Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=2)([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]#[N:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=2)([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][NH2:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: N#CC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: NCC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of 2-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(5-fluoropyridin-2-yl)-3-phenylpropanenitrile (1.6 g, 4.12 mmol), prepared as described in Procedure 4, in CH3OH (40 mL) was added CoCl2.6H2O (1.07 g, 8.25 mmol). The resulting solution turned purple in color. NaBH4 (1.57 g, 41.2 mmol) was then added in portions over 10 min. The resulting black solution was stirred at rt for 1 h. After this time, the reaction mixture was concentrated under reduced pressure, quenched with 6N HCl (4 mL), and diluted with sat. ammonium chloride (40 mL). The aqueous phase was extracted with CH2Cl2 (4×50 mL). The combined organic portions were washed successively with sat. NaHCO3 (50 mL) and sat. NaCl (50 mL), then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a yellow oil. The yellow oil was dissolved in CH2Cl2 and loaded directly onto a silica gel ISCO cartridge (40 g) with elution at 35 mL/min gradient 0 to 5% CH3OH in CH2Cl2 over 22 min (RT=17-19 min) 2-(3-Fluoro-5-(trifluoromethyl)phenyl)-2-(5-fluoropyridin-2-yl)-3-phenylpropan-1-amine (1.0 g, 60% yield) was isolated as a pale yellow oil. LCMS: RT=1.68 min [M+H] 393.04 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.31 min (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) ppm 3.29-3.37 (m, 2 H), 3.59 (t, J=13.2 Hz, 2 H), 6.62 (d, J=7.0 Hz, 2 H), 6.97 (d, J=10.1 Hz, 1 H), 7.06-7.14 (m, 5 H), 7.20 (d, J=8.35 Hz, 1H), 7.34 (td, J=8.57, 3.08 Hz, 1 H), 8.45 (d, J=3.08 Hz, 1 H). The racemate (1.0 g) was dissolved in CH3OH and resolved by chiral prep HPLC (Chiralpak AD 20μ column, 5×50 cm isocratic elution with 100% EtOH/CH3OH(50/50)/0.1% DEA, 50 mL/min, monitoring at 254 nm). Enantiomer 1 (470 mg) was isolated as a yellow oil: analytical chiral HPLC (Diacel Chiralpak AD 10μ column, 4.6×250 mm isocratic elution with 100% EtOH/CH3OH(50/50)/0.1% DEA, 1 mL/min, monitoring at 254 nm), RT=3.70 min. Enantiomer 2 (470 mg) was isolated as a yellow oil: analytical chiral HPLC (Diacel Chiralpak AD 10μ column, 4.6×250 mm isocratic elution with 100% EtOH/CH3OH(50/50)/0.1% DEA, 1 mL/min, monitoring at 254 nm), RT=4.05 min.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].O.O.[C:15](O)(=[O:19])[C:16](O)=[O:17]>Cl>[CH3:5][N:4]1[C:3]2[C:2](=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][CH:6]=2)[NH:1][C:16](=[O:17])[C:15]1=[O:19]
Reactant: O=C(O)C(=O)O
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Solvent: O
Product: Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Yield: 76.6 %

Procedure:
A mixture of 1.0 g (5.9 mmol) 2-amino-4-nitro-N-methylaniline and 1.5 g (11.9 mmol) oxalic acid dihydrate in 50 ml 4N hydrochloric acid was refluxed for 3 h. After cooling to 25° C., the precipitate was filtered off and washed with water. The crude product was recrystallized (dimethylformamide-water) to give 1.0 g (78%) of 1-methyl-6-nitroquinoxaline-2,3-(1H,4H)-dione. M.p. 356° C. NMR (DMSO-d6): 12.2 (1H, broad s), 7.9 (1H, d), 7.8 (1H, s), 7.4 (1H, d), 3.47 (3H, s).
Reaction SMILES: [Mg].[CH3:2]I.[I:4][CH:5]=[CH:6][C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl-].[NH4+]>CCOCC>[OH:13][C:7]([CH3:2])([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:6]=[CH:5][I:4]
Reactant: CCCCCC(=O)C=CI
Reactant: CI
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCC(C)(O)C=CI
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a Grignard solution prepared from 1.05 g (0.41 moles) of magnesium and 6.2 g (0.435 moles) of methyl iodide in 30 ml of dry ether under argon is added dropwise 10 g of 1-iodo-1-octen-3-one (Example 183) in 45 ml of ether. The resulting solution is stirred at ambient temperature for one hour. After the addition of 75 ml of saturated ammonium chloride the ether layer is separated and the aqueous layer is separated and the aqueous layer is extracted several times with ether. The combined ether extracts are washed successively with ammonium chloride and water, dried and taken to dryness to give 9.24 g of product as an oil; λ max 2,89, 3,23,6.24 and 10.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2([C:13]3([CH3:21])[CH2:16][C:15]([F:18])([F:17])[C:14]3([F:20])[Cl:19])[CH2:12][O:11]2)=[CH:4][CH:3]=1.[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([C:13]2([CH3:21])[CH2:16][C:15]([F:18])([F:17])[C:14]2([F:20])[Cl:19])([OH:11])[CH2:12][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: CC1(C2(C#Cc3ccc(Cl)cc3)CO2)CC(F)(F)C1(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C(O)(C#Cc2ccc(Cl)cc2)Cn2cncn2)CC(F)(F)C1(F)Cl
Yield: 77.4 %

