Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:4].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:25]([N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][N:5]([C@@H:13]2[CH2:15][C@H:14]2[C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=2)[C:3](=[O:4])[C:2]([F:23])([F:1])[F:24])[CH2:8][CH2:9]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccc(I)cc1)C(F)(F)F
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(N(CC1CCN(Cc2ccccc2)CC1)[C@@H]1C[C@H]1c1ccc(I)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.7 %

Procedure:
To a solution of 2,2,2-trifluoro-N-((trans)-2-(4-iodophenyl)cyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (250 mg, 0.553 mmol) in 1,2-dichloroethane (DCE) (4 mL) were added benzaldehyde (0.067 mL, 0.663 mmol) and sodium triacetoxyborohydride (176 mg, 0.829 mmol), and the mixture was stirred at room temperature for 18 h. The mixture was quenched with water (4 ml) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 100% EtOAc/hexanes) to give 194 mg of product as pale yellow viscous oil. MS: (M+H)+=543.3. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.29-1.52 (m, 3H), 1.57-1.93 (m, 4H), 2.04-2.25 (m, 2H), 2.37-2.51 (m, 1H), 2.91-3.22 (m, 3H), 3.40-3.66 (m, 4H), 6.89-7.07 (m, 2H), 7.27-7.40 (m, 5H), 7.64 (d, J=8.34 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:4](=O)[CH2:5][C:6](=O)[C:7]([CH3:10])([CH3:9])[CH3:8])[CH3:3].Cl.[N+:15]([C:18]1[CH:22]=[N:21][NH:20][C:19]=1[NH2:23])([O-:17])=[O:16]>C(O)(=O)C>[C:2]([C:4]1[CH:5]=[C:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:20]2[N:21]=[CH:22][C:18]([N+:15]([O-:17])=[O:16])=[C:19]2[N:23]=1)([CH3:13])([CH3:3])[CH3:1]
Reactant: Nc1[nH]ncc1[N+](=O)[O-]
Reactant: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C(C)(C)C)n2ncc([N+](=O)[O-])c2n1
Yield: 46 %

Procedure:
36.85 g of 2,2,6,6-tetramethyl-3,5-heptanedione, 200 cc of acetic acid and 32.91 g of 4-nitro-2H-pyrazol-3-ylamine hydrochloride (prepared in accordance with H. Dorn and H. Dilcher, Liebigs Ann. Chem., 707,141, 1967) were introduced into a 500 ml three-necked flask fitted with a condenser, a thermometer and a magnetic bar. The mixture was refluxed for 8.5 hours. The solution was poured, hot, onto ice. The yellow solid which precipitated was filtered off. It was recrystallized from an acetic acid/water mixture. Drying under vacuum and over phosphoric anhydride yielded 25.4 g of 5,7-di-tert-butyl-3-nitropyrazolo[1,5-a]pyrimidine (yield=46%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH:9]([CH3:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([OH:18])[CH:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH:28](Br)[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C)C=O>[CH2:32]([O:31][C:29]([CH:28]1[O:17][C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH:9]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:20])[CH3:8])[CH3:19])=[CH:12][C:13]=2[O:18]1)=[O:30])[CH3:33]
Reactant: CCOC(=O)C(Br)Br
Reactant: CC(Cc1ccc(O)c(O)c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1Oc2ccc(CC(C)N(C)C(=O)OC(C)(C)C)cc2O1
Temperature: 100 °C
Yield: 34.2 %

Procedure:
To 2.5 g (8.8 mmol) of 1C was added 20 mL of anhydrous N, N-dimethylformamide (DMF) followed by 3.68 g (26 mmol) of anhydrous K2CO3 and 3 mL (23 mmol) of ethyl dibromoacetate. The reaction mixture was heated to 100° C. for 4.5 hours and then allowed to cool to room temperature. This was concentrated to dryness under reduced pressure, and 50 mL of water was added to the residue. The mixture was adjusted to pH 3 using 1N HCl and extracted with 4×50 mL of dichloromethane. Organic layers were combined, dried (anhydrous Na2SO4), and concentrated to dryness. The residue was purified by flash column silica gel chromatography using 15% ethyl acetate in hexane to give 1.1 g (3.01 mmol, 34%) of 1D as a colorless oil (M+Na, 388).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([NH2:19])=[C:11]([O:17][CH3:18])[CH:12]=[C:13]([F:16])[C:14]=2[F:15])=[C:4]([F:20])[CH:3]=1.[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3[C:14]([F:15])=[C:13]([F:16])[CH:12]=[C:11]([O:17][CH3:18])[C:10]=3[NH:19][C:21]2=[O:22])=[C:4]([F:20])[CH:3]=1
Reactant: COc1cc(F)c(F)c(Nc2ccc(Br)cc2F)c1N
Reactant: O=C(n1ccnc1)n1ccnc1
Product: COc1cc(F)c(F)c2c1[nH]c(=O)n2-c1ccc(Br)cc1F
Yield: 74.4 %

