Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].C[C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[C:15](=[O:26])[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.[CH3:27]N(C)C=O.O>CO>[OH:26][CH:15]([C:5]1[N:6]=[C:7]([C:9]2[CH:14]=[C:13]([CH3:27])[CH:12]=[CH:11][CH:10]=2)[O:8][CH:4]=1)[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1
Reactant: CN(C)C=O
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)COc1ccc(C#N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cccc(-c2nc(C(O)COc3ccc(C#N)cc3)co2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Sodium borohydride (0.654 mg) was added to a suspension of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-oxoethoxy]benzonitrile (5.5 g) in methanol (100 ml)-N,N-dimethylformamide (50 ml), followed by stirring at room temperature for 1 hour. The reaction solution was poured into water and the crystals which separated out were collected by filtration to give 4-[2-hydroxy-2-(5-methyl-phenyl-4-oxazolyl)ethoxy]benzonitrile (5.1 g, 92.7%). Recrystallization from acetone afforded colorless neddles, m.p. 176°-177° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([OH:13])=[O:12])[CH2:3]1.S(=O)(=O)(O)O.[CH3:19]O>CCC(O)(C)C>[CH3:19][O:12][C:11]([CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[CH2:3]1)=[O:13]
Reactant: CO
Reactant: O=C1CC(C(=O)O)c2ccccc21
Agent: O=S(=O)(O)O
Solvent: CCC(C)(C)O
Product: COC(=O)C1CC(=O)c2ccccc21
Temperature: 25 °C

Procedure:
A solution of 10.0 g of 3-oxo-indan-1-carboxylic acid (56.8 mmol, 1.0 equivalent) and 0.25 mL of concentrated sulfuric acid in 20 mL of methanol was heated to a reflux for 4 hours. The reaction mixture was then cooled to room temperature and diluted with 100 mL of methyl-tert-butyl alcohol. The organic solution was washed twice with 60 mL of a saturated aqueous sodium bicarbonate solution, and once with 50 mL of a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated. The title compound crystallized as a white solid upon concentration, (10.4 g, 96%); mp: 46–47° C.; 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J=7.6 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.44 (t, J=7.6 Hz, 1H), 4.29 (dd, J=8.0, 3.4 Hz, 1H), 3.76 (s, 3H), 3.13 (dd, J=19.1, 3.4 Hz, 1H), 2.86 (dd, J=19.1, 8.0 Hz, 1H); 13C NMR (100 MHz, CD3OD): δ 204.4, 172.5, 151.3, 136.5, 135.2, 129.1, 126.7, 124.1, 52.9, 43.8, 39.7; IR (neat, cm−1): 2954, 1710, 1602, 1462, 1435, 1403, 1319, 1241, 1206, 1168, 1092, 1044, 1014,986, 881, 837, 760, 686, 580, 538.
Reaction SMILES: [N+]([O-])([O-])=O.[NH4+].[Ce].[F:7][C:8]([F:25])=[CH:9][CH:10]1[CH2:14][N:13](CC2C=CC(OC)=CC=2)[C:12](=[O:24])[CH2:11]1>CC#N.O.O>[F:7][C:8]([F:25])=[CH:9][CH:10]1[CH2:14][NH:13][C:12](=[O:24])[CH2:11]1
Reactant: COc1ccc(CN2CC(C=C(F)F)CC2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: O=C1CC(C=C(F)F)CN1
Temperature: 4 °C
Reaction time: 5 h