Procedure:
31.8 g of 2-[2-(4-chlorophenyl)-ethin-1-yl]-2-(2,3,3-trifluoro-2-chloro-1-methylcyclobut-1-yl)-oxirane are added at room temperature to a stirred mixture of 6.4 g of 1,2,4-triazole, 12.6 g of ground potassium carbonate and 300 ml of acetonitrile. The reaction mixture is refluxed for 12 hours, and then cooled and filtered. The filtrate is concentrated under reduced pressure, and the remaining residue is purified by column chromatography (ethyl acetate) on silica gel. 29 g (75.5% of theory) of 1-(4-chlorophenyl)-3-(2,3,3-trifluoro-2-chloro-1-methyl-cyclobut-1-yl)-4-(1,2,4-triazol-1-yl)-but-1-in-3-ol are obtained in form of a viscous oil.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[CH2:8]2.[Br:22][C:23]([CH3:28])([CH3:27])[C:24](Br)=[O:25]>>[Br:22][C:23]([CH3:28])([CH3:27])[C:24]([N:11]([CH:2]1[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)[NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:25]
Reactant: CC(C)(Br)C(=O)Br
Reactant: O=[N+]([O-])c1ccc(NNC2C3CC4CC(C3)CC2C4)cc1
Product: CC(C)(Br)C(=O)N(Nc1ccc([N+](=O)[O-])cc1)C1C2CC3CC(C2)CC1C3

Procedure:
1-(Adamantan-2-yl)-2-(4-nitrophenyl)hydrazine and 2-bromoisobutyrylbromide were used for a similar reaction and treatment as Process 3 of Example 1, and 2-bromo-N-(adamantan-2-yl)-2-methyl-N′-(4-nitrophenyl)propane hydrazide was obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][O:18][C:19]4[CH:40]=[CH:39][C:22]([C:23]([NH:25][C@H:26]([C:34]([O:36]CC)=[O:35])[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:24])=[CH:21][CH:20]=4)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][O:18][C:19]4[CH:40]=[CH:39][C:22]([C:23]([NH:25][C@H:26]([C:34]([OH:36])=[O:35])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:24])=[CH:21][CH:20]=4)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(OCc2ccc3ccc4nc(C)[nH]c(=O)c4c3c2)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccc3ccc(COc4ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc4)cc3c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
Diethyl N-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoyl)-L-glutamate (0.18 g, 0.33 mmol) was suspended in ethanol (2 ml) and 0.25 N NaOH (8 ml) and stirred 1.5 hours at room temperature with intermittent periods of sonication. Additional ethanol (4 ml) and warming were required to obtain a homogeneous solution. The solution was stirred 3 hours at room temperature and then adjusted to pH 3 with 1 N HCl. The resulting suspension was filtered, and the white solid washed with water and dried under high vacuum to give N-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoyl)-L-glutamic acid (0.158 g). 1H NMR (DMSO-d6, 300 MHz) δ: 1.87-2.16 (m, 2H, glu CH2). 2.35 (t, J=7 Hz, 2H, glu CH2), 2.44 (s, 3H, CH3), 4.33-4.43 (m, 1H, glu CH), 5.43 (s, 2H, CH2O), 7.16 (d, J=9 Hz, 2H, Ar), 7.64 (d, J=9 Hz, 1H, Ar), 7.74 (dd, J=8,2 Hz, 1H, Ar), 7.88 (d, J=9 Hz, 2H, Ar), 8.08 (d, J=8 Hz, 1H, Ar), 8.26 (d, J=9 Hz, 1H, Ar), 8.47 (d, J=8 Hz, 1H, glu NH), 9.94 (s, 1H, Ar), 12.36 (br s, 2H, CO2H's ), 12.59 (s, 1H, N2H). Anal. Calculated for C26H23N3O7.1/4H2O: C, 63.22; H, 4.79; N, 8.51. Found: C, 63.23; H, 4.80; N, 8.48.
Reaction SMILES: [F:1][C:2]1[C:3]([N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([CH3:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:19]N1C(=O)CCC1=O>ClC1C=CC=CC=1>[Br:19][CH2:18][C:10]1[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:12][N:8]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cn(-c2ncccc2F)nc1C
Solvent: Clc1ccccc1
Product: CCOC(=O)c1cn(-c2ncccc2F)nc1CBr
Yield: 39.5 %

