=CN=1)C#N.[Cl:19][C:20]1[CH:25]=[C:24]([C:26]([C:28]2[CH:29]=[C:30]([NH:53][C:54](=[O:56])[CH3:55])[CH:31]=[C:32]([C:34]3[CH:42]=[CH:41][CH:40]=[C:39]4[C:35]=3[CH:36]=[CH:37][N:38]4[Si](C(C)C)(C(C)C)C(C)C)[CH:33]=2)=[O:27])[CH:23]=[CH:22][N:21]=1>>[Cl:19][C:20]1[CH:25]=[C:24]([C:26]([C:2]2[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=2)=[O:27])[CH:23]=[CH:22][N:21]=1.[Cl:19][C:20]1[CH:25]=[C:24]([C:26]([C:28]2[CH:29]=[C:30]([NH:53][C:54](=[O:56])[CH3:55])[CH:31]=[C:32]([C:34]3[CH:42]=[CH:41][CH:40]=[C:39]4[C:35]=3[CH:36]=[CH:37][NH:38]4)[CH:33]=2)=[O:27])[CH:23]=[CH:22][N:21]=1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: CC(=O)Nc1cc(C(=O)c2ccnc(Cl)c2)cc(-c2cccc3c2ccn3[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: N#Cc1ccnc(Cl)c1
Product: CC(=O)Nc1cc(C(=O)c2ccnc(Cl)c2)cc(-c2cccc3[nH]ccc23)c1
Product: O=C(c1cc(Br)cc(Br)c1)c1ccnc(Cl)c1

Procedure:
(2-Chloro-pyridin-4-yl)-(3,5-dibromo-phenyl)-methanone was prepared from 1,3,5-tribromobenzene and 2-chloro-isonicotinonitrile as described in Example 25. This was converted to N-[3-(2-chloro-pyridine-4-carbonyl)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]-acetamide in the same manner as described for Example 82. N-[3-(2-Chloro-pyridine-4-carbonyl)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]-acetamide was deprotected to give N-[3-(2-chloro-pyridine-4-carbonyl)-5-(1H-indol-4-yl)-phenyl]-acetamide as described in Example 75. 1H NMR (400 MHz, CD3COCD3): δ 10.48 (s, 1H), 9.53 (s, 1H), 8.63 (d, J=5.0 Hz, 1H), 8.41 (t, J=1.7 Hz, 1H), 8.14 (t, J=1.6 Hz, 1H), 7.82 (t, J=1.5 Hz, 1H), 7.79 (s, 1H), 7.71 (dd, J=5.0, 1.3 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.43 (t, J=2.8 Hz, 1H), 7.23-7.15 (m, 2H), 6.74 (s, 1H), 2.15 (s, 3H).
Reaction SMILES: C[C-:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[C-:7]1(C)[CH:11]=[CH:10][CH:9]=[CH:8]1.[Zr+2:13].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C>C1(C)C=CC=CC=1>[O-:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O-:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH-:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH-:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.[Zr+2:13]
Reactant: Oc1ccccc1
Reactant: C[c-]1cccc1
Agent: [Zr+2]
Solvent: Cc1ccccc1
Product: [O-]c1ccccc1
Product: c1cc[cH-]c1

Procedure:
In a flask containing 50 ml of toluene, 1.988 millimoles of dimethyl zirconocene were dissolved. Successively under stirring 3.976 millimoles of phenol were added. The solution develops methane according to the reaction:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)C.O.[NH2:14][NH2:15]>C(O)C>[N:6]1([CH2:5][C:4]([NH:14][NH2:15])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: NN
Reactant: CCOC(=O)CN1CCCCC1
Solvent: CCO
Solvent: O
Product: NNC(=O)CN1CCCCC1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
3.86 g of piperidin-1-yl-acetic acid ethyl ester was dissolved in 40 mL of ethanol, added with 3.39 mL of hydrazine monohydrate, and stirred at 70° C. for 5 hours. After allowing the solution to cool to room temperature, the solvent was evaporated, to afford 3.8 g of the title compound as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:5]2[N:6]([C:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[C:13]([CH3:20])[CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1.F[P-](F)(F)(F)(F)F.CN([C+](N(C)C)N1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[Br:1][C:2]1[N:3]=[C:4]([NH:21][CH2:22][CH:23]([CH3:24])[CH3:25])[C:5]2[N:6]([C:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([NH:29][CH:26]4[CH2:28][CH2:27]4)=[O:16])=[C:13]([CH3:20])[CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: Cc1cc(-c2cnc3c(NCC(C)C)nc(Br)cn23)ccc1C(=O)O
Reactant: NC1CC1
Agent: CN(C)[C+](N(C)C)n1n[n+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2cnc3c(NCC(C)C)nc(Br)cn23)ccc1C(=O)NC1CC1
Temperature: 23 °C
Reaction time: 8 h
Yield: 14.8 %

