Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])=[CH:8][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:16])([CH3:15])[CH:13]=[O:14])=[CH:8][CH:7]=1
Reactant: CC(C)(CO)c1ccc(-c2ccco2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C=O)c1ccc(-c2ccco2)cc1
Reaction time: 0.75 h
Yield: 87.7 %

Procedure:
To a solution of 2-(4-furan-2-yl-phenyl)-2-methyl-propan-1-ol (6.56 g, 30 mmol) (reference example 53) in CH2Cl2 (200 mL) is added Dess-Martin periodinane (22.5 g, 53 mmol) and the resulting mixture stirred for 45 min then concentrated. The residue is purified by flash chromatography (eluting with 10% ethyl acetate in hexanes) to give 5.64 g of title compound. 1H NMR (CDCl3) δ 1.48 (s, 6H), 6.47 (m, 1H), 6.66 (d, J=3 Hz, 1H), 7.30 (d, J=8 Hz, 2H), 7.46 (s, 1H), 7.68 (d, J=8 Hz, 2H), 9.50 (s, 1H). MS (EI) m/z 214 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].[CH3:15][O:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][NH:19]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][CH2:22][C@@H:18]3[CH2:17][O:16][CH3:15])=[O:13])[S:10][C:3]=12
Reactant: COCC1CCCN1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: COC[C@H]1CCCN1C(=O)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate and 2-methoxymethyl-pyrrolidine by a procedure analogous to Example 1C. MS: 312/314 (MH+); HPLC Rf: 4.87 min; HPLC purity: 99%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[C:15](OC)=[O:16])[C:11]([CH:19]([CH3:21])[CH3:20])=[N:10][C:9]=2[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[CH2:15][OH:16])[C:11]([CH:19]([CH3:21])[CH3:20])=[N:10][C:9]=2[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)/C=C/n1c(C(C)C)nc(-c2ccncc2)c1-c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1nc(-c2ccncc2)c(-c2ccc(F)cc2)n1/C=C/CO
Reaction time: 1 h

Procedure:
A stirred suspension in toluene of methyl (E)-3-[5-(4-fluorophenyl)-2-(1-methylethyl)-4-(4-pyridinyl)-1H-imidazol-1-yl]-2-propenoate, 1'-oxide, (0.22 g), at -78° under nitrogen was treated with diisobutylaluminium hydride (1.5M in toluene; 0.8 ml). The mixture was stirred at -40° for 1 h and then allowed to warm to 0° before addition of water (1 ml) and ethyl acetate (20 ml). After stirring for 0.5 h the organic layer was separated, washed with brine, dried and evaporated to dryness. The residue was purified by CC eluting with a mixture of ethyl acetate, petroleum ether (bp. 40°-60°) and methanol (5:5:2) to give the title compound (0.05 g), δ(CDCl3) 8.39(m,2H,C-2 and C-6 protons of pyridine), 6.60(d,1H,J15 Hz,NCH=CH), 5.58(dd,1H,J15 and 6 Hz,NCH=CH), 4.18(m,2H,CH2OH), 3.17(septet,1H,J7 Hz,CH(CH3)2), 1.42(d,6H,J7 Hz,CH(CH3)2).
Reaction SMILES: [ClH:1].[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[NH:11][C:12]1[N:13]=[CH:14][C:15]2[CH2:20][N:19](C(OC(C)(C)C)=[O:22])[CH2:18][C:16]=2[N:17]=1>O1CCCC1.O.C(OC)(C)(C)C>[OH2:22].[ClH:1].[ClH:1].[CH2:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2][CH:3]1[NH:11][C:12]1[N:13]=[CH:14][C:15]2[CH2:20][NH:19][CH2:18][C:16]=2[N:17]=1
Reactant: CC(C)(C)OC(=O)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(c1)CC(Nc1ncc3c(n1)CNC3)C2
Temperature: 50 °C
Yield: 80.4 %