Procedure:
In a 200 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, cerium ammonium nitrate (11.2 g, 0.02 mol, 3 eq) is added to a solution of 4-(2,2-difluoro-vinyl)-1-(4-methoxy-benzyl)-pyrrolidin-2-one a4 (1.8 g, 6.8 mmol in MeCN/H2O (respectively 70 ml/110 ml) cooled at 4° C. After 5 h at 10° C., the reaction mixture is diluted with water, extracted with AcOEt, dried on MgSO4 and concentrated in vacuo. The residue is diluted with toluene, the solid is filtrated and the solvent is evaporated. The residue is purified by chromatography on silicagel (CH2Cl2/MeOH: 99/01 (v/v)) to afford fraction A1 (0.5 g of the expected compound) and fraction B (0.7 g of a mixture of synthetic intermediates and starting materials). Fraction B is again reacted with cerium ammonium nitrate as above (CAN: 0.78 g, MeCN (30 ml), H2O (50 ml)) to afford after purification, another fraction A2 (0.3 g). Fractions A1+A2 put together give 0.8 g of 4-(2,2-difluoro-vinyl)-pyrrolidin-2-one as (81%) contaminated by traces of 4-methoxybenzoic acid.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.O.ON1C2C=CC=CC=2N=N1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(#N)C>[N:21]1([C:7]([C@H:2]2[NH:1][C:5](=[O:6])[CH2:4][CH2:3]2)=[O:9])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: C1COCCN1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C1CC[C@@H](C(=O)N2CCOCC2)N1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
The reaction vessel is charged with 30 g L-pyroglutamic acid and 4.71 g 1-hydroxybenzotriazole hydrate. The solids are then suspended in 190 ml anhydrous acetonitrile and the mixture is then heated to 45° C. Subsequently, 20.24 ml morpholine is added via a dropping funnel within 20 min, and the dropping funnel is then washed with 5 ml anhydrous acetonitrile. The resulting mixture is then heated to 65° C. and 29.32 g N—-N′-diisopropylcarbodiimide added within 1 h via a dropping funnel. After complete addition, the dropping funnel is washed with 5 ml anhydrous acetonitrile and the reaction mixture is stirred at 65° C. for an additional 30 min. The resulting suspension is then cooled to ambient temperature, filtered and the filter cake washed with 3×30 ml acetonitrile. The filtrate is concentrated under heating and reduced pressure to approx. ½ of its original volume and the residue is then seeded with 16 mg (S)-5-(morpholine-4-carbonyl)pyrrolidine-2-one. Concentration under reduced pressure is continued until approx ⅓ of the original volume of the filtrate is reached. While further concentrating the filtrate under reduced pressure and removing approx. 95 ml of distillate, simultaneously 210 ml 2-methyltetrahydrofuran is added. The suspension is then cooled to 0° C. and the solids are isolated by filtration. The filter cake is washed with 3×20 ml cooled 2-methyltetrahydrofuran and dried at 55° C. under vacuum to give 42.54 g of (S)-5-(morpholine-4-carbonyl)pyrrolidine-2-one as fine white crystals (98.0% purity by HPLC, ee (HPLC)>99.6% [4-a, R1=H; R4=morpholine]).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17](F)=[C:16]([CH3:21])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([SH:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([S:39][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[C:16]([CH3:21])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: SCc1ccccc1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1SCc1ccccc1
Temperature: 90 °C
Yield: 80 %

Procedure:
To a solution of 5-(3,5-dichlorophenyl)-3-(4-fluoro-3-methylphenyl)-4,5-dihydro-5-(trifluoromethyl)isoxazole (i.e. the product from Step B of Example 2) (2.6 g, 6.65 mmol) and potassium carbonate (2.3 g, 16.6 mmol) in N,N-dimethylformamide (25 mL) was added benzyl mercaptan (0.782 mL, 6.65 mmol). The reaction mixture was heated at 90° C. for 4 h. The reaction mixture was then cooled and excess-water was added, and the mixture was extracted with ethyl acetate (2×100 mL). The organic extracts were dried (MgSO4) and concentrated under reduced pressure to provide a solid residue. The crude product was partially purified by silica gel column chromatography eluted with mixtures of hexane and ethyl acetate to afford a product containing the title compound (about 80% purity, 2.8 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:23]=[CH:22][C:13]([O:14][CH2:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](OB(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH2:18]([N:17]([CH2:20][CH3:21])[CH2:16][CH2:15][O:14][C:13]1[CH:22]=[CH:23][C:10]([C:9]#[C:8][C:5]2[CH:4]=[CH:3][C:2]([C:29]3[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)=[CH:7][N:6]=2)=[CH:11][CH:12]=1)[CH3:19]
Reactant: COc1ccc(OB(O)O)cc1
Reactant: CCN(CC)CCOc1ccc(C#Cc2ccc(Br)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN(CC)CCOc1ccc(C#Cc2ccc(-c3ccc(OC)cc3)cn2)cc1
Temperature: 110 °C