Procedure:
To a solution of ethyl 1-(3-fluoro-2-pyridyl)-3-methyl-pyrazole-4-carboxylate (10.2 g, 40.9 mmol) in chlorobenzene (205 mL), N-bromosuccinimide (8 g) is added at room temperature. The reaction mixture is stirred and irradiated under a 100 W lamp at room temperature overnight. Then more N-bromosuccinimide (2 g) is added and after 2 hr., no starting material is detected. Solids are filtered and solvent is evaporated. The crude is purified by normal phase Isco chromatography using as eluent dichloromethane and methanol to give 5.3 g of ethyl 3-(bromomethyl)-1-(3-fluoro-2-pyridyl)pyrazole-4-carboxylate. MS (m/z): 328; 330 (M+1; M+3).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[CH2:25][C:26]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:33]=1[CH3:34])=[O:27]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:12]([CH2:25][C:26]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][C:33]=3[CH3:34])=[O:27])[C@H:11]([C:13]([F:14])([F:15])[F:16])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: Cc1ccncc1C(=O)CBr
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1ccncc1C(=O)CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
A suspension of 100 mg (0.394 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 385.42 mg (1.18 mmol) of cesium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at room temperature. 139.57 mg (0.473 mmol) of 2-bromo-1-(4-methylpyrid-3-yl)ethanone hydrobromide are then added. After stirring overnight at room temperature, the reaction mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 140 mg of (8S)-2-chloro-9-[2-(4-methylpyrid-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, corresponding to the following characteristics:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:39]N1C(=O)CCC1=O>C(Cl)Cl>[Br:39][CH:13]1[C:14](=[O:17])[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a cooled (0° C.) solution of N-benzyloxycarbonyl-4-piperidone (501, 27.3 g 117 mmol) in DCM (3 ml/mmol) was added DIPEA (25.5 ml, 146.2 mmol, 1.25 eg) and trimethylsilyl trifluoromethane sulfonate (25.4 ml, 141 mmol, 1.2 eg). The mixture was stirred for 30 minutes at 0° C. Next, N-bromosuccinimide (21.2 g, 119.3 mml, 1.02 eg) was added and stirring was continued for 16 hrs at room temperature. The reaction mixture was washed with 5% NaHCO3 and the organic layer was dried (MgSO4) and subsequently concentrated under reduced pressure. The resulting oil was purified by silica gel chromatography (diethyl ether/petroleum ether, 1/1 to 1/0, v/v, Rf 0.1) giving 502 in a yield of 90% as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([OH:7])=O.[NH2:20][CH2:21][CH2:22][OH:23]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([NH:20][CH2:21][CH2:22][OH:23])=[O:7]
Reactant: NCCO
Reactant: O=C(O)c1cc(Br)ncc1Nc1ccc(I)cc1F
Product: O=C(NCCO)c1cc(Br)ncc1Nc1ccc(I)cc1F

Procedure:
2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethyl)-isonicotinamide was synthesized according to General Method 3, starting with 145 mg (0.33 mmol) of 2-bromo-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid 51 mg (0.83 mmol) of 2-amino-ethanol. LC/MS: [8.98 min, 480, 482]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11]C(=O)OC(C)(C)C)[CH2:9][CH3:10])=[C:4]([F:19])[C:3]=1[C:20]([C:22]1[CH:23]=[N:24][C:25]([S:28][CH3:29])=[N:26][CH:27]=1)=[O:21].Cl.O1CCOCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:11])[CH2:9][CH3:10])=[C:4]([F:19])[C:3]=1[C:20]([C:22]1[CH:23]=[N:24][C:25]([S:28][CH3:29])=[N:26][CH:27]=1)=[O:21]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2cnc(SC)nc2)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2cnc(SC)nc2)c1F
Reaction time: 18 h
Yield: 125.1 %

