Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([NH2:11])[CH3:10].C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([NH:11][C:41]([C:37]1[CH:36]=[C:35]2[C:40](=[CH:39][CH:38]=1)[N:32]([CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]3[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:30][CH:29]=1)[C:33]([CH3:45])=[C:34]2[CH3:44])=[O:42])[CH3:10]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1cccc(F)c1Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(F)c3Cl)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(2-chloro-3-fluorophenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 504 [M+H]+.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][CH2:6][S:5](=[O:9])(=[O:8])[NH:4]1)[CH3:2].Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:18])=[C:13]([F:33])[CH:12]=1>>[CH3:31][C:30]1[C:25]([N:22]2[CH2:23][CH2:24][N:19]([C:17]([C:14]3[CH:15]=[CH:16][C:11]([N:4]4[C@H:3]([CH2:1][CH3:2])[CH2:7][CH2:6][S:5]4(=[O:9])=[O:8])=[CH:12][C:13]=3[F:33])=[O:18])[CH2:20][CH2:21]2)=[N:26][CH:27]=[C:28]([CH3:32])[CH:29]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: CC[C@@H]1CCS(=O)(=O)N1
Product: CC[C@@H]1CCS(=O)(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(F)c1
Yield: 13 %

Procedure:
Using (R)-3-ethylisothiazolidine 1,1-dioxide (150 mg) described in Preparation Example 3 and (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (439 mg) described in Preparation Example 114 and by the reaction and treatment in the same manner as in Example 1, the title compound (60 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]([N:16]3[CH2:19][CH:18]([O:20][C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH2:17]3)=[O:15])=[N:11][N:10]=2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.[CH2:36]([C:38]1([OH:42])[CH2:41][NH:40][CH2:39]1)[CH3:37].CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:36]([C:38]1([OH:42])[CH2:41][N:40]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH:18]3[CH2:19][N:16]([C:14]([C:12]4[O:13][C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)=[N:10][N:11]=4)=[O:15])[CH2:17]3)=[CH:28][CH:27]=2)[CH2:39]1)[CH3:37]
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4)C3)o2)cc1
Reactant: CCC1(O)CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCC1(O)CN(Cc2ccc(OC3CN(C(=O)c4nnc(-c5ccc(OC)cc5)o4)C3)cc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
To a solution of 55A (0.20 g, 0.53 mmol) in DCM (10 mL) was added 70A (0.20 g, 0.93 mmol) followed by DIPEA (0.17 mL, 0.95 mmol). The mixture was stirred at RT for 20 min and then sodium triacetoxyborohydride (0.22 g, 1.05 mmol) was added. The mixture was stirred at RT overnight and then washed with an aqueous solution of Na2CO3. The organic solution was filtered through a phase separator and then the solvent was removed by evaporation. The product was purified on a silica gel column using ethyl acetate and then 5% methanol in DCM where the methanol contained 2M ammonia. There was obtained 128 mg (52%) of 70 as a solid. 1H NMR (500 MHz, CDCl3): δ 0.95 (t, 3H), 1.77 (q, 2H), 3.02 (d, 2H), 3.30 (d, 2H), 3.60 (s, 2H), 3.88 (s, 3H), 4.32 (m, 1H), 4.63 (m, 1H), 4.72 (m, 1H), 5.10 (m, 2H), 6.71 (d, 2H), 7.01 (d, 2H), 7.22 (d, 2H), 8.10 (d, 2H), MS (APCI+) m/z 465 [M+H]+, LC purity: 97%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]3[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=3[O:32][CH3:33])=[O:22])=[C:16]([F:34])[CH:15]=2)[CH2:9]1)=O)(C)(C)C.[ClH:35].O1CCOCC1>C1COCC1>[ClH:35].[C:30]([C:28]1[CH:27]=[CH:26][C:25]([O:32][CH3:33])=[C:24]([NH:23][C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([C@@H:10]3[O:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[CH:15][C:16]=2[F:34])=[O:22])[CH:29]=1)#[N:31]
Reactant: COc1ccc(C#N)cc1NC(=O)Nc1ccc([C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1ccc(C#N)cc1NC(=O)Nc1ccc([C@H]2CNCCO2)cc1F
Temperature: 60 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
To a solution of (S)-2-{4-[3-(5-Cyano-2-methoxy-phenyl)-ureido]-3-fluoro-phenyl}-morpholine-4-carboxylic acid tert-butyl ester (97 mg, 106 μmol, Eq: 1.00) in THF (4 ml) was added 4M−HCl in dioxane (0.773 ml, 3.09 mmol, Eq: 15). The reaction mixture was stirred at 60° C. for 5 h. To the cooled mixture was then added ethyl acetate and the suspension was filtered off and dried under high vacuo to give the target compound as an off-white solid (63 mg, 75%). MS (ISP): 369.1 ([M+H]+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].C([O:13][C:14](=O)[CH2:15][C:16]([CH3:18])=O)C.[OH-].[Na+]>C(O)(=O)C.O.C(Cl)Cl>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:14](=[O:13])[CH:15]=[C:16]([CH3:18])[NH:10]1
Reactant: CCOC(=O)CC(C)=O
Reactant: NNc1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(=O)n(-c2ccccc2F)[nH]1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
A stirred suspension of 2-fluorophenylhydrazine hydrochloride (1000 g, 5535 mmol) in acetic acid (1000 ml) and water (1000 ml) was heated at 45° C. Ethylacetoacetate (700 ml) was added dropwise over 30 mins and this was stirred at 88° C. for 2 hr. The resulting mixture was cooled to 5° C. and poured onto ice (3000 g) and DCM (4500 ml). 30% NaOH (aq) (2400 ml) was added and the mixture was stirred for 15 mins, then separated and extracted with DCM (1500 ml). The organic extracts were washed with 1M NaOH (aq) (1500 ml). The aqueous phases were combined and ice (1500 g) and DCM (3600 ml) were added. To the stirred mixture was added 32% HCl (aq) (2400 ml) until the pH was adjusted to pH 1-2. The biphasic mixture was separated, extracted with DCM (1500 ml) and the organic extracts washed with brine/water 4:1 (2000 ml), dried over MgSO4 and evaporated to dryness to give a dark solid. To a stirred solution of the crude product in DCM (2000 ml) was added silica gel (350 g). This was filtered and the filtrate was evaporated. Purification by chromatography with MeOH in EtOAc gave the title compound as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:14])=[C:6]([C:8](=[O:13])[CH2:9][CH2:10][C:11]#[N:12])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:24][C:25]([N:27]1[CH2:32][CH:31]([CH3:33])[N:30]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH2:29][CH:28]1[CH3:42])=[O:26]>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH2:24][C:25]([N:27]2[CH2:32][C@H:31]([CH3:33])[N:30]([CH2:34][C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[CH2:29][C@H:28]2[CH3:42])=[O:26])=[C:6]([C:8](=[O:13])[CH2:9][CH2:10][C:11]#[N:12])[CH:7]=1
Reactant: CC1CN(C(=O)CCl)C(C)CN1Cc1ccc(F)cc1
Reactant: N#CCCC(=O)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C(=O)CCC#N
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.8 %