Procedure:
A mixture of 200 mg (0.54 mmol) {2-[4-(5-bromo-pyridin-2-ylethynyl)-phenoxy]-ethyl}-diethyl-amine, 163 mg (1.07 mmol) 4-methoxy-phenylboric acid, 31 mg (0.03 mmol) tetrakis-triphenylphosphane-palladium and 0.27 mL of a 2 M aqueous Na2CO3 solution in 5 mL 1,4-dioxane is heated for 20 h at 110° C. under a nitrogen atmosphere. The solvent is distilled off i.vac., the residue is taken up in water, exhaustively extracted with EtOAc and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified on silica gel (EtOAc/MeOH/NH3 95:5:0.5). The product fractions are evaporated down, the residue is triturated with diethyl ether, suction filtered and washed with diisopropylether.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].CN1CCOCC1.[NH:39]1[C:43]([CH2:44][NH2:45])=[N:42][CH:41]=[N:40]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH:39]1[C:43]([CH2:44][NH:45][C:3](=[O:4])[CH:2]([OH:1])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]=[C:15]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:18]=4[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=3)=[CH:8][CH:7]=2)=[N:42][CH:41]=[N:40]1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCc1ncn[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCc1ncn[nH]1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 58.6 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 30 mg, 0.070 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.046 mL, 0.417 mmol), (1H-1,2,4-triazol-5-yl)methanamine (12.28 mg, 0.125 mmol), and BOP (55.4 mg, 0.125 mmol). This was stirred overnight and then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 15 mL/min, 220 nM, retention time=32.9 min) to give single enantiomer N-((1H-1,2,4-triazol-5-yl)methyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (22 mg, 0.041 mmol, 58.8% yield): LCMS=512.2 [M+H]; 1H NMR (400 MHz, methanol-d4) δ ppm 8.11-8.24 (2 H, m), 7.66-7.78 (4 H, m), 7.54-7.66 (3 H, m), 6.04 (1 H, s), 5.19 (1 H, s), 4.51 (2 H, s). HPLC Peak RT=8.4 min (Analytical Method C).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=2[NH:8]S(C2C=CC(C)=CC=2)(=O)=O)=[O:5])[CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:24].[OH-].[NH4+]>>[NH2:8][C:7]1[CH:19]=[CH:20][CH:21]=[CH:22][C:6]=1[C:4](=[O:5])[CH2:1][CH2:2][CH2:3][OH:24]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(S(=O)(=O)Nc2ccccc2C(=O)C2CC2)cc1
Agent: [NH4+]
Agent: [OH-]
Product: Nc1ccccc1C(=O)CCCO
Temperature: 90 °C
Yield: 80 %

Procedure:
The product of example 2 (1.5 g, 4.7 mmol) is treated with 96% sulfuric acid and heated to 90° C. for 15 minutes. The solution is cooled, adjusted to pH 9 with ammonium hydroxide and extracted with methylene chloride. The combined extracts are concentrated in vacuo to provide 1-(o-aminophenyl)-4-hydroxy-1-butanone (80% yield, mp 58-61° C.). The product is identified by NMR and MS analyses.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1>>[N+:11]([C:10]1[C:2]([NH:1][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=2)=[CH:3][C:4]2[O:8][CH2:7][O:6][C:5]=2[CH:9]=1)([O-:13])=[O:12]
Reactant: OCCc1ccc(Br)cc1
Reactant: Nc1cc2c(cc1[N+](=O)[O-])OCO2
Product: O=[N+]([O-])c1cc2c(cc1Nc1ccc(CCO)cc1)OCO2

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 45 from 5-amino-6-nitro-1,3-benzodioxol and 4-bromophenylethyl alcohol.
Reaction SMILES: [NH2:1][C@H:2]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([NH:5][CH2:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[N+:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36](Cl)(=[O:38])=[O:37])([O-:29])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[C:14]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][NH:5][C:3](=[O:4])[C@H:2]([NH:1][S:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N+:27]([O-:29])=[O:28])(=[O:37])=[O:38])[CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: N[C@H](Cc1ccccc1)C(=O)NCC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC(c1ccccc1)c1ccccc1)[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 74.3 %