Procedure:
To a solution of 411 mg (1 mmol) 4-(6-Bromo-8-isobutylamino-imidazo[1,2-a]pyrazin-3-yl)-2-methyl-benzoic acid which was prepared according to intermediate example 49b in 4 mL 1-methylpyrrolidin-2-one were added 114.9 mg cyclopropanamine, 760 mg bis(dimethylamino)(3-oxido-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)methylium hexafluorophosphate and 685 μL N-ethyl-N-isopropylpropan-2-amine and the mixture was stirred overnight at 23° C. After filtration and removal of the solvent the residue was purified by chromatography to give 65.5 mg (15%) of the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:24]=[C:12]3[NH:13][C:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH:19]([CH3:23])[CH2:18]4)=[N:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.CCN(CC)CC.[ClH:36]>C(Cl)Cl.C(Cl)(Cl)Cl>[OH2:2].[ClH:36].[CH3:23][CH:19]1[CH2:18][CH:17]([C:14]2[NH:13][C:12]3=[CH:24][C:9]([C:6]4[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=4)=[N:10][C:11]3=[CH:16][N:15]=2)[CH2:22][CH2:21][NH:20]1
Reactant: COc1ccc(-c2cc3[nH]c(C4CCNC(C)C4)ncc-3n2)cc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1CC(c2ncc3nc(-c4ccc(O)cc4)cc-3[nH]2)CCN1
Product: O
Temperature: -70 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
The suspension of 4-methoxy-1-(2-methyl-4-piperidylpyrrolo[4,5-d]pyrimidin-6-yl)benzene (Example 71(e)) (0.138 g, 0.43 mmol) in anhydrous CH2Cl2 (12 mL) was cooled to −70° C. under nitrogen atmosphere. Boron tribromide (Aldrich Chemical Company) (0.41 mL, 4.3 mmol) in CH2Cl2 (4 mL) was added dropwise. The reaction mixture was stirred at −70° C. to room temperature for 16 h. The solution was poured into 40 mL of ice-water. The resulting mixture was basified with Et3N to pH 10 and stirred for a period of 3 h. The precipitate that formed was collected by filtration, washed with H2O, and dried in a vacuum oven to give 78.7 mg (60%),of a tan solid. A portion of this material (74 mg, 0.24 mmol) was dissolved in minimum amount of CHCl3 and ethereal hydrogen chloride (1N, 0.26 mL, 0.26 mmol) was added dropwise. The mixture was stirred at room temperature for 20 min. Solvent was then evaporated in vacuo to give a brown solid, which was recrystallized from MeOH/H2O to give 25 mg of the title compound as light-tan crystals. MP:>300° C. (dec). 1H NMR (DMSO-d6; 400 MHz): δ 1.70 (m, 6), 2.55 (s, 3), 4.03 (m, 4), 6.73 (s, 1), 6.93 (d, 2, J=8.54), 7.79 (d, 2, J=8.54), 10.04 (s, 1), 11.75 (br s, 1), 14.15 (br s, 1); MS m/z: 309 (M+1), 307 (M−1). Calcd for C18H21ClN4OH2O: C, 59.58; H, 6.39; N, 15.44. Found: C, 59.13; H, 6.33; N, 15.20.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O.CO>O1CCCC1>[N:1]1([C:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(C(=O)N2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C(=O)N2CCCC2)cc1