Procedure:
To a solution of 4-(5-chloro-2-hydroxy-phenyl)-4-oxo-butyronitrile (0.15 g, 0.70 mmol) in acetonitrile (4 mL) was added potassium carbonate (0.16 g, 1.16 mmol), potassium iodide (0.040 g, 0.24 mmol) and (2-chloro-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.21 g, 0.70 mmol). The reaction was stirred for 20 hours at ambient temperature. Tetrahydrofuran (8 mL) was added and solids were removed by filtration. The filtrate was concentrated and the crude product purified by flash chromatography to give the title compound (0.31 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:14]N1C(C)(C)C(=O)N(Br)C1=O>OS(O)(=O)=O>[Br:14][C:8]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]([CH3:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: Cc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 181.6 %

Procedure:
To stirred solution of 2-methyl-3-nitrobenzoic acid (50 g, 276.2 mmol) in conc. H2SO4 (200 mL), 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (43.4 g, 151.8 mmol) was added portion wise at room temperature and reaction mass was stirred at room temperature for 5 h. On completion, reaction mass was poured on ice cold water, solid precipitated was filtered, resulting residue was washed with water and dried under vacuum to give the desired compound (71.7 g, 100%).
Reaction SMILES: [C@H:1]12[CH2:14][CH:4]([N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6]1)[CH2:3][NH:2]2.[Cl:15][C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Cl:15][C:16]1[N:17]=[N:18][C:19]([N:2]2[CH2:3][CH:4]3[CH2:14][C@H:1]2[CH2:6][N:5]3[C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CC1CN2
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CC1CN2c1ccc(Cl)nn1

