Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:24])([S@@:4]([NH:6][C@@:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])([CH:14]([F:16])[F:15])[CH2:8][C:9](OCC)=[O:10])=[O:5])[CH3:3].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[F:16][CH:14]([F:15])[C@@:7]([NH:6][S@:4]([C:2]([CH3:3])([CH3:1])[CH3:24])=[O:5])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[CH2:8][CH:9]=[O:10]
Reactant: CCOC(=O)C[C@](N[S@@](=O)C(C)(C)C)(c1ccccc1F)C(F)F
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)N[C@@](CC=O)(c1ccccc1F)C(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 30.9 %

Procedure:
Intermediate XVI-1: In a dry flask under an inert atmosphere the light yellow solution of (S)-ethyl 3-((S)-1,1-dimethylethylsulfinamido)-4,4-difluoro-3-(2-fluorophenyl)butanoate (XV-2) (2.59 g, 7.09 mmol) in DCM (75 ml) was treated dropwise with DIBAH (1 M in toluene; 10.6 ml, 10.6 mmol) keeping the internal temperature below −72° C. After complete addition the reaction mixture was stirred at −78° C. for 30 min. For the workup, the mixture was quenched with a saturated solution of NH4Cl (10 ml), left to warm to room temperature and stirred for 30 min. The thick suspension was filtered through a layer of Dicalite® which was washed twice with DCM. The filtrate was treated with a half-saturated solution of NH4Cl and extracted three times with DCM. The combined organic layers were dried over MgSO4 and evaporated. The crude product was purified by chromatography on silica gel (eluent: heptane/AcOEt; gradient: 30-50% AcOEt) to yield the (S)—N—((S)-1,1-difluoro-2-(2-fluorophenyl)-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide (XVI-1) (704 mg, 31% yield) as a light yellow oil and the starting ester XV-2 (1.28 g, 49% yield) as a colorless oil. MS: m/z=322.4 (M+H)+.
Reaction SMILES: [C:1]([C:7]1[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]2[O:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][C:11]=2[CH:18]=1)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].C=O.Cl.[CH3:24]NC.Cl>CN(C)C=O.C(O)(=O)C>[CH2:24]=[C:2]([CH:3]([CH3:5])[CH3:4])[C:1]([C:7]1[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]2[O:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][C:11]=2[CH:18]=1)=[O:6]
Reactant: CNC
Reactant: Cc1c(C(=O)CC(C)C)cc2cc(C(=O)O)oc2c1C
Agent: C=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C=C(C(=O)c1cc2cc(C(=O)O)oc2c(C)c1C)C(C)C
Temperature: 95 °C