Procedure:
Charge 670 mL of 5 M hydrochloric acid (3.35 mol) to a solution of tert-butyl 2-(2,3-dihydro-1H-inden-2-ylamino)-5,7-dihydro-6H pyrrolo[3,4-d]pyrimidine-6-carboxylate (226 g, 641.25 mmol) in tetrahydrofuran (2.0 L) at 17° C., maintaining the internal temperature below 26° C. during the addition. Heat the resulting solution to 50° C. for 16 h, cool to 25° C. and dilute with 500 mL of water and 500 mL of tert-butylmethylether. Separate the resulting layers and extract with tert-butylmethylether (3×1 L). Concentrate the water phase down to a reaction volume of ca. 200 mL, and filter the resulting slurry. Rinse the cake with tert-butylmethylether (2×200 mL) and dry to give the title product (177 g, 80%) as a light brown solid. MS (m/z): 253.2 (M-2HCl—H2O+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].C([Mg]Cl)(C)C.C[O:21][B:22](OC)[O:23]C.Cl>O1CCCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:2]([B:22]([OH:23])[OH:21])[CH:7]=1
Reactant: FC(F)(F)COc1ccc(Cl)cc1Br
Reactant: COB(OC)OC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: OB(O)c1cc(Cl)ccc1OCC(F)(F)F
Temperature: -70 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a mixture of 2-bromo-4-chloro-1-(2,2,2-trifluoro-ethoxy)-benzene (3.0 g, 10.4 mmol) and tetrahydrofuran (60 ml), cooled to −70° C., was added a solution of isopropylmagnesium chloride in tetrahydrofuran (2 M, 5.7 ml). After warming to 0° C., the mixture was stirred for 1 hour. After cooling to −70° C., the mixture was treated with trimethylborate (1.2 g, 11.4 mmol). After stirring at room temperature for 12 hours, the mixture was treated with hydrochloric acid (2 M, 20 ml). After stirring for 40 minutes, the mixture was extracted with ethyl acetate (2×50 ml). The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated with hexane (50 ml). Filtration and drying of the solid under reduced pressure gave 5-chloro-2-(2,2,2-trifluoro-ethoxy)-phenylboronic acid (1.6 g, 61% yield). 1H NMR (acetone-d6) δ 4.86 (q, 2H, J=8.5 Hz, CH2), 7.12 (d, 2H, J=4.6 Hz, OH), 7.20 (d, 1H, J=8.8 Hz, Ar), 7.49 (dd, 1H, J=8.8 Hz, J=2.8 Hz, Ar), 7.76 (d, 1H, J—2.7 Hz, Ar).
Reaction SMILES: [O:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C)[P:15](N(C)C)N(C)C>C1(C)C=CC=CC=1>[N:10]12[P:15]3[N:7]([CH2:6][CH2:5][N:4]3[CH2:3][CH2:2][O:1][CH2:12][CH2:11]1)[CH2:8][CH2:9]2
Reactant: C1CNCCOCCNCCN1
Reactant: CN(C)P(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: C1CN2CCN3CCN(CCO1)P23
Yield: 102.5 %

Procedure:
A solution of 2.50 g of 1-oxa-4,7,10-triazacyclododecane and 2.35 g of hexamethylphosphorous triamide in 25 ml of toluene is refluxed for forty hours. It is then concentrated to dryness in a rotary evaporator, to give 2.97 g (100%) of 10-oxa-1,4,7-triaza-13-phosphatricyclo[5.5.1.04,13 ]tridecane as a brittle, white solid. Sublimation at 80° C (0.007 mm) gives 2.08 g of white crystals having a melting point of 68°-70° C.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=[CH:9]2)[N:3]=1.Cl.[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH2:20])[CH3:16].C(N(CC)CC)C>CN(C)C=O.C(O)C>[C:12]([C:11]1[C:2]([NH:20][CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:21])=[N:3][C:4]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)#[N:13]
Reactant: CCOC(=O)CN
Reactant: N#Cc1c2cccccc-2nc1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1nc2cccccc-2c1C#N
Yield: 73.5 %

Procedure:
To a suspended solution of 3 g (0.016 mol) of 2-chloro-3-cyano-1-azaazulene in 10 ml of dimethylformamide and 50 ml of ethanol were added 6.7 g (0.048 mol) of glycine ethylester hydrochloride and 6.5 g (0.064 mol) of triethylamine. The reaction mixture was heated under reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in chloroform, and the chloroform layer was washed with water and dried. Then, the chloroform was evaporated under reduced pressure to give 3.0 g of 3-cyano-2-ethoxycarbonylmethylamino-1-azaazulene having mp of 186° to 188° C. To a solution of obtained 3-cyano-2-ethoxycarbonylmethylamino-1-azaazulene in 100 ml of ethanol were added 5 to 6 ml of 2N aqueous solution of sodium hydroxide, and the reaction mixture was heated at 60° to 70° C. for 30 minutes. The precipitate of sodium salt of title compound was filtered, washed with ether and dried to give 2.6 g of sodium salt of title compound (yield: 65%).
Reaction SMILES: C([Zn][CH2:4][CH3:5])C.[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>O>[C:7]1([CH:6]([OH:13])[CH2:4][CH3:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[Zn]CC
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: O
Product: CCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 43 %