Procedure:
Intermediate I-8a was prepared from N2-(4-bromo-2-fluoro-phenyl)-3,4-difluoro-6-methoxy-benzene-1,2-diamine (I-6a: 12.5 g, 0.036 mol) and 1,1′-carbonyldiimidazole (14.6 g, 0.0900 mol) using procedures analogous to the preparation of Intermediate (I-7a) above to afford 10 g of the product (74% yield). H1NMR (DMSO-d6, 300 MHz): δ 11.72 (s, 1H), 7.86 (dd, 1H), 7.68-7.58 (m, 2H), 7.02-6.92 (m, 1H), 3.88 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(#N)C>[CH2:15]([NH:22][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1NCc1ccccc1
Temperature: 92 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A mixture of 2-chloro-5-nitro-benzenesulfonamide (2.20 kg, 9.30 mol), benzylamine (1.5 L, 13.9 mol), triethylamine (2.5 L, 18.1 mol), and acetonitrile (22.0 L) were heated at 92° C. for 20 h. The mixture was then cooled to 40° C., and was then partially concentrated in vacuo. The residue was added to 0° C. water (22.0 L) and the resulting suspension was allowed to warm to 23° C. and stirred for 2 h. The suspension was filtered and the solid was then washed with water (5 L). The washed solid was suspended in absolute ethanol (11 L), and was then filtered and washed with absolute ethanol (5 L). The solid was further dried in vacuo at 45° C. to afford the desired product, 2-benzylamino-5-nitro-benzenesulfonamide (2.40 kg, 7.81 mol, 84%), as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 4.64 (2H, d, J=4.6 Hz), 6.81 (1H, d, J=9.4 Hz), 7.23-7.44 (6H, m), 7.77 (2H, bs), 8.11 (1H, dd, J1=9.4 Hz, J2=2.3 Hz), 8.49 (1H, d, J=3.1 Hz). LC-MS (ESI) calcd for C13H13N3O4S 307.06, found 308.2 [M+H+] (100%), 615.2 [2M+H+] (81%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][CH2:13][C:14]1[NH:15][CH2:16][CH2:17][N:18]=1.[Mn]([O-])(=O)(=O)=O.[K+].CO>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][CH2:13][C:14]1[NH:18][CH:17]=[CH:16][N:15]=1
Reactant: O=[N+]([O-])c1ccc(CCCC2=NCCN2)c(F)c1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: O=[N+]([O-])c1ccc(CCCc2ncc[nH]2)c(F)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 68.2 %

Procedure:
Compound 121 (888 mg, 3.53 mmol) was first dissolved in acetonitrile (100 mL), with potassium permanganate (1.12 g, 7.07 mmol) and alumina (4.9 g) added into the solution in batch. After stirring the resulting mixture at room temperature for 40 min, CH3OH (1 mL) was added to reduce excess oxidant. The mixture was then filtered and the solid material was washed with DCM:CH3OH=10:1. The filtrate was evaporated to dryness to give the compound 122 (600 mg, 68%) as a light yellow oil. The crude product was used directly for the next step without purification. 1H NMR (400 MHz, CDCl3) δ7.94-7.99 (m, 1H), 7.85-7.91 (m, 1H), 7.35-7.41 (m, 1H), 6.96 (br s, 2H), 2.75-2.85 (m, 4H), 2.06-2.19 (m, 2H).
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH:18]([CH3:22])[O:19][CH2:20][CH:21]=3)[CH:14]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>>[CH3:22][CH:18]1[CH:17]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)[CH2:21][CH2:20][O:19]1
Reactant: [H][H]
Reactant: CC1OCC=C1c1ccc2c(c1)CN(Cc1ccccc1)C2
Product: CC1OCCC1c1ccc2c(c1)CNC2