Procedure:
A mixture of 5-isovaleryl-6,7-dimethylbenzofuran-2-carboxylic acid (8.5 g.), paraformaldehyde (2.0 g.), dimethylamine hydrochloride (3.3 g.) and acetic acid (1 ml.) is heated at 95°C. for 2.5 hours, treated with dimethylformamide (75 ml.), heated an additional 3.5 hours, poured into ice water (300 ml.) containing hydrochloric acid (5 ml.). The product is extracted into ether, washed with water, dried over magnesium sulfate, the solvent evaporated at reduced pressure to afford 5-(2-methyleneisovaleryl)-6,7-dimethylbenzofuran-2-carboxylic acid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH:14]1([CH2:17][O:18][C:19]2[CH:24]=[C:23](F)[CH:22]=[CH:21][C:20]=2[N+:26]([O-:28])=[O:27])[CH2:16][CH2:15]1>CN(C=O)C>[CH:14]1([CH2:17][O:18][C:19]2[CH:24]=[C:23]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:22]=[CH:21][C:20]=2[N+:26]([O-:28])=[O:27])[CH2:15][CH2:16]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(F)cc1OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
Diethyl malonate (9.8 g, 1.1 eq.) was added to a stirred suspension of sodium hydride (60% in mineral oil, 2.09 g) in 88 mL DMF over 15 min. at 0° C. under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. A solution of 2-cyclopropylmethoxy-4-fluoro-1-nitrobenzene (10 g, 1 eq.) in DMF (88 mL) was added drop wise at 0° C., and the reaction mixture was heated to 100° C. for 3 h. The reaction mixture was allowed to cool to room temperature, poured into ice water and extracted with EtOAc (3×100 mL). The combined organic phases were washed with water (3×100 mL), brine (100 mL) and dried (MgSO4). Evaporation of solvent under reduced pressure gave 10.0 g of crude product which was purified by silica gel chromatography (hexane/EtOAc) gave 7.0 g of the desired product (42%)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[C:27]([NH:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)(=[O:29])[CH3:28].C(=O)(O)[O-].[Na+].O>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:27]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])=[O:15])[C:5]3[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=3[N:7]=2)=[CH:33][CH:32]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: CC(=O)Nc1ccc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3cnn(C(C)C)c3n2)cc1
Temperature: 110 °C
Yield: 55.4 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (80 mg, 0.21 mmol) and [4-(acetylamino)phenyl]boronic acid (57.5 mg, 0.32 mmol) in DME/water (3 ml:1 ml). PdCl2(dppf)-CH2Cl2 adduct (8.7 mg, 0.010 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (53.9 mg, 0.64 mmol) was added, the vessel was sealed, and the insoluble light brown mixture was heated at 110° C. for 2.5 h. After cooling, 2 mL of water was added to the dark grey mixture and solids that precipitated were filtered. EtOAc was added, the mixture was heated and some hexanes were added. The solids were filtered, dissolved in DCM/MeOH (1:1) and 1 mL of DMF. The contents were pre-absorbed onto silica gel and purified by silica gel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH4OH). The isolated product was treated with MeOH, and the solids that precipitated were filtered, washed with hexanes and dried to afford the title compound (55 mg, 52%) as a white solid. LCMS E-S (M+H)=473.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.57 (s, 1 H), 10.18 (s, 1 H), 8.93 (t, J=4.93 Hz, 1 H), 8.35 (s, 1 H), 8.22 (m, J=8.84 Hz, 2 H), 8.13 (s, 1 H), 7.76 (m, J=8.84 Hz, 2 H), 5.91 (s, 1 H), 5.28-5.37 (m, 1 H), 4.41 (d, J=4.80 Hz, 2 H), 2.23 (s, 3 H), 2.13 (s, 3 H), 2.09 (s, 3 H), 1.54 (d, J=6.82 Hz, 6 H).
Reaction SMILES: [F:1][C:2]1([F:28])[CH2:5][N:4]([C:6]([C:8]2[C:12]3[CH:13]=[C:14]([CH:26]=O)[C:15]([N:18]4[CH2:23][C@@H:22]([CH3:24])[O:21][C@H:20]([CH3:25])[CH2:19]4)=[C:16]([F:17])[C:11]=3[O:10][N:9]=2)=[O:7])[CH2:3]1.[NH:29]1[C:36](=[O:37])[CH2:35][C:33](=[O:34])[NH:32][C:30]1=[O:31]>C(O)C>[F:28][C:2]1([F:1])[CH2:3][N:4]([C:6]([C:8]2[C:12]3[CH:13]=[C:14]4[C:15](=[C:16]([F:17])[C:11]=3[O:10][N:9]=2)[N:18]2[CH2:23][C@@H:22]([CH3:24])[O:21][C@@H:20]([CH3:25])[C@@H:19]2[C:35]2([C:33](=[O:34])[NH:32][C:30](=[O:31])[NH:29][C:36]2=[O:37])[CH2:26]4)=[O:7])[CH2:5]1
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(C(=O)N4CC(F)(F)C4)noc3c2F)C[C@@H](C)O1
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CCO
Product: C[C@@H]1CN2c3c(cc4c(C(=O)N5CC(F)(F)C5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Yield: 81.5 %

