Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:19][CH:18]=[C:17]([CH3:29])[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+].CO.C(Cl)(Cl)Cl>CCO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:19][CH:18]=[C:17]([CH3:29])[N:16]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2ccc(C)nc2-c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(-c2ccc(C)nc2-c2ccc(O)cc2)cc1
Yield: 8905.6 %

Procedure:
The 2-(4-benzyloxyphenyl)-3-(4-methoxyphenyl)-6-methylpyridine (14 g, .37 mmol) and ammonium formate (3.5 g, 55 mmol) were stirred in 1 L of EtOH, then 5% Pd/ C (5.8 g, 3 mmol Pd) was added and the reaction mixture warmed to 50°-55° C. The reaction mixture was stirred at 55° C. for 1 h at which time the TLC (MeOH/ CHCl3, 1:9) indicated the starting material was consumed. After cooling, the reaction mixture was filtered, concentrated, and the residue triturated with Et2O to give 9.6 g (90% yield) of white solid: mp 190° C.; 1H NMR (CDCl3) d 2.66 (s, 3H, Pyr-CH3), 3.82 (s, 3H, OCH3), 6.53-6.56 (d, 2H, J=8 Hz, ArH), 6.80-6.83 (d, 2H, J=8 Hz, ArH), 7.06-7.18 (m, 6H, ArH, ArOH), 7.59-7.62 (d, 1H, J=8 Hz, ArH); MS(FD) 291(M+). Anal. Calcd for C19H17NO2 : C, 78.33; H, 5.88; N, 4.81. Found: C, 78.11; H, 5.93; N, 4.72.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][N:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]2[CH2:14][CH2:15][N:16]([C:17](=[O:33])[CH:18]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:6]12)=[O:4].[OH-].[Na+]>CO>[C:29]([O:28][C:26]([NH:25][CH:18]([CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)[C:17]([N:16]1[CH:6]2[CH:7]([N:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:9][CH:5]2[C:3]([OH:4])=[O:2])[CH2:14][CH2:15]1)=[O:33])=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)C1CN(S(C)(=O)=O)C2CCN(C(=O)C(NC(=O)OC(C)(C)C)C3CCCCC3)C12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(C(=O)O)CN2S(C)(=O)=O)C1CCCCC1
Reaction time: 0.67 h
Yield: 91.8 %

Procedure:
A solution of 28 (1.1 g, 2.3 mmol) in MeOH (20 mL) was treated with 1M NaOH (10 mL) at ambient temperature. After 40 min, the solution was concentrated, acidified with 1M HCl until pH˜2, and extracted with EtOAc. The organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 29 (1.0 g) as a light yellow-colored foam which was used without further purification. 1H NMR (CDCl3, 300 MHz): δ5.23 (d, J=9.0 Hz, 1H), 4.71 (d, J=6.3 Hz, 1H), 4.33-4.16 (m, 2H), 4.16-4.06 (m, 2H), 3.82-3.78 (m, 1H), 3.73-3.66 (m, 2H), 3.17 (m, 1H), 2.92 (s, 3H), 2.66 (dd, J=5.1, 13.5 Hz, 1H), 2.13 (m, 1H), 1.77-1.55 (m, 6H), 1.43 (s, 9H), 1.29-1.01 (m, 6H) ppm.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:9]=[C:10]([CH3:11])[C:5]2=[C:4]([CH2:18][OH:19])[CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:9]=[C:10]([CH3:11])[C:5]2=[C:4]([CH2:18][O:19][S:21]([CH3:20])(=[O:23])=[O:22])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nn(C2CCCCO2)c2nc(Br)cc(CO)c12
Solvent: ClCCl
Product: Cc1nn(C2CCCCO2)c2nc(Br)cc(COS(C)(=O)=O)c12
Reaction time: 0.33 h
Yield: 85.6 %