Procedure:
Prepared in analogy to Example A62(c) from 2-benzyl-5-(2-methyl-2,5-dihydro-furan-3-yl)-2,3-dihydro-1H-isoindole and hydrogen. Yellow oil. MS (m/e): 204.1 ([M+H]+, 100%).
Reaction SMILES: [N:1]1([CH2:6]/[CH:7]=[C:8](/[C:16]2[N:21]=[C:20](/[CH:22]=[CH:23]/[CH:24]=[O:25])[CH:19]=[CH:18][CH:17]=2)\[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:26]([Mg]Cl)[CH2:27][CH3:28]>C1COCC1>[N:1]1([CH2:6]/[CH:7]=[C:8](/[C:16]2[N:21]=[C:20](/[CH:22]=[CH:23]/[CH:24]([OH:25])[CH2:26][CH2:27][CH3:28])[CH:19]=[CH:18][CH:17]=2)\[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(/C(=C\CN2CCCC2)c2cccc(/C=C/C=O)n2)cc1
Reactant: CCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCC(O)/C=C/c1cccc(/C(=C/CN2CCCC2)c2ccc(C)cc2)n1
Temperature: 25 °C
Yield: 56.7 %

Procedure:
A stirred solution of 3-(6-[3-pyrrolidin-1-yl-1-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-prop-2E-enal (925 mg, 2.78 mmol) in anhydrous THF (30 ml) at -78° C. was treated dropwise with a solution of n-propyl magnesium chloride (1.53 ml, 2.0 M in diethylether, 3.06 mmol). The reaction mixture was allowed to warm slowly to room temperature (~2 hours). The reaction was quenched with water (3 ml) and THF removed under reduced pressure. The residue was taken up in 1M HCl and then basified with solid sodium bicarbonate to pH 8. The product was extracted with ethyl acetate (×3). The organics were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by column chromatography eluting with 5-8% methanol in DCM. Product containing fractions were combined and solvent removed to provide 1-(6-[3-pyrrolidin-1-yl-1-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-hex-1E-en-3-ol as a pale pink foam (593 mg, 57%). 1H-NMR; δ (CDCl3), 7.44 (1H, t, J=7.7 Hz), 7.24-7.18 (3H, m), 7.12-7.07 (3H, m), 6.89 (1H, dd, J=15.7, 6.2 Hz), 6.68 (2H, m), 4.38 (1H, m), 3.35 (2H, d, J=7.1 Hz), 2.41 (4H, bs), 1.86 (3H, s), 1.71-1.61 (2H, m), 1.58-1.42 (2H, m), 1.47 (3H, t, J=7.0 Hz).
Reaction SMILES: [CH2:1](I)[CH3:2].[CH2:4]([O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([OH:22])[CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:4]([O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([O:22][CH2:1][CH3:2])[CH:13]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(OCc2ccccc2)ccc1C(=O)OC