Procedure:
0.397 g (2.0 mmol) of 1,1-dimethylethyl (1S)-2,5-diazabicyclo[2.2.1]heptane-5-carboxylate, 0.328 g (2.2 mmol) of 3,6-dichloropyridazine and 1.3 g (4 mmol) of caesium carbonate in 30 ml of toluene are placed into a 100 ml three-necked round-bottomed flask and the mixture is refluxed for 48 h.
Reaction SMILES: [F:1][C:2]([F:14])([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[BH4-].[Na+]>CO>[F:14][C:2]([F:1])([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[CH:3]([O:5][CH3:6])[OH:4]
Reactant: COC(=O)C(F)(F)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(O)C(F)(F)c1ccc(F)cc1
Temperature: -57.5 °C
Reaction time: 1.25 h
Yield: 94.6 %

Procedure:
A solution of methyl difluoro(4-fluorophenyl)acetate (2.04 g, 10.0 mmol) from Step E in methanol (10.0 mL) was cooled to −60° C. Sodium borohydride (380 mg, 10.0 mmol) was added in 5 portions at 10 to 15 min. intervals. The mixture was cooled to −60 to −55° C. prior to each addition and allowed to warm to −45° C. following each addition. After the last addition, the mixture was stirred 1.25 h at −50 to −45° C. The mixture was cooled to −60° C. and quenched with 1 N aq. HCl (30 mL), with the temperature rising to −20° C. near the end of the addition. After warming to 0° C., the mixture was extracted with ether (3×20 mL). The combined ether layers were washed with water (2×20 mL), dried (sodium sulfate), decanted, and evaporated to give 1.95 g of crude 2,2-difluoro-2-(4-fluorophenyl)-1-methoxyethanol as a pale yellow oil.
Reaction SMILES: [Se](=O)=O.O.[CH2:5]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:23]/[C:24](/[C:29]#[N:30])=[C:25](\[NH2:28])/[C:26]#[N:27]>O1CCOCC1.C(O)(=O)C>[CH2:5]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:23]=[C:24]([C:29]#[N:30])[C:25]([C:26]#[N:27])=[N:28][CH:21]=2)=[CH:16][CH:15]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCOc1ccc(C(C)=O)cc1
Reactant: N#C/C(N)=C(/N)C#N
Agent: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCOc1ccc(-c2cnc(C#N)c(C#N)n2)cc1
Reaction time: 2 h
Yield: 81.3 %

Procedure:
Selenium dioxide in an amount of 11.4 g (0.1 mol) was mixed with 100 ml of dioxide and 2 ml of water. The mixture was stirred for 2 hours at 70°-75° C., and a solution of 24.8 g (0.1 mol) of p-octyloxyacetophenone in 60 ml of dioxane was added thereto. After 2 hours of refluxing, the mixture was cooled to precipitate metal selenium, which was then removed by filtration. Into the filtrate were added 10.8 g (0.1 mol) of diaminomaleonitrile and 3.0 ml of acetic acid, and the mixture was refluxed for 2 hours at 90°-93° C. After the reaction, the mixture was subjected to cooling and filtration, and the filtrate was condensed to obtain a crude product. The crude product was subjected to recrystallization from hexane to obtain 27.2 g (82% yield) of the product. The meling point: 79° C., IR (νcm-1): 2245 (C≡N).
Reaction SMILES: [Cl-].[F:2][C:3]([F:29])([F:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)([OH:17])[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.[CH2:39]([O:41][P:42]([C:47]1[CH:52]=[CH:51][C:50]([CH2:53]Cl)=[CH:49][CH:48]=1)([O:44][CH2:45][CH3:46])=[O:43])[CH3:40]>CS(C)=O.O>[CH2:45]([O:44][P:42]([C:47]1[CH:48]=[CH:49][C:50]([CH2:53][N:14]2[CH2:13][CH2:12][CH:11]([C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([F:2])([F:28])[F:29])=[CH:9][CH:8]=3)([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=3)[OH:17])[CH2:16][CH2:15]2)=[CH:51][CH:52]=1)([O:41][CH2:39][CH3:40])=[O:43])[CH3:46]
Reactant: OC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C1CCNCC1
Reactant: CCOP(=O)(OCC)c1ccc(CCl)cc1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CCOP(=O)(OCC)c1ccc(CN2CCC(C(O)(c3ccc(C(F)(F)F)cc3)c3ccc(C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1.3 grams (0.004 mole) of 4-(diethylphosphono)phenylmethanol and two drops of pyridine in 10 mL of methylene chloride was added 0.39 mL (0.005 mole) of thionyl chloride. Upon completion of the addition, the reaction mixture was stirred for 30 minutes, then washed with 10 mL of water and 10 mL of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding the intermediate 4-(diethylphosphono)phenylmethyl chloride. The chloride was not further characterized. A solution of 2.7 grams (0.005 mole) of 4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine (prepared as in Step A of Example 17) in 10 mL of dimethyl sulfoxide was stirred, and 2.5 mL (excess) of diisopropylethylamine was added. To this was then added a solution of the methyl chloride, prepared above, in one mL of dimethyl sulfoxide. Upon completion of the addition, the reaction mixture was stirred at ambient temperature for one hour, then poured into water, and the mixture was extracted with one 150 mL portion of methylene chloride. The extract was washed with one 50 mL portion of an aqueous solution saturated with ammonium chloride and one 50 mL portion of water. The extract was concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with pure ethyl acetate as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 1.6 grams of N-[4-(diethylphosphono)phenylmethyl]-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl.Cl.[CH2:3]([NH2:8])[CH2:4][CH2:5][CH2:6][NH2:7].CN(C=O)C.[C:14](Cl)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[OH-].[Na+]>O>[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:8][C:14](=[O:15])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: NCCCCNC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 46.3 %