Procedure:
To a solutuion of 130 mg [6-bromo-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-methanol in 5 ml of dry DCM at 0° C. 77 μl of TEA were added, after 10 min followed by the addition of 60 mg of methanesulfonyl chloride. After 20 min at 0° C. the reaction was brought to rt and extracted with sat. aqueous ammonium chloride solution. The organic layer was separated, dried over sodium sulphate and freeze-dried to obtain 138 mg (85%) of the title compound as a crude product, which was used without purification in the subsequent step.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:7]([C:10]([CH3:16])([CH3:15])[CH2:11][C:12](Cl)=[O:13])=[N+:8]=[N-:9]>ClCCCl>[N:7]([C:10]([CH3:16])([CH3:15])[CH2:11][C:12]([N:2]([CH2:3][CH2:4][CH2:5][CH3:6])[CH3:1])=[O:13])=[N+:8]=[N-:9]
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Reactant: CCCCNC
Solvent: ClCCCl
Product: CCCCN(C)C(=O)CC(C)(C)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a stirred ice cold solution of N-methylbutan-1-amine (8.88 mL, 2 equiv, 74.4 mmol) in anhydrous DCE (65 mL) was added 3-azido-3-methylbutanoyl chloride (6.02 g, 37.2 mmol) in small portions over 5 min. The reaction was removed from the ice bath and stirred at room temperature for 1 h. The reaction mixture was poured into a separatory funnel and washed with 1 M HCl (2×100 mL). The organic layer was separate and dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a yellow oil (7.11 g, 90.1%). This material was used without further purification. 1HNMR (CDCl3, 400 MHz): δ 0.91-0.98 (m, 3H), 1.27-1.37 (m, 2H), 1.46 (s, 6H), 1.47-1.57 (m, 2H), 2.49 (s, 2H), 2.92 (s, 1.35H), 3.02 (s, 1.48H) methyl rotamers, 3.28-3.39 (m, 2H). LRMS (ESI+) for C10H20N4O (212.2); Found: 213 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.Cl.[NH2:13][C:14]1[C:19](O)=[CH:18][C:17]([F:21])=[CH:16][N:15]=1.O>C[Si](OP(=O)=O)(C)C>[Br:11][C:5]1[CH:6]=[C:7]([C:8]2[O:10][C:19]3[C:14]([N:13]=2)=[N:15][CH:16]=[C:17]([F:21])[CH:18]=3)[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(F)cc1O
Reactant: Nc1ncc(Br)cc1C(=O)O
Agent: C[Si](C)(C)OP(=O)=O
Agent: Cl
Solvent: O
Product: Nc1ncc(Br)cc1-c1nc2ncc(F)cc2o1
Temperature: 100 °C
Yield: 20 %

Procedure:
2-amino-5-bromo-pyridine-3-carboxylic acid (797 mg) and 2-amino-5-fluoro-pyridin-3-ol, hydrochloride (400 mg) powders were mixed together and the resulting mixture was portionwise added in trimethylsilyl polyphosphate (4.5 g) stirred at 100° C. The mixture was stirred at 140° C. overnight. After cooling, water (20 ml) was added. The resulting precipitate was collected by filtration, washed with a 2N aqueous solution of HCl and water. The resulting solid was triturated in Ethyl acetate, collected by filtration to afford 5-bromo-3-(6-fluorooxazolo[4,5-b]pyridin-2-yl)pyridin-2-amine (150 mg). NMR Spectrum: (DMSO-d6) 7.10 (bs, 2H), 7.66 (dd, 1H), 8.31 (d, 1H), 8.39 (d, 1H), 8.49 (dd, 1H); Mass spectrum: M+H+ 309-311.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([F:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:23]([F:26])([F:25])[F:24])=[O:22].N(OCCC(C)C)=O.C(Br)(Br)[Br:36]>>[Br:36][C:2]1[N:6]([C:7]2[C:12]([F:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:23]([F:26])([F:25])[F:24])=[O:22]
Reactant: N#Cc1nn(-c2c(F)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Reactant: BrC(Br)Br
Agent: CC(C)CCON=O
Product: N#Cc1nn(-c2c(F)cc(C(F)(F)F)cc2Cl)c(Br)c1S(=O)C(F)(F)F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of 5-amino-1-(2-chloro-6-fluoro-4-(trifluoromethyl)phenyl)-4-(trifluoromethylsulfinyl)-1H-pyrazole-3-carbonitrile (130 g, 310.3 mmol, 1.00 eq.) in CHBr3 (520 mL) was added dropwise isoamyl nitrite (109 g, 930.8 mmol, 3.00 eq.) at 55˜60° C. After all the isoamyl nitrite was added, the solution was stirred at 60° C. for 30 min. Then the mixture was concentrated under vacuum to give red solid. The solid was recrystallized with isopropyl alcohol to give 5-bromo-1-(2-chloro-6-fluoro-4-(trifluoromethyl)phenyl)-4-(trifluoromethylsulfinyl)-1H-pyrazole-3-carbonitrile (110 g, 73%) as yellow solid.
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[N:5]([C:9]([C@H:12]3[C@H:19]4[C@H:15]([O:16][C:17]([CH3:21])([CH3:20])[O:18]4)[C:14]([CH2:22][O:23][C:24]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:13]3)=[CH:10][N:11]=2)[CH:6]=[CH:7][N:8]=1>C(O)(C)C>[CH3:21][C:17]1([CH3:20])[O:16][C@@H:15]2[C:14]([CH2:22][O:23][C:24]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:13][C@@H:12]([C:9]3[N:5]4[CH:6]=[CH:7][N:8]=[C:3]([NH2:1])[C:4]4=[N:11][CH:10]=3)[C@@H:19]2[O:18]1
Reactant: N
Reactant: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C[C@H]2c1cnc2c(Cl)nccn12
Solvent: CC(C)O
Product: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C[C@H]2c1cnc2c(N)nccn12
Temperature: 100 °C