Procedure:
To a stirred solution of the product of step 1 (12.3 g, 35.6 mmol) in methylene chloride (200 mL) was added 2-nitrobenzenesulfonyl chloride (9.00 g, 40.6 mmol) followed by triethylamine (6.4 mL, 46 mmol). After 30 minutes the reaction was concentrated and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was dried (sodium sulfate) and concentrated. The resulting amber foam was purified by flash chromatography over silica (hexane/ethyl acetate) to afford 14.0 g (74%) of product as a colorless foam: 1H NMR (CDCl3) δ 7.95–7.87 (m, 1H), 7.76–7.62 (m, 3H), 7.35–7.15 (m, 10H), 7.06–6.94 (m, 3H), 6.90–6.83 (m, 2H), 6.42 (t, J=5.6, 1H), 5.80 (d, J=5.8, 1H), 4.12 (t, J=8.1, 1H), 4.01–3.82 (m, 3H), 3.18–3.08 (m, 1H), 2.68–3.57 (m, 1H) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([F:30])[C:22]=1[F:31])[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:17][CH2:16][C:11]4([O:15][CH2:14][CH2:13][O:12]4)[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)=[C:23]([F:30])[C:22]=1[F:31])[CH3:19]
Reactant: CCOc1ccc(B(O)O)c(F)c1F
Reactant: Brc1ccc(C2=CCC3(CC2)OCCO3)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1ccc(-c2ccc(C3CCC4(CC3)OCCO4)cc2)c(F)c1F
Temperature: 25 °C
Yield: 75.7 %

Procedure:
8-(4-Bromophenyl)-1,4-dioxaspiro(4.5)dec-7-ene (s71) (30.0 g), 4-ethoxy-2,3-difluorophenylboronic acid (s70) (24.6 g), potassium phosphate (K3PO4; 64.7 g), dichlorobistriphenylphosphine palladium (II) (Pd(Ph3P)2Cl2; 2.1 g) and 1,4-dioxane (300 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and heated to reflux for 2 hours. After the reaction mixture had been cooled to 25° C., it was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder. Pd/C (1.5 g) was added to the purified product, and the mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder, and then by recrystallization from a mixed solvent of toluene and heptane (toluene:heptane=1:1 by volume) to give 8-(4′-ethoxy-2′,3′-difluoro-(1,1′-biphenyl)-4-yl)-1,4-dioxaspiro(4.5)decane (s72) (28.8 g). The yield based on the compound (s71) was 75.7%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)[CH2:16][CH2:15]1
Reactant: CN1CCNCC1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Product: CN1CCN(c2n[nH]c(=O)c3ccccc23)CC1

Procedure:
4-chlorophthalazin-1-one and 1-methylpiperazine were treated using methods similar to that described in Examples 1A to give the title compound. MS (APCI+) M/Z 245 (M+H)+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:36])[C@@H:6]([NH2:35])[CH2:7][S:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:27]4[O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:26]=4[CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.Cl>O1CCCC1.CO>[NH2:35][C@@H:6]([CH2:7][S:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:27]4[O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:26]=4[CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[C:5]([OH:36])=[O:4]
Reactant: COC(=O)[C@@H](N)CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N[C@@H](CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O
Reaction time: 1 h
Yield: 85.6 %

Procedure:
2N Sodium hydroxide (0.5 mL) was added to a stirred solution of the amino methyl ester, (2R)-Methyl-2-Amino-3-(4′-dibenzofuran-4-ylbipheny-4-ylmethylsulfanyl)-propionate (100 mg) in a mixture of tetrahydrofuran (5 mL) and methanol (1 mL). The solution was stirred for 1 hour and then acidified to pH 3 with 2N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (3×10 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 25% methanol in methylene chloride as eluent, afforded the title compound as a cream solid (83 mg, 86%); Rf: 0.10 (25% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz): δ 11.20 (3H, br s, NH, OH), 7.94 (1H, d, J=9 Hz, Ar—H), 7.91 (1H, d, J=8 Hz, Ar—H), 7.86 (2H, d, J=9 Hz, Ar—H), 7.67 (2H, d, J=9 Hz, Ar—H), 7.48-7.57 (4H, m, Ar—H), 7.21-7.39 (5H, m, Ar—H), 4.02 (1H, dd, J=8, 5 Hz, CHN), 3.74 (2H, s, PhCH2S), 2.94 (1H, dd, J=16, 5 Hz, CHHCHN), 2.86 (1H, dd, J=16, 8 Hz, CHHCHN); ESI-LCMS e/z calcd for C28H23NO3S 453.560, found 454 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)=[N:6][CH:7]=1.[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[C:20]#[CH:21])[CH3:17].C(N(CC)CC)C>C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]Br>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[C:20]#[C:21][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)=[N:6][CH:7]=1)[CH3:17]
Reactant: Fc1ccc(-c2ccc(Br)cn2)cc1F
Reactant: C#CC(OCC)OCC
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(C#Cc1ccc(-c2ccc(F)c(F)c2)nc1)OCC
Reaction time: 2 h