Procedure:
1,4-butanediamine dihydrochloride (5.96 g, 37 mmol) was dissolved in water (15 mL), and DMF (50 mL) was added. With rapid stirring, CBZ-Cl (1.0 mL, 7.0 mmol) was added dropwise over 2 minutes. The cloudy solution had pH~2.8. The pH was adjusted to 9.0 with 5N NaOH, (clear solution) and stirred for 2 hr. The reaction mixture was acidified to pH=1.25, extracted with ether (2×), made basic (pH>10) with 5N NaOH, and extracted with dichloromethane (2×). The dichloromethane fractions were combined and washed with water (2×), dried and evaporated in vacuo to provide the crude mono-CBZ amine (0.72 g, 3.24 mmol, 46%) which was used as is in the next step.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.C(O)=O.[Cl:30][C:31]1[N:39]=[C:38](Cl)[C:37]([F:41])=[CH:36][C:32]=1[C:33]([OH:35])=[O:34]>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[Cl:30][C:31]1[N:39]=[CH:38][C:37]([F:41])=[CH:36][C:32]=1[C:33]([OH:35])=[O:34]
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=CO
Product: O=C(O)c1cc(F)cnc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88.5 %

Procedure:
To a round-bottomed flask under a N2 atmosphere were added degassed DMF (270 mL), Pd(OAc)2 (0.05 eq, 2.7 g, 11.9 mmol), PPh3 (0.1 eq, 6.2 g, 23.8 mmol), and degassed Et3N (6 eq, 200 mL, 1428.6 mmol). The mixture was stirred for 20 minutes, HCOOH (3 eq, 28 mL, 714.3 mmol) was then added. 5 minutes later, 2,6-dichloro-5-fluoronicotinic acid (50 g, 238.1 mmol) was added. The mixture was stirred at 50° C. The reaction was followed by analysis (1H NMR) of a worked-up aliquot. When all starting material was consumed (24 h), the mixture was cooled to 0° C. and water (500 mL) was added. After 20 minutes, The mixture was filtered through a pad of Celite that was rinsed with water. The mixture was basified to pH 9 with 30% aq. NaOH and washed with EtOAc (2×). HCl (12 N) was added slowly to pH 1 and the solution was saturated with NaCl. The mixture was extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated under reduced pressure to give 37 g (88%) of a beige solid used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1>C(OCC)C.C(OCC)C.CCO>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH2:19][C:3]([O:7][CH2:8][CH3:9])=[O:10])=[CH:14][CH:13]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Into a 1000 mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of sodium hydride (10.1 g, 420.83 mmol, 2.10 equiv) in diethyl ether (400 mL). To the resulting mixture was then added diethyl carbonate (35.6 g, 301.69 mmol, 1.50 equiv) in 10 min at 0° C., followed by addition of a solution of 1-(4-bromophenyl)ethanone (40 g, 202.02 mmol, 1.00 equiv) in diethyl ether/EtOH (100 mL/1 mL) dropwise with stirring at 0° C. in 20 min. The resulting solution was heated to reflux for 3 hr. The reaction was then quenched by the addition of water/ice. The pH value of the solution was adjusted to about 5-6 with HCl (1 mol/L). The resulting solution was extracted with diethyl ether (3×200 mL), the organic layers combined and dried over anhydrous magnesium sulfate, then concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100) to yield ethyl 3-(4-bromophenyl)-3-oxopropanoate as yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:14])[N:4]([CH:11]([CH3:13])[CH3:12])[C:5]([S:9][CH3:10])=[N:6][C:7]=1[OH:8].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:14])[N:4]([CH:11]([CH3:12])[CH3:13])[C:5]([S:9][CH3:10])=[N:6][C:7]=1[O:8][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=1
Reactant: CSc1nc(O)c(Br)c(=O)n1C(C)C
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc(OCc2ccc(Cl)cc2)c(Br)c(=O)n1C(C)C
Yield: 55.3 %