Procedure:
3-(3,3-difluoroazetidine-1-carbonyl)-6-((2R,6R)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-5-carbaldehyde (Intermediate 245, 2.08 g, 5.23 mmol) was dissolved in ˜100 ml of ethanol and heated with barbituric acid (0.704 g, 5.50 mmol) at 105° C. (external temperature) for 6 days. The reaction was absorbed onto celite then purified on by silica gel chromatography using a gradient of DCM to ethyl acetate. Fractions were combined and concentrated. This material was then purified by Supercritical Fluid Chromatography (separation of diastereomers), using a Chiralpak AD, 21×250 mm, 5μ column (elution with 40% isopropanol, 60% CO2 at 60 ml/min, 40° C., and 100 bar with detection at 220 nm), to give the title compound (2.16 g, 4.26 mmol, 81%) as the first eluting compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:37])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:36])[CH:30]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:37]=[C:19]1[CH2:20][C:21]([C:23]2[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:36])[CH:30]=3)[CH:26]=[CH:27][CH:28]=2)=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[NH:18]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C#N)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (2-{3-[3-(2-cyano-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M180) (304 mg, 0.58 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (147 mg, 62%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[C:18]2[CH:19]=[CH:20][C:21]([C:24]([NH:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[N:22][CH:23]=2)=[CH:4][CH:3]=1.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:5]2[CH:6]=[CH:7][C:2]([C:39]3[CH:40]=[CH:41][C:36]([C:35]([F:46])([F:45])[F:34])=[CH:37][CH:38]=3)=[CH:3][CH:4]=2)=[C:11]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([NH:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[N:22][CH:23]=2)[CH:12]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(OC)ccc2CNc2ccc(Br)cc2)cn1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(OC)ccc2CNc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cn1
Temperature: 25 °C

Procedure:
Ethyl 3-(5-(2-(((4-bromophenyl)amino)methyl)-5-methoxyphenyl)picolinamido)propanoate (200 mg, 0.39 mmol), (4-(trifluoromethyl)phenyl)boronic acid (111 mg, 0.59 mmol), Pd(dppf)Cl2 (43 mg, 0.06 mmol), and K2CO3 (108 mg, 0.78 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL) and the resulting mixture was heated to 80° C. After 2 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:18]=1.Cl.N1C=CC=CC=1>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)=[CH:7][C:6]=2[CH:18]=1
Reactant: COc1ccc(-c2cc3cc(Br)ccc3o2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc(-c2cc3cc(Br)ccc3o2)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
A mixture of 81 (0.3 g, 1 mmol) and Pyridine HCl (5 g) was heated to 200° C. After 1 hr, the reaction was cooled and then diluted with water. The aqueous layer was extracted with EtOAc, dried over MgSO4 and concentrated to give a solid. The solid was triturated with CH2Cl2 and filtered to give a solid (0.11 g, 39%); Mp=228–229° C.; 1H NMR (DMSO-d6) δ 9.95 (br s, 1 H), 7.79 (d, 1 H, J=2.0 Hz), 7.74 (d, 2 H, J=8.8 Hz), 7.55 (d, 1 H, J=8.8 Hz), 7.39 (dd, 1 H, J=8.8 Hz, 2.4 Hz), 7.16 (s, 1 H), 6.88 (d, 2 H, J=8.8 Hz); MS 287/289[M−H]−
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)([OH:5])[CH3:4])#[CH:2].[OH:20][C:21]1[CH:30]=[C:29](I)[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]>>[OH:20][C:21]1[CH:30]=[C:29]([C:2]#[C:1][C:3]([OH:5])([CH3:4])[C:6]2[CH:15]=[CH:14][C:13]3[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=3[CH:7]=2)[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: C#CC(C)(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: COC(=O)c1ccc(C#CC(C)(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1O