Procedure:
Ethyl iodide (0.14 mL) was added to a mixture of methyl 4-benzyloxy-2-hydroxybenzoate (0.30 g) and potassium carbonate (0.32 g) in N,N-dimethylformamide (2.9 mL) at room temperature with stirring. The mixture was stirred at that temperature for 1.6 hrs and at 50° C. for 1.4 hrs. Water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (0.29 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.N1C=CC=CC=1.[CH2:37]=[C:38]1[O:41][C:40](=[O:42])[CH2:39]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:23][C:40](=[O:42])[CH2:39][C:38](=[O:41])[CH3:37])([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1
Reactant: C=C1CC(=O)O1
Reactant: N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)CC(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
To a solution of (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine (28 mg, 0.07 mmol), prepared as described in Procedure 3, 4, 5 and 6, in DCM (1 mL) was added pyridine (0.01 mL, 0.12 mmol). The reaction was cooled to 0° C., followed by the addition of 4-methyleneoxetan-2-one (0.01 mL, 0.13 mmol). The reaction mixture was stirred at rt for 2 h and concentrated. The residue was purified by preparative HPLC (Axia luna column, 30×75 mm, 40-100% ACN/H2O with 0.1% TFA over 10 min, flow rate 40 mL/min, monitoring at 220 nm) to yield (R)—N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-oxobutanamide (Example 251) as colorless oil (23 mg, 58% yield). LCMS: RT=3.71 min [M+H] 510.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 8.23 (1H, s), 7.04-7.20 (5H, m), 6.96-7.02 (2H, m), 6.87-6.92 (3H, m), 6.61 (2H, d, J=7.07 Hz), 5.87 (1H, t, J=2.78 Hz), 3.94 (1 H, d, J=12.88 Hz), 3.71 (1H, d, J=12.88 Hz), 3.43 (2H, s), 2.24 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=3)=[C:11]3[O:12][CH2:13][CH2:14][CH2:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:36]([CH:33]4[CH2:35][CH2:34]4)=[O:37])[CH:18]=3)=[C:11]3[O:12][CH2:13][CH2:14][CH2:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(-c2c(-c3ccc(F)cc3)nn3c2OCCC3)ccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1cc(-c2c(-c3ccc(F)cc3)nn3c2OCCC3)ccn1)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
93 mg (0.3 mmol) of 4-[2-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl]pyridin-2-amine and 46 mg (0.36 mmol, 1.2 eq) of Huenigs base are dissolved in 2 mL tetrahydrofuran. To this are added 63 mg of cyclopropanecarbonyl chloride (0.6 mmol, 2 eq) and the reaction mixture is stirred for 16 hrs at room temperature. Next, the volatile components are removed under vacuum and the crude material treated with 3 mL NH3 in methanol (7 molar). The mixture is stirred for 16 hrs at room temperature and then evaporated. The crude product is purified by preparative HPLC (Phenomenex AMA Gemini C18; 110 A; 10 μm 100×30 mm, gradient: 0-2.0 mins 80% water, 20% acetonitrile, 2.0-12.0 mins linear gradient up to 25% water, 75% acetonitrile, 12.0-16.0 mins 5% water, 95% acetonitrile, modifier 15% NH4OH in H2O, addition of the modifier at 1.0 mL/min throughout the separation). 38.2 mg (33%) of N-{4-[2-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl]pyridin-2-yl}cyclo-propanecarboxamide are obtained as a colourless solid.
Reaction SMILES: [OH-:1].[K+].Br[C:4]1[CH:23]=[CH:22][C:7]([CH2:8][C:9]2[C:10]([CH2:20][CH3:21])=[N:11][N:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[N:14][C:13]=23)=[CH:6][CH:5]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:20]([C:10]1[C:9]([CH2:8][C:7]2[CH:22]=[CH:23][C:4]([OH:1])=[CH:5][CH:6]=2)=[C:13]2[N:14]=[C:15]([CH3:19])[CH:16]=[C:17]([CH3:18])[N:12]2[N:11]=1)[CH3:21]
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(Br)cc1
Reactant: [OH-]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [K+]
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(O)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Potassiumhydroxide (1.96 g, 34.9 mmol) was dissolved in 30 ml of a 1:1 mixture of argon-flushed dioxane and water. After addition of 3-(4-bromo-benzyl)-2-ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidine (3) (4 g, 11.62 mmol), Pd2(dba)3 (426 mg, 0.465 mmol) and tetramethyl Xphos (894 mg, 1.859 mmol), the mixture was flushed with argon and stirred for 1 h at 100° C. Then the mixture was treated with 1N HCl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2 SO4 and evaporated. Purification by chromatography (silica gel, ethylaceta/n-heptane) gave a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12]([C:14]2[N:19]=[C:18]([NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[C:17]([N+:27]([O-])=O)=[CH:16][CH:15]=2)=[C:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:10]=1.O.O.[Sn](Cl)Cl>CCO>[NH2:27][C:17]1[C:18]([NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[N:19][C:14]([C:12]2[NH:13][C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])=[N:10][C:11]=2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:15][CH:16]=1
Reactant: CC(C)S(=O)(=O)Nc1nc(-c2[nH]c(-c3c(Cl)cccc3Cl)nc2-c2ccccc2)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CC(C)S(=O)(=O)Nc1nc(-c2[nH]c(-c3c(Cl)cccc3Cl)nc2-c2ccccc2)ccc1N
Temperature: 25 °C
Yield: 85.3 %

Procedure:
Heat a mixture of propane-2-sulfonic acid {6-[2-(2,6-dichlorophenyl)-5-phenyl-3H-imidazol-4-yl]-3-nitropyridin-2-yl}amide (0.262 g, 0.49 mmol) and tin (II) chloride dihydrate (0.55 g, 2.46 mmol) in EtOH (10 mL) at 100° C. for 1 h. Cool to RT and concentrate to a slurry. Pour the reaction mixture into saturated NaHCO3 (20 mL) and add a filtering agent. Filter and wash with EtOAc. Separate the layers and extract successively with saturated NaHCO3 and saturated aqueous NaCl. Dry the organic layer over Na2SO4 and concentrate to give the title compound (0.21 g, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[NH:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>>[CH3:34][O:33][C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:48]2[CH2:47][CH2:46][CH:45]([NH:44][C:36]3[NH:35][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=3)[CH2:50][CH2:49]2)([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Reactant: c1ccc2[nH]c(NC3CCNCC3)nc2c1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 4.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-difluorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine and (1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([CH2:27][NH:28]C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[CH3:36][C:37]1[N:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1>>[NH2:28][CH2:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:40]3[CH:41]=[N:42][C:37]([CH3:36])=[CH:38][CH:39]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:19])([F:20])[F:18])=[CH:12][CH:11]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](CN)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (S)-tert-butyl ((1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate (Stage 108.1) and (6-methylpyridin-3-yl)boronic acid. LC-MS (Condition 6) tR=0.79 min, m/z=472.0 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].CC(C)([O-])C.[K+]>O.CN1CCCC1=O>[CH3:18][C:17]1[C:12]([NH:11][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cccnc1N
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cccnc1Nc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 36.9 %