Procedure:
A mixture of 2.00 g of crude 5-bromo-2-(3,4-difluorophenyl)pyridine (GC purity 81%), 1.12 ml of 3,3-diethoxy-1-propine, 0.138 g of tetrakis(triphenylphosphine)palladium, 0.052 g of copper(I) bromide and 36 ml of triethylamine was heated to boiling for 2 hours. After cooling the reaction mixture was diluted with 100 ml of diethyl ether, washed twice with 40 ml of water each time, dried over sodium sulphate, filtered, the filtrate was boiled briefly with active charcoal, filtered and concentrated. The crude 5-(3,3-diethoxy-1-propynyl)-2-(3,4-difluorophenyl)pyridine, (2.58 g; GC purity 72%), obtained as a brown-black oil, was used directly in the next step.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:20]=[N:21][NH:22][CH:23]=4)[CH:18]=[C:13]3[C:12]([C:24]3[N:29]=[C:28]([O:30][CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]4)[CH:27]=[N:26][CH:25]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH2:45][CH3:46].[H-].[Na+]>CN(C=O)C>[CH2:45]([N:22]1[CH:23]=[C:19]([C:17]2[CH:18]=[C:13]3[C:12]([C:24]4[N:29]=[C:28]([O:30][CH:31]5[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:36]5)[CH:27]=[N:26][CH:25]=4)=[CH:11][N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:8])=[O:9])[C:14]3=[N:15][CH:16]=2)[CH:20]=[N:21]1)[CH3:46]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cncc(-c3cn(S(=O)(=O)c4ccccc4)c4ncc(-c5cn[nH]c5)cc34)n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(-c2cnc3c(c2)c(-c2cncc(OC4CCN(C(=O)OC(C)(C)C)CC4)n2)cn3S(=O)(=O)c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 4-({6-[1-(phenylsulfonyl)-5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]pyrazin-2-yl}oxy)piperidine-1-carboxylate (0.075 g, 0.13 mmol) and iodoethane (11 pt, 0.14 mmol) in DMF (1.3 mL) at 0° C. was added sodium hydride (60% mineral oil dispersion; 6.0 mg, 0.15 mmol). The reaction mixture was stirred at 0° C. for 1 h then quenched with aqueous saturated sodium bicarbonate (5 mL). The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford tert-butyl 4-({6-[5-(1-ethyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]pyrazin-2-yl}oxy)piperidine-1-carboxylate as a yellow oil. LRMS (ESI) calculated for C32H35N7O5S [M+H]+, 630.2; found 630.2.
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Cl:20][C:21]1[C:29]([Cl:30])=[C:28]([Cl:31])[C:27]([Cl:32])=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Cl:20][C:21]1[C:29]([Cl:30])=[C:28]([Cl:31])[C:27]([Cl:32])=[CH:26][C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Reactant: O=C(Cl)c1cc(Cl)c(Cl)c(Cl)c1Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1cc(Cl)c(Cl)c(Cl)c1Cl)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,3,4,5-Tetrachlorobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,3,4,5-tetrachlorobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10]([CH2:12][C:13](OCC)=[O:14])#[N:11]>>[C:10]([CH2:12][C:13]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([CH3:9])[CH:4]=1)=[O:14])#[N:11]
Reactant: Cc1cc(N)ccc1F
Reactant: CCOC(=O)CC#N
Product: Cc1cc(NC(=O)CC#N)ccc1F
Temperature: 180 °C
Reaction time: 14 h
Yield: 93.7 %

Procedure:
A mixture of 4-fluoro-3-methylaniline (2.50 g, 20.0 mmol) and ethyl cyanoacetate (2.70 g, 24.0 mmol) was stirred at 180° C. for 14 hr. After cooling to room temperature, the obtained solid was washed with hexane and collected by filtration to give the title compound (3.60 g, 95%) as a brownish-red solid.