Procedure:
Step 3 To a solution of tert-butyl N-[(1R)-1-(4-chloro-2-fluoro-3-{[2-(methylsulfanyl)pyrimidin-5-yl]carbonyl}phenyl)propyl]carbamate (20.0 mg, 0.04 mmol) in DCM (1 mL) was added 4M HCl in dioxane (0.04 mL, 0.16 mmol, 4 eq) and the reaction stirred for 18 h. The mixture was concentrated and then triturated with diethyl ether (˜5 mL) and the pale green solid filtered off and dried in a vacuum oven to give (1R)-1-(4-chloro-2-fluoro-3-{[2-(methylsulfanyl)pyrimidin-5-yl]carbonyl}phenyl)propan-1-amine (17.0 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]2[C:24]=1[CH:25]=[N:26][C:27]([CH3:34])=[N:28]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C@@H:8]([CH2:18][CH3:19])[CH2:9][C@@:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:22][C:23]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]3[C:24]=2[CH:25]=[N:26][C:27]([CH3:34])=[N:28]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1cccc(F)c1OC
Reactant: Cc1ncc2c(N)ccc(F)c2n1
Agent: [Ti+4]
Agent: CC[O-]
Product: CC[C@@H](C[C@@](O)(C=Nc1ccc(F)c2nc(C)ncc12)C(F)(F)F)c1cccc(F)c1OC

Procedure:
In the same way as in Example 31, 123 mg (0.40 mmol) of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 72 mg (0.60 mmol) of 5-amino-8-fluoro-2-methylquinazoline and 0.22 ml of titanium tetraethoxide are reacted to give (2R*,4S*)-4-(3-fluoro-2-methoxyphenyl)-1-[(8-fluoro-2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)hexan-2-ol. 170 mg of crude imine are cyclized in the same way as in Example 31 at −30° C. with 2.8 ml (2.8 mmol) of 1 M boron tribromide solution to give the desired product. Purification by chromatography on silica gel (dichloromethane/ethyl acetate 0-40%) gives 68 mg of product.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:36]1[N:37]=[C:38]([NH:41][C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:39][CH:40]=1)\[C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:12]([CH2:16]Cl)[CH2:13][S:14](=[O:15])[C@H:9]12)=[O:6].[I-:61].[Na+]>CC(C)=O>[CH3:1][O:2]/[N:3]=[C:4](/[C:36]1[N:37]=[C:38]([NH:41][C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:39][CH:40]=1)\[C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:12]([CH2:16][I:61])[CH2:13][S:14](=[O:15])[C@H:9]12)=[O:6]
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The oily substance obtained in (A) was dissolved in 120 ml of acetone, and 1.6 g (10.7 mmol) of sodium iodide was added thereto. The mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water, and extracted with ethyl acetate. The extract solution was washed with a 5% sodium thiosulfate aqueous solution, with water and with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain an oily substance.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([C@H:5]1[C@H:12]2[C@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[C:7]([CH2:15][O:16][C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6]1)[OH:4].[Cl:36][C:37]1[C:42](Cl)=[N:41][CH:40]=[CH:39][N:38]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:36][C:37]1[C:42]([NH:1][CH2:2][C@H:3]([C@H:5]2[C@H:12]3[C@H:8]([O:9][C:10]([CH3:13])([CH3:14])[O:11]3)[C:7]([CH2:15][O:16][C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:6]2)[OH:4])=[N:41][CH:40]=[CH:39][N:38]=1
Reactant: Clc1nccnc1Cl
Reactant: CC1(C)O[C@H]2[C@H]([C@H](O)CN)C=C(COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2O1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)O[C@H]2[C@H]([C@H](O)CNc3nccnc3Cl)C=C(COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2O1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
(S)-2-amino-1-((3aS,4S,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethanol (1-5) (2 g, 3.82 mmol, 1.0 eq) was dissolved in DMF (15.3 mL). 2,3-Dichloropyrazine (1.20 g, 7.63 mmol, 2 equiv) was added followed by triethylamine (2.13 mL, 15.3 mmol, 4 equiv). The reaction was stirred 20 hours at 60° C. Over a period of 52 hours 2,3-dichloropyrazine (299 mg, 1.91 mmol, 0.5 equiv) was added every 3 hours. The reaction was concentrated and purified via flash chromatography on silica gel column (ethyl acetate/hexanes) to yield (S)-2-(3-chloropyrazin-2-ylamino)-1-((3aS,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethanol (1-6) as a white foam. 1H NMR (500 MHz, CDCl3) δ 7.91 (d, 1H, J=1.5 Hz), 7.62 (d, 1H, J=1.5 Hz), 7.21-7.48 (m, 15H), 5.84 (2 s, 1H), 5.62 (m, 1H), 4.97 (t, 1H, J=6 Hz), 4.60-4.77 (2 d, 1H, J=7 Hz), 3.95 (d, 1H, J=14 Hz), 3.75 (m, 2H), 3.31 (m, 1H), 2.57-2.88 (m, 2H), 1.36 (s, 3H), 1.32 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:15](OCC)=[O:16].C(Cl)(=O)C>O1CCOCC1>[CH:11]([C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:15](=[O:16])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1)([CH3:13])[CH3:12]
Reactant: CCOC(=O)Cl
Reactant: CC(C)c1ccc(N)c(C(=O)O)c1
Solvent: C1COCCO1
Solvent: CC(=O)Cl
Product: CC(C)c1ccc2[nH]c(=O)oc(=O)c2c1
Reaction time: 3 h