Procedure:
Following the basic procedure of Example 11(d), by reacting 2 g (7.8 mmol) of 1-ethynyl-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethanol with 2.2 g (7.9 mmol) of methyl 2-hydroxy-4-iodobenzoate, there were obtained, after chromatography on a silica column eluted with a mixture of dichloromethane and heptane (50/50), 2.77 g (87%) of the expected ester, with a melting point of 110°-115° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21]([O:23]CC)=O)[N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:28]=1.C[Al](C)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:26])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21]([N:37]3[CH2:38][CH2:39][N:34]([CH2:33][C:29]4[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=4)[CH2:35][CH2:36]3)=[O:23])[N:17]=2)(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: c1cncc(CN2CCNCC2)c1
Reactant: CCOC(=O)c1noc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)n1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)N3CCN(Cc4cccnc4)CC3)no2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AT using ethyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,2,4-oxadiazole-3-carboxylate (27 mg, 0.07 mmol), 1-(pyridin-3-ylmethyl)piperazine (40 mg, 0.23 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (2 mL). A portion of the crude product was purified using prep method D.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[C:15]2[O:16][C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C.O>[CH2:37]([O:36][C:34]([CH2:33][O:1][C:2]1[CH:3]=[C:4]([CH2:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[C:15]2[O:16][C:17]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:19]=2)[CH:5]=[CH:6][CH:7]=1)=[O:35])[CH3:38]
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc(CC2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCOC(=O)COc1cccc(C[C@@H]2CCCC[C@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-[2-[(3-hydroxyphenyl)methyl]-cyclohexyl]-4,5-diphenyloxazole (320 mg), ethyl bromoacetate (0.13 ml), and potassium carbonate (270 mg) in acetonitrile (3.0 ml) was stirred at room temperature overnight and a mixture of ethyl acetate and water was added thereto. The organic layer was separated, washed with water (twice) and brine, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was chromatographed over silica gel using n-hexane--ethyl acetate as an eluent. The first eluate gave cis- or trans-1-[(3-ethoxycarbonylmethoxyphenyl)methyl]-2-(4,5-diphenyloxazol-2-yl)cyclohexane (isomer A) (79 mg) as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[N:21]1[CH:20]=[CH:19][C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[S:24][C:14]=3[N:15]=2)=[CH:23][CH:22]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-dichlorobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C@@H:3]([C:5]([OH:7])=[O:6])N.N([O-])=O.[Na+].[Br-:14].[K+]>S(=O)(=O)(O)O>[Br:14][CH:3]([C:2]([F:9])([F:8])[F:1])[C:5]([OH:7])=[O:6]
Reactant: N[C@H](C(=O)O)C(F)(F)F
Reactant: [Br-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)C(Br)C(F)(F)F
Temperature: 0 °C

Procedure:
3,3,3-Trifluoroalanine (88 g.) is dissolved in a mixture of potassium bromide (250 g.) and 2.5 N sulfuric acid (1.240 ml.). The solution is chilled to 0° C. with an ice-salt bath and sodium nitrite (65.5 g.) is added in small portions over a one hour period with vigorous stirring. The reaction mixture is stirred in the cooling bath for another hour and then extracted with ether. The organic layer is washed with water, dried over magnesium sulfate and concentrated to dryness in vacuo to yield 2-bromo-3,3,3-trifluoropropanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[N:30]1([C:36](=[O:44])[CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:9]([C:27]([N:41]3[CH2:40][CH2:39][N:38]([CH2:37][C:36]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[O:44])[CH2:43][CH2:42]3)=[O:28])[NH:10][CH:11]([CH2:22][C:23]([CH3:25])([CH3:26])[CH3:24])[C:12]2([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:13]#[N:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)N2CCN(CC(=O)N3CCOCC3)CC2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 51.9 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example 1d was reacted with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (65.0 mg, 0.30 mmol), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2S,3R,4R,5R)-4-(3-chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl-propyl)-5-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile (45.5 mg, 51.9%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8](Br)[CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:12].[N+:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:13]([O-:15])=[O:14])[CH:21]=3)[CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:12]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Cn1c(=O)[nH]c2ccc(Br)cc21
Product: Cn1c(=O)[nH]c2ccc(-c3cccc([N+](=O)[O-])c3)cc21