Procedure:
29.0 g (0.146 mol) of monomethyl terephthalate chloride was reacted with 14.2 g (200 mmol) of pyrrolidine and 21.0 g (208 mmol) of triethylamine in 350 ml of dichloromethane. After the treatment in an ordinary manner, methyl 4-(1-pyrrolidylcarbonyl)benzoate was obtained. 29.0 g of the ester was hydrolyzed with 12.0 g of sodium hydroxide in a mixed solvent comprising 70 ml of water, 70 ml of methanol and 70 ml of tetrahydrofuran. After the completion of the reaction, the solvent was evaporated. 1 N hydrochloric acid was added to the residue and the obtained mixture was treated with dichloromethane as the extraction solvent in an ordinary manner to obtain the title compound.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:17]1([CH2:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.CCCCCC>[C:1]([N:5]([C:24](=[O:25])[CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
N'-t-butyl-N-benzoylhydrazine (2 g) was stirred in toluene (35 ml) and 50% aqueous sodium hydroxide (1 g) at 5° C. Phenylacetylchloride (1.5 g) was added slowly, dropwise to the reaction mixture, warmed to room temperature and stirred 1 hour. The reaction mixture was diluted with hexane (50 ml) and filtered off to yield a solid product. The filter cake was washed with hexane and water and allowed to air dry. The white solid product obtained in 90% yield melted at 167-169° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[CH3:17][O:18][CH2:19][CH2:20][NH2:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH:21][CH2:20][CH2:19][O:18][CH3:17]
Reactant: COCCN
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COCCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
In 43 ml of dichloromethane were dissolved 2.45 g of 3,5-bistrifluoromethylbenzaldehyde, 835 mg of 2-methoxyethylamine and 687 μl of acetic acid, added thereto was 3.12 g of sodium triacetoxy borohydride, and the mixture was stirred at room temperature for an hour under nitrogen atmosphere. The reaction mixture was washed with a 0.5M aqueous sodium hydroxide solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=19:1→9:1), to give 2.76 g of 3,5-bistrifluoromethylbenzyl-2-methoxyethylamine.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][NH2:11])[CH:6]=[CH:7][C:8]=1[Cl:9].[CH3:12][CH2:13][O:14][C:15]([CH:17]([C:21]([CH3:23])=O)[C:18]([CH3:20])=O)=[O:16]>>[CH2:13]([O:14][C:15]([C:17]1[C:18]([CH3:20])=[N:11][N:10]([C:5]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=2)[C:21]=1[CH3:23])=[O:16])[CH3:12]
Reactant: NNc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Agent: Cl
Product: CCOC(=O)c1c(C)nn(-c2ccc(Cl)c(Cl)c2)c1C
Yield: 32 %

Procedure:
In analogy to the procedure described in Example 38A], 3,4-dichlorophenylhydrazine hydrochloride and ethyl diacetoacetate gave the title compound in 32% yield as yellow solid. MS: 313.0 (MH+, 2 Cl).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2].[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[F:21])[C:15](O)=[O:16].O>N1C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[F:21])[C:15]([NH:10][C:7]1[N:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=1)=[O:16]
Reactant: Nc1ncc([N+](=O)[O-])cn1
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1ncc([N+](=O)[O-])cn1)c1ccc(F)c(Cl)c1
Temperature: 100 °C
Yield: 55.1 %

Procedure:
To 5-nitropyrimidin-2-amine (1.0 g, 7.1 mmol) in pyridine (10 mL) was added 3-chloro-4-fluorobenzoic acid (1.7 g, 9.7 mmol). The reaction mixture was heated at 100° C. for 4 hrs and allowed to cool to rt. 15 mL H2O was added. A precipitate was collected by filtration and purified by silica gel chromatography, eluting with CH2Cl2 followed by 10% EtOAc/CH2Cl2 to give 1.16 g (55% yield) 1C. RP HPLC ret. t.: 2.22 min. and (M+H)+: 297.
Reaction SMILES: [CH2:1]([S:6]([NH:9][C:10](=[O:30])[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[CH:12]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5].O1CCCC1.C(O)C.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH2:1]([S:6]([NH:9][C:10](=[O:30])[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[CH:12]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCS(=O)(=O)NC(=O)c1ccc([N+](=O)[O-])c(NCc2ccc(Cl)cc2Cl)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCS(=O)(=O)NC(=O)c1ccc(N)c(NCc2ccc(Cl)cc2Cl)c1
Temperature: 100 °C
Yield: 54.6 %