Procedure:
0.3 g of 4-fluoronitrobenzene, 0.46 g of 2-amino-3-methylpyridine, and 0.353 g of K2CO3 were added to a solution of 2.5 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 1 hour and 0.286 g of potassium tert-butoxide was then added. Heating was then continued for 6 hours and, after cooling to room temperature, the reaction medium was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 0.18 g of 3-methyl-N-(4-nitrophenyl)pyrid-2-amine (7) was obtained.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[CH2:6]1[CH2:12][S:9](=[O:11])(=[O:10])[O:8][CH2:7]1.C1COCC1>C(#N)C>[CH:1]1([NH:5][CH2:7][CH2:6][CH2:12][S:9]([OH:11])(=[O:10])=[O:8])[CH2:4][CH2:3][CH2:2]1
Reactant: O=S1(=O)CCCO1
Reactant: NC1CCC1
Solvent: CC#N
Solvent: C1CCOC1
Product: O=S(=O)(O)CCCNC1CCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
A mixture of cyclobutylamine (1.11 g, 15.6 mmol) and 1,3-propane sultone (2 g, 17 mmol) in acetonitrile (18 mL) was heated at reflux. The mixture turned to a lump within 15 minutes. THF (10 mL) was added. The reflux was maintained for 1 hour. The mixture was cooled to room temperature. The solid was collected by filtration, rinsed with acetonitrile (2×4 mL), air-dried for 60 minutes (2.41 g). The solid was suspended in methanol (20 mL) and the suspension was heated at reflux until all the solid material was dissolved. The mixture was then cooled to room temperature. The solid thus formed was collected by suction filtration, rinsed with methanol (2×4 mL), air-dried for 20 minutes, and further dried in a vacuum oven at 40° C. for 18 hours. Compound EC was obtained as a white solid (1.81 g, 60% yield). 1H NMR (500 MHz, D2O) δ 1.70-1.77 (m, 2H), 1.94-2.03 (m, 4H), 2.18 (br s, 2H), 2.85 (t, J=6.8 Hz, 1H), 2.95 (t, J=7.3 Hz, 1H), 3.63-3.66 (m, 1H). 13C NMR (125 MHz, D2O) δ 14.5, 21.5, 26.1, 43.6, 48.0, 51.8. ES-MS 194 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C:8](=[N:21][S:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])[C:9]([F:20])([F:19])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:7]=1.[CH3:29][Mg+].[Br-]>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C:8]([NH:21][S:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])([C:9]([F:20])([F:19])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:14])[CH3:13])[CH3:29])[CH:7]=1
Reactant: CC(C)(C)S(=O)N=C(c1cc(Br)ccc1F)C(F)(F)CO[Si](C)(C)C(C)(C)C
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CC(C)(C)S(=O)NC(C)(c1cc(Br)ccc1F)C(F)(F)CO[Si](C)(C)C(C)(C)C
Temperature: -35 °C

Procedure:
To a solution of N-(1-(5-bromo-2-fluorophenyl)-3-(tert-butyldimethylsilyloxy)-2,2-difluoro-propylidene)-2-methylpropane-2-sulfinamide (12 g, 24.04 mmol) in diethyl ether (120 mL) was added CH3MgBr (3M in Diethyl ether) (41 mL, 120 mmol) at −25° C. The reaction mixture was brought to 0° C. and maintained for 30 min. Reaction mixture was again cooled to −35° C. and quenched by drop wise addition of saturated ammonium chloride solution. Organic layer was separated and washed with brine and dried over anhydrous sodium sulphate. Crude compound was purified by column chromatography on silica gel with 8% ethyl acetate in Hexane to furnish title compound as a colorless liquid. Yield=8.8 g (71%). TLC (20% ethyl acetate in Hexane): Rf=0.33),