Procedure:
In 20 ml of N,N-dimethylformamide were dissolved 1.0 g of 5-bromo-6-hydroxy-2-methylthio-3-i-propyl-4(3H)-pyrimidinone and 0.74 g of 4-chlorobenzylbromide, and then 1 g of potassium carbonate was added thereto. The mixture was subjected to a reaction at 80° C. for 3 hours. After allowing to cool in air, the resulting solution was poured into 50 ml of water and then extracted twice with 30 ml of ethyl ether. The ethyl ether layer was washed with water, dried over anhydrous sodium sulfate and freed of solvent by distillation under reduced pressure to give 1.25 g of a crude product. The product was purified by means of column chromatography (on silica gel, eluting with benzene) to give 0.8 g of the intended product as an oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.[CH3:19][CH:20]1[NH:24][C:23](=O)[CH2:22][CH2:21]1.P(Cl)(Cl)(Cl)=O>>[CH3:19][CH:20]1[N:24]=[C:23]([N:6]2[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:16]=[CH:15][C:14]=3[O:13][C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:22][CH2:21]1
Reactant: FC(F)(F)c1ccc2c(c1)Nc1ccccc1O2
Reactant: CC1CCC(=O)N1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CCC(N2c3ccccc3Oc3ccc(C(F)(F)F)cc32)=N1

Procedure:
Reaction of 2-(trifluoromethyl)phenoxazine, 5-methyl-2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provides the free base 10-(5-METHYL-1-PYRROLIN-2-YL)-2-(TRIFLUOROMETHYL)PHENOXAZINE as a distillable oil, b.p. 145°-152° C. at 0.03 mm Hg. Conversion of the free base to the hydrochloride salt affords 10-(5-METHYL-1-PYRROLIN-2YL)-2-(TRIFLUOROMETHYL)PHENOXAZINE HYDROCHLORIDE, m.p. 192.5°-195.5° C. (dec.) (corr.)., in a 45% overall yield.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1>O>[N+:1]([C:11]1[CH:12]=[C:7]([O:6][CH3:5])[CH:8]=[CH:9][C:10]=1[O:13][CH3:14])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(OC)cc1
Solvent: O
Product: COc1ccc(OC)c([N+](=O)[O-])c1

Procedure:
To a mixture of 100 ml concentrated nitric acid and 200 ml water is added 34.20 (0.30 mole) 1,4-dimethoxybenzene over a period of half an hour. After an additional fifteen minutes of stirring, the mixture is poured over ice. The resulting crystals are collected by filtration and crystallized from ethanol yielding bright yellow needles with a melting point of 68°-70° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](O)[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][N:4]=1.P(Cl)(Cl)([Cl:18])=O>>[CH3:1][S:2][C:3]1[N:8]=[C:7]([Cl:18])[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ncc(-c2ccccc2)c(O)n1
Product: CSc1ncc(-c2ccccc2)c(Cl)n1

Procedure:
Prepared from 2-methylsulphenyl-4-hydroxy-5-phenyl-pyrimidine by reacting with phosphorus oxychloride at reflux temperature, melting point: 99° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.Br[CH2:13][C:14]([OH:16])=[O:15].CO>C1COCC1.O>[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:9][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1
Reactant: O=C(O)CBr
Reactant: OCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)COCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a flask containing NaH (1 g, 25 mmol) in dry THF (25 mL) at 0° C., was added a solution of 4-bromobenzyl alcohol (2.11 g, 11.3 mmol) in dry THF (10 mL). The solution was stirred at 0° C. for 1 h, then a solution of bromoacetic acid (1 g, 7.14 mmol) in dry THF (10 mL) was added. The solution was refluxed for 3 h, then cooled. A solution of MeOH (1 mL) in water (100 mL) was added, and mixture was extracted with EtOAc (2×20 mL). The water layer was acidified by 1N HCl to pH=2, then extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine, dried (Na2SO4) and concentrated to give 67A. (1.66 g, 95%). MS (ESI) m/z 169.0 (M-OCH2CO2 H)+.