Procedure:
Prepared from 1-methyl-6-bromo-1,3-dihydro-benzoimidazol-2-one and 3-nitro-phenyl boronic acid in the same fashion as that of Example 5. White solid: mp 264-265° C.; 1H-NMR (DMSO-d6) δ 11.0 (s, 1H), 8.47 (t, 1H, J=1.5 Hz), 8.19-8.15 (m, 2H), 7.75 (t, 1H, J=8.25 Hz), 7.58 (d, 1H, J=1.5 Hz), 7.43 (dd, 1H, J=8.25, 1.5 Hz), 7.1 (d, 1H, J=8.25 Hz), 3.37 (s, 3H); MS (ES) m/z 268([M−H]−, 50%); Anal. Calc. For C14H11N3O3: C, 62.45, H, 4.12, N, 15.61. Found: C, 61.48, H, 4.36 N, 14.75.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:10]2[CH2:15][CH2:14][CH:13]([NH:16]C(=O)OC(C)(C)C)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl>C1COCC1.CO.O1CCOCC1>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([S:9][CH:10]2[CH2:11][CH2:12][CH:13]([NH2:16])[CH2:14][CH2:15]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Sc2ccc(C(F)(F)F)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NC1CCC(Sc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.1 %

Procedure:
tert-Butyl (4-{[4-(trifluoromethyl)phenyl]thio}cyclohexyl)carbamate (0.38 g, 1.01 mmol) was dissolved in THF:MeOH 8:2 (10 ml) and HCl in 1,4-dioxane (4M, 2 ml) was added. The reaction mixture was stirred at rt for 15 h, and then evaporated. The crude product was diluted with EtOAc (100 ml), washed with a mixture of saturated aqueous Na2CO3 and water (1:2, 100 ml) and water (2×100 ml). The organic layer was dried over Na2SO4, filtrated and evaporated to yield the title compound (0.27 g, 97%) as a 50:50 mixture of cis and trans isomers. 1H-NMR (CDCl3, 500 MHz): δ 7.56-7.48 (m, 4H), 7.46-7.39 (m, 4H), 3.59-3.52 (m, 1H), 3.17-3.07 (m, 1H), 2.90-2.79 (m, 1H), 2.78-2.68 (m, 1H), 2.13-2.03 (m, 2H), 1.99-1.14 (m, 18H); 13C-NMR (CDCl3, 125 MHz): δ 141.6, 141.0, 130.2, 129.7, 125.9, 125.9, 50.0, 48.9, 45.0, 44.0, 36.6, 32.3, 32.1, 30.5, 29.2, 29.0, 28.6.
Reaction SMILES: C(O)C.[CH2:4]([O:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N+:19]([O-])=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[NH4+]>[Fe].O>[CH2:4]([O:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[NH2:19])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(F)cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To an ethanol (25 mL)-water (25 mL) mixture containing 2-(benzyloxy)-4-fluoro-1-nitrobenzene obtained were added iron (2.79 g, 50.0 mmol) and ammonium chloride (535 mg, 10.0 mmol) at room temperature, and the mixture was stirred at 100° C. for 1 hr. After cooling to room temperature, the reaction mixture was filtered through Celite (registered trademark) and the filtrate was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to afford the title compound as a brownish red oil (1.26 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16]>>[CH3:13][N:14]([C:4]([C:3]1[CH:7]=[CH:8][C:9]([I:11])=[CH:10][C:2]=1[F:1])=[O:5])[O:15][CH3:16]
Reactant: CNOC
Reactant: O=C(O)c1ccc(I)cc1F
Agent: Cl
Product: CON(C)C(=O)c1ccc(I)cc1F

Procedure:
The product was prepared from 2-fluoro-4-iodo-benzoic acid (EP-A-0327190) and N,O-dimethylhydroxylamine hydrochloride by a similar method to Preparation 30, as a yellow oil, b.p. 120-122° C. (0.5 mmHg), which was characterised by NMR. 1H-NMR (300OMHz, CDCl3): δ=3.44(s,3H), 3.53(s,3H), 7.14(t,1H), 7.51(d,1H), 7.56(dd,1H) ppm.