Procedure:
To a Schlenk flask containing degassed dry dichloromethane (10 mL) was added the polymer of Example 2 (28.6 mg, 0.1 mmol based on the biphenyl subunit) and diethylzinc (0.42 mL, 4 mmol). The resulting mixture was stirred at r.t. for 2.5 h. Benzaldehyde (0.2 mL, 2 mmol) was then added and the reaction mixture was stirred at r.t. for 112 h. Water (5 mL) and 1N HCl (5 mL) were added to quench the reaction. The polymer catalyst was filtered off and recovered. The organic layer in the filtrate was separated and the aqueous layer was extracted with dichloromethane. The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. 1H NMR spectroscopic analysis of this crude product indicated a complete conversion and the ratio of 1-phenyl-1-propanol to benzyl alcohol (a side product) was 53:47. Column chromatography on silica gel (eluent: EtOAc/hexanes=1/4) gave 1-phenyl-1-propanol as a colorless liquid (117 mg, 43%). GC analysis on a chiral column (β-Dex capillary column, Supelco Company) showed an ee of 13%.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([C@@H:8]([CH2:10][C:11]([OH:13])=[O:12])[NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[C:18](OC(=O)C)(=[O:20])[CH3:19].Cl>O>[C:18]([NH:9][C@H:8]([CH2:10][C:11]([OH:13])=[O:12])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H](CC(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N[C@H](CC(=O)O)c1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
p-Nitro-β-phenylalanine (10.0 g, 48 mmol) was mixed with 40 ml of water and adjusted to pH 14 with 25% sodium hydroxide aqueous solution. After being cooled to 5° C., 10.7 ml of acetic anhydride (105 mmol) and 25% sodium hydroxide aqueous solution were simultaneously dropped into the mixture to keep it at a pH range of 11.5˜12 and the resulting mixture was stirred for 1.5 hours at a room temperature. After the mixture was adjusted to pH 2 with conc. HCl and stirred for one hour, the resulting precipitated crystal was filtered and dried under reduced pressure to give 11.6 g of acetyl-p-nitro-β-phenylalanine at a yield of 96.9%.
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.[CH2:13]1[C:18](=O)[N:17](Br)[C:15](=[O:16])[CH2:14]1.CC1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28]C=1C(OC)=O>C(Cl)(Cl)(Cl)Cl>[N+:32]([C:30]1[CH:31]=[C:13]2[C:14](=[CH:28][CH:29]=1)[C:15](=[O:16])[NH:17][CH2:18]2)([O-:34])=[O:33]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1NCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
AIBN (84 mg, 0.51), NBS (1.1 gram, 6.4 mmol), and the methyl 2-methyl-4-nitrobenzoate (1 g, 5.1 mmol) from step 1 of this example were suspended in CCl4 and the mixture heated under N2 at 79 C overnight. The solution was filtered, and concentrated in vacuum. The residue was dissolved in 7 N ammonia in methanol (15 ml) and the solution stirred for 2 hours at RT. The mixture was concentrated in vacuum. and the resulting solid suspended in EtOAc (21.5 ml), heated at 80° C. for 30 minutes with stirring, cooled RT and aged at −20° C. for the 3 days. The solid was isolated by filtration to give the titled compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CON(C)[C:10]([CH:12]1[CH2:14][CH:13]1[CH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:25]#[N:26])=[O:11]>O1CCCC1>[CH:10]([CH:12]1[CH2:14][CH:13]1[CH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:25]#[N:26])=[O:11]
Reactant: CON(C)C(=O)C1CC1Cc1ccc2[nH]cc(C#N)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1c[nH]c2ccc(CC3CC3C=O)cc12
Reaction time: 0.5 h
Yield: 57 %