Procedure:
A mixture of 2-amino-5-isopropylbenzoic acid (30. g, 16.7 mmol) and ethyl chloroformate (1.75 mL, 18.4 mmol) in dioxane (20 mL) was heated under reflux for 2 h. After cooling, acetyl chloride (1.4 mL) was added and heating under reflux continued for another 3 h. After cooling, the mixture was evaporated and the resulting solid digested with tert-butyl methyl ether: heptane (1:1, 20 mL) by heating under reflux for 1 h. The soild was then filtered off and washed with tert-butyl methyl ether: heptane (1:1, 10 mL). Yield 3.1 g (89%). m/z 204 (M—H−).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([I:14])[C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH2:16](O)CO>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[C:3]([CH3:16])=[C:4]([I:14])[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1
Reactant: CCOc1c(C(C)=O)cc(Cl)c(F)c1I
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1c(C(C)O)cc(Cl)c(C)c1I
Temperature: 0 °C
Yield: 110.6 %

Procedure:
A solution of 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone (20.0 g, 58.4 mmol; Example 212, step 1) and 1,2-ethanediol (6.5 mL, 120 mmol) in toluene (190 mL) was treated with p-toluenesulfonic acid monohydrate (1.1 g, 5.8 mmol). The flask was fitted with a Dean-Stark trap that was filled with sieves, and refluxed for 3 h. The reaction mixture was cooled and added to ice cooled saturated sodium bicarbonate solution (250 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to a crude orange oil. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (0%-20%) to give the desired product (22 g, 99%). LCMS for C12H14ClFIO3 (M+H)+: m/z=387.0; Found: 386.9.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:7]=1[C:8]([C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([O:19]C)=[CH:12][C:11]=1[CH3:21])=[O:9].Cl.O>C(Cl)Cl>[Cl:5][C:6]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:7]=1[C:8]([C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([OH:19])=[CH:12][C:11]=1[CH3:21])=[O:9]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(O)c([N+](=O)[O-])cc1C(=O)c1c(Cl)cccc1Cl
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Aluminumchloride (1.5 g; 11 mmol) is added to a solution of 2,6-dichloro-5'-nitro-4'-methoxy-2'-methyl-benzophenone (1.8 g; 5.3 mmol) in methylenechloride (6 ml). The mixture is stirred for 30 minutes at 20° C. and for 1 hour at 45° C., 5 ml conc. hydrochloric acid/ice are added. After shaking with 20 ml of methylenechloride the organic layer is treated with 2N hydrochloric acid and with water. After drying the solvent is evaporated, the residue purified by chromatography (flash column filled with 30 g of silicagel, elution with toluene). The residue from the main fraction is treated with diisopropylether to give yellow crystalls; (1.2 g; 73% y); mp. 170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:12])[C:7]=1[CH2:8][C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:34][NH2:35])[CH:30]=[CH:31][CH:32]=1>C1COCC1>[Cl:12][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([NH:35][CH2:34][CH:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH3:25])[CH:28]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:11]
Reactant: COc1cccc(C(CN)c2ccccc2)c1
Reactant: O=C(O)Cc1c(Cl)cncc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cccc(C(CNC(=O)Cc2c(Cl)cncc2Cl)c2ccccc2)c1
Yield: 90.2 %

Procedure:
By working in a way similar to that described in example 4 but using (3.5-dichloro-pyridin-4-yl)-acetic acid (5.15 g, 25 mmoles), carbonyldiimidazole (4.24 g, 26.14 mmoles), THF (75 ml) and 2-(3-methoxy-phenyl)-2-phenyl-ethylamine (5.4 g, 23.76 mmoles), obtained as described in example 42, 8.9 g of the title compound were obtained (yield: 85.7%), m.p.: 142-143° C.