Procedure:
N-(n-pentanesulfonyl)-3-(2,4-dichlorobenzylamino)-4-nitrobenzamide (38.9 g) was mixed with 200 ml of tetrahydrofuran, 200 ml of ethanol and 800 ml of water. Sodium hydrosulfite (214.2 g) was added all at once to the mixture with stirring. Immediately, the mixture was placed on an oil bath at 90° C. and refluxed for 40 minutes. The mixture was then cooled down and separated into aqueous and organic layers. The organic layer was concentrated, and water was added to the resulting residue. The precipitate thus formed was separated by filtration, and washed subsequently with water and ethyl acetate. Ethanol (520 ml) was added to the resulting solid, and the mixture was refluxed at 100° C. to dissolve the solid completely. Water (230 ml) was added to the heated solution, and the mixture was cooled with stirring for 1 hour. The resulting crystals were separated through filtration, washed with a solution of ethanol/water (7:3) and dried to give pale-yellow crystals (19.9 g) of N-(n-pentanesulfonyl)-4-amino-3-(2,4-dichlorobenzylamino)benzamide (31).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:10][O:11][C:12]=1[CH3:13])=[O:7].[F:20][C:21]([F:37])([F:36])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.O[C:39]1C=CC(Cl)=CC=1N1CCNCC1>C(OCC)(=O)C>[CH2:13]([C:12]1[O:11][N:10]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]=1[C:6]([NH:5][CH2:4][CH2:3][CH2:2][N:33]1[CH2:34][CH2:35][N:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][CH2:22][C:21]([F:20])([F:36])[F:37])[CH2:31][CH2:32]1)=[O:7])[CH3:39]
Reactant: Oc1ccc(Cl)cc1N1CCNCC1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NCCCCl
Reactant: FC(F)(F)COc1ccccc1N1CCNCC1
Solvent: CCOC(C)=O
Product: CCc1onc(-c2ccccc2)c1C(=O)NCCCN1CCN(c2ccccc2OCC(F)(F)F)CC1
Yield: 54 %

Procedure:
The title compound was obtained following the procedure described in Example 2 but substituting Compound 19A for Compound 2B and 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine for 1-(2-hydroxy-5-chlorophenyl)piperazine. The crude was taken up with ethyl acetate and purified by flash chromatography eluting (ethyl acetate-2 N ammonia in methanol 98:2) to afford the title compound (54%). M.p. 102-104° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]3([CH3:31])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH2:21][CH2:20]2)[C:12]=1[OH:32].[Cl:33][C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[ClH:33].[F:10][C:11]1[C:12]2[O:32][C:34](=[O:36])[N:18]([CH:19]3[CH2:20][CH2:21][N:22]([C:25]4([CH3:31])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH2:23][CH2:24]3)[C:13]=2[CH:14]=[C:15]([CH3:17])[CH:16]=1
Reactant: Cc1cc(F)c(O)c(NC2CCN(C3(C)CCOCC3)CC2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)c2oc(=O)n(C3CCN(C4(C)CCOCC4)CC3)c2c1
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
DIPEA (0.14 mL, 0.79 mmol) was added to a solution of 2-fluoro-4-methyl-6-{[1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinyl]amino}phenol (D17, 51 mg, 0.16 mmol) in DCM (5 mL) at room temperature under argon. The reaction was cooled to 0° C. and the triphosgene (19 mg, 0.07 mmol) was added. The mixture was stirred for 30 min at 0° C., followed by a further 15 min at room temperature. The reaction was quenched with sat. NaHCO3 (5 mL) and partitioned between DCM and H2O. The aqueous layer was extracted with DCM (2×) and the combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give the crude product, which was purified via flash column chromatography (silica, DCM to 0.5% NH3/9.5% MeOH/90% DCM) to give the free base of the title compound as a white solid. The free base was dissolved in DCM (2 mL) at 25° C. HCl (0.24 mL, 0.24 mmol, 1 M in Et2O) was then added and the reaction was stirred for 15 min. The solvent was removed by rotary evaporation to give 7-fluoro-5-methyl-3-[1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one hydrochloride (E4, 47 mg, 70%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:5][S:11]([CH3:10])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a solution of 2-fluorobenzyl alcohol (4.40 g, 34.9 mmol) in dichloromethane (40 mL) was added methanesulfonyl chloride (3.24 mL, 41.9 mmol) and triethylamine (5.84 mL, 41.9 mmol) on an ice bath, the solution was warmed to room temperature and stirred overnight. The reaction solution was diluted with dichloromethane, washed with an aqueous solution of 5% sodium bicarbonate, then, dried over anhydrous magnesium sulfate, the solvent was evaporated, and the title compound (4.62 g, 65%) was obtained as a brown oil. This was used in the next reaction without purification.