Procedure:
A suspension of lithium aluminum hydride (0.020 g, 0.53 mmol) in anhydrous tetrahydrofuran (5 ml) at −45° C. was treated with a solution 2-(3-cyano-1H-indol-5-ylmethyl)-cyclopropanecarboxylic acid methoxy-methyl-amide in 5 ml tetrahydrofuran. After 30 min at −45° C. an additional 0.53 mmol lithium aluminum hydride was added. The reaction was quenched with water followed by 1 N sodium hydroxide after another 30 min. The aluminum salts were removed by filtration and the filtrate was concentrated in vacuo to afford 5-(2-Formyl-cyclopropylmethyl)-1H-indole-3-carbonitrile (0.034 g, 57%) as a light yellow film. 1H-NMR (400 MHz, CDCl3) 9.07 (1H, d, J=5.16 Hz), 7.71 (1H, s), 7.58 (1H, s), 7.39 (1H, d, J=8.2 Hz), 7.22 (1H, m), 6.98 (1H, s), 2.80 (2H, m), 1.86 (2H), 1.40 (1H, m), 1.11 (1H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([NH:11][C:12](=[O:14])[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[O-]CC.[Na+].Br[CH:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22]>C(O)C>[CH2:9]([O:8][C:6](=[O:7])[C:5]([NH:11][C:12](=[O:14])[CH3:13])([CH:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH3:10]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CC(Br)c1cccc2ccccc12
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(NC(C)=O)(C(=O)OCC)C(C)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Acetylaminopropanedioic acid diethyl ester (20.8 g) was added to a solution of sodium ethoxide in ethanol (prepared from sodium (2.2 g) and ethanol (100 ml)). After the mixture was stirred for 10 minutes at ambient temperature, 1-(1-bromoethyl)naphthalene was added. The reaction mixture was stirred for 18 hours at room temperature. The precipitated solid was collected by filtration and dissolved in chloroform. The chloroform solution was dried over magnesium sulfate and evaporated to give 2-acetylamino-2-[1-(1-naphthyl)ethyl]propanedioic acid diethyl ester (21.59 g).
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([C:23]([NH:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:24])[CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])C1C=CC=CC=1>C(O)C.[Pd]>[C:19]([O:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][C@@H:11]([C:23]([NH:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:24])[NH2:10])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC[C@H](N)C(=O)NCCNC(=O)OC(C)(C)C

Procedure:
A solution of 390 mg (0.77 mmol) of benzyl{(1S)-4-[(tert-butoxycarbonyl)amino]-1-[({2-[(tert-butoxycarbonyl)amino]ethyl}amino)carbonyl]butyl}carbamate (Example 79A) in 50 ml of ethanol is hydrogenated after the addition of 40 mg of palladium on activated carbon (10%) at RT under atmospheric pressure for 4 h. The mixture is filtered through kieselguhr, and the residue is washed with ethanol. The filtrate is evaporated to dryness in vacuo. The product is reacted without further purification.
Reaction SMILES: OO.[O:3]1CCOCC1.[F:9][C:10]1[C:18]([O:19][CH3:20])=[C:17]2[C:13]([C:14](=[O:22])C(=O)[NH:16]2)=[C:12]([CH3:23])[CH:11]=1.[OH-].[Na+]>O>[NH2:16][C:17]1[C:18]([O:19][CH3:20])=[C:10]([F:9])[CH:11]=[C:12]([CH3:23])[C:13]=1[C:14]([OH:22])=[O:3]
Reactant: COc1c(F)cc(C)c2c1NC(=O)C2=O
Reactant: C1COCCO1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(F)cc(C)c(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
With cooling with ice, a solution of 30% aqueous hydrogen peroxide (6.3 ml, 61.5 mmol) diluted with water (8.2 ml) was added to a dioxane (50 ml) solution of 6-fluoro-7-methoxy-4-methyl-1H-indole-2,3-dione (I-28) (2.57 g), at the same temperature, a water (230 ml) solution of sodium hydroxide (6.15 g, 153.8 mmol) was dropwise added, taking 1 hour, followed by stirring for 4 hours with gradually heating up to room temperature. The reaction liquid was washed twice with chloroform, acetic acid was added to the aqueous layer followed by controlling at pH of 3 to 4 and extraction three times with ethyl acetate, the organic layer was washed twice with saturated brine, then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with chloroform alone was concentrated under reduced pressure to obtain the entitled compound (1.54 g, 28% from I-30) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]([F:21])([F:20])[S:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([S:12][C:11]([F:21])([F:10])[F:20])[CH:14]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1cccc(SC(F)(F)F)c1
Product: Fc1cnc(Cl)nc1Nc1cccc(SC(F)(F)F)c1

Procedure:
In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-(trifluoromethylthio) aniline were reacted to provide 2-chloro-5-fluoro-N4-[3-(trifluoromethylthio)phenyl]-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.13 (bs, 1H), 7.92 (bs, 1H), 7.89-7.84 (m, 1H), 7.48-7.45 (m, 2H), 7.04 (bs, 1H); LCMS: purity: 97%; MS (m/e): 325(MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[Br:13]Br>ClC1C=CC=CC=1.[Fe]>[Br:13][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: BrBr
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Agent: [Fe]
Solvent: Clc1ccccc1
Product: O=C1OC(=O)c2cc(Br)ccc21
Temperature: 110 °C

Procedure:
36.5 grams of 4-chlorophthalic anhydride were dissolved in 5.5 grams of chlorobenzene. The mixture was heated to 110° C. 0.029 grams of iron powder was added and 10 grams of bromine were added over a three hour period. The reaction temperature was increased to 135° C. and another 5 grams of bromine were added. The reaction mixture was then heated to 165° C. and another 6.2 grams of bromine were added. The mixture was analyzed by a gas chromatographic method and it was found that the 4-chlorophthalic anhydride had not reacted to form 4-bromophthalic anhydride.
Reaction SMILES: [N:1]([C:4](=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Br:16])[C:5]([O:7][CH3:8])=[O:6])=[N+]=[N-]>C1(C)C=CC=CC=1>[Br:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[NH:1]2
Reactant: COC(=O)C(=Cc1ccccc1Br)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2c(Br)cccc2[nH]1
Yield: 11.7 %

Procedure:
A solution of 116 g (0.41 mol) of methyl 2-azido-3-(2-bromophenyl)prop-2-enoate in 1.5 l of toluene is added dropwise over 4 h, with mechanical stirring, to a solution of 2 l of toluene heated to reflux and reflux is maintained for an additional 1 h. The solvent is evaporated under reduced pressure and the residue is taken up in 2 l of cyclohexane. The precipitate is collected by filtration, washed with toluene and dried under reduced pressure 37.85 g (149 mmol) of product are isolated. The mother liquors are concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel. 12.2 g (48 mmol) of additional product are isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(Cl)Cl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCCc2ccc(Cl)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(CCCOC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
Tert-butyl 4-[3-(4-chlorophenyl)propoxy]-piperidine-1-carboxylate (0.151 g, 0.427 mmol) prepared in Reference example 114 was dissolved in methylene chloride (4 ml), to which trifluoroacetic acid was added, and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with sodium hydroxide aqueous solution, and the mixture was extracted with methylene chloride twice. The extracts were combined and washed with brine. The organic layer was dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was dried in vacuo to afford 4-[3-(4-chlorophenyl)propoxy]piperidine (0.109 g, yield 92%) as a brown oil.
Reaction SMILES: B.O1CCC[CH2:3]1.[CH3:7][C:8]([O:11][C:12]([NH:14][CH:15]([C:26]([OH:28])=O)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)=[O:13])([CH3:10])[CH3:9].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.Cl>O1CCOCC1>[OH:28][CH2:26][CH:15]([N:14]([CH3:3])[C:12](=[O:13])[O:11][C:8]([CH3:7])([CH3:9])[CH3:10])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1cccc(C(F)(F)F)c1
Reactant: C1CCOC1
Agent: B
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CN(C(=O)OC(C)(C)C)C(CO)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A quantity of 438 ml of borane-tetrahydrofuran complex (1M solution in THF, 438 mmol) was introduced with ice cooling. Then 35 g (110 mmol) of N-Boc-2-(3-trifluoromethylphenyl)-DL-glycine were added in portions. The reaction mixture was stirred at RT for 2 h and then cautiously admixed with pieces of ice. After the end of the evolution of gas, the solvent was removed on a rotary evaporator. The aqueous residue was admixed with saturated sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue was taken up in acetonitrile and 2.5% strength aqueous sodium hydrogen carbonate solution. Then 25.18 ml (109.62 mmol) of di-tert-butyl dicarbonate were added and the mixture was stirred at RT for 3 h. The acetonitrile was removed on a rotary evaporator. The residue was extracted three times with ethyl acetate, dried over sodium sulphate, filtered and freed from the solvent on a rotary evaporator. The residue was again admixed with 438 ml of borane-tetrahydrofuran complex (1M solution in THF, 438 mmol) and stirred at 70° C. for 3 h. It was worked up again, and an excess of a 4N solution of hydrogen chloride in dioxane was added to the complete work-up mixture, which was stirred overnight. Thereafter the solvent was removed on a rotary evaporator. The residue was dried in an HV and then admixed once again with 400 ml of borane-tetrahydrofuran complex (1M solution in THF, 400 mmol) and stirred overnight. It was then worked up and again, as described above, reacted with 25.18 ml (109.62 mmol) of di-tert-butyl dicarbonate. The crude product obtained after work-up was purified by preparative HPLC. Drying in an HV gave 10.2 g (29% of theory) of the title compound.