Procedure:
Liquid ammonia (10 mL) was added to 8-chloro-3-((3aS,4S,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)imidazo[1,2-a]pyrazine (1-8) (180 mg, 0.32 mmol, 1 equiv) in isopropanol (10 mL). The resulting solution was placed in a high pressure vessel and heated to 100° C. (pressure did not exceed 600 psi) for 20 h. The resulting amber solution was concentrated, and the residue was purified via reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA present) to afford 3-((3aS,4S,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)imidazo[1,2-a]pyrazin-8-amine (1-9) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.7 (d, 1H, J=5.5 Hz), 7.21-7.50 (m, 17H), 6.06 (s, 1H), 5.19 (d, 1H, J=5.5 Hz), 4.66 (d, 1H, J=5.5 Hz), 4.33 (m, 1H), 3.91 (d, 1H, J=14 Hz), 3.83 (d, 1H, J=14 Hz), 1.43 (s, 3H), 1.33 (s, 3H). LRMS m/z (M+H) 544.9 found, 545.2 required.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]([CH2:16][CH3:17])[C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1.ClCCl>[Cl:25][CH2:26][C:27]([NH:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]([CH2:16][CH3:17])[C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1)=[O:28]
Reactant: O=C(Cl)CCl
Reactant: CCc1cc(-c2ccc(CN)s2)c(C)[nH]c1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(-c2ccc(CNC(=O)CCl)s2)c(C)[nH]c1=O
Reaction time: 2 h
Yield: 46.2 %

Procedure:
To a solution of 5-(5-aminomethylthiophen-2-yl)-3-ethyl-6-methyl-1H-pyridin-2-one (0.5 g, 2 mmol) and triethylamine (0.6 mL) in THF (5 mL) and dichloromethane (20 mL) is added chloroacetyl chloride (0.24 mL, 3 mmol) at 0° C. After 2 hr at rt, the mixture is quenched with aqueous NaHCO3 solution, and extracted with EtOAc. The extracts are washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue is chromatographed on SiO2, eluting with CH2Cl2-5% MeOH to afford 0.3 g of 2-chloro-N-[5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophen-2-ylmethyl]-acetamide. A mixture of so formed 2-chloro-N-[5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophen-2-ylmethyl]-acetamide (0.15 g, 0.46 mmol), and excess of pyrrolidine and potassium carbonate in acetonitrile (10 mL) is heated for 6 hr at 75° C., and extracted with EtOAc. The extracts are washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue is chromatographed on SiO2, eluting with CH2Cl2-10% MeOH to afford the free base, which is dissolved in HCl-EtOAc and concentrated. Lyophilization in acetonitrile and water affords 60 mg (33%) of N-[5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophen-2-ylmethyl]-2-(pyrrolidin-1-yl)acetamide hydrochloride as a solid. LC/MS: RT 1.93 min; m/e 360 (M+H); 1H NMR (DMSO-d6, δ, ppm): 10.5 (1H, brs), 9.4 (1H, t), 7.2 (1H, s), 6.98 (1H, d), 6.95 (1H, d), 4.5 (2H, d), 4.1 (2H, d), 3.55 (2H, brs), 3.02 (2H, brs), 2.4 (2H, q), 2.25 (3H, s), 1.8-2.05 (4H, m), 1.22 (3H, t).
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].Cl[CH2:31][CH2:32][CH2:33][C:34]([N:36]1[CH:41]([CH3:42])[CH2:40][CH2:39][CH2:38][CH:37]1[CH3:43])=[O:35]>O.CC(C)CC(=O)C>[NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:31][CH2:32][CH2:33][C:34]([N:36]3[CH:41]([CH3:42])[CH2:40][CH2:39][CH2:38][CH:37]3[CH3:43])=[O:35])[CH2:11][C@H:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Reactant: CC1CCCC(C)N1C(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCC(=O)N2C(C)CCCC2C)C[C@H]1OC
Reaction time: 3 h
Yield: 70.7 %

Procedure:
A mixture of 4.5 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide, 2.12 parts of sodium carbonate, 0.1 parts of potassium iodide and 120 parts of 4-methyl-2-pentanone was stirred and refluxed for 15 minutes using a water separator. Then there were added 3.92 parts of 1-(4-chloro-1-oxobutyl)-2,6-dimethylpiperidine and stirring was continued first for 3 hours at reflux and then overnight at room temperature. Water was added. The product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 5.25 parts (70.7%) of cis-4-amino-5-chloro-N-[1-[4-(2,6-dimethyl-1-piperidinyl)-4-oxobutyl]3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 202.1° C. (compound 47).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]5[CH:28]=[CH:27][C:26](OC)=[CH:25][CH:24]=5)[N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl-].[CH3:32]C1C=CC=CC=1C[Zn+].O1C2C=CC(C3(C(NC4C=CC=C(Br)N=4)=O)CC3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[CH3:32])[N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccccc1C[Zn+]
Reactant: COc1ccc(Cc2cccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)n2)cc1
Agent: O=C(Nc1cccc(Br)n1)C1(c2ccc3c(c2)OCO3)CC1
Agent: [Cl-]
Product: Cc1ccccc1Cc1cccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)n1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-(2-methylbenzyl)pyridin-2-yl)cyclopropanecarboxamide (VRT-810361) was synthesized using the procedure of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-(4-methoxybenzyl)pyridin-2-yl)cyclopropanecarboxamide by reacting (2-methylbenzyl)zinc(II) chloride with 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N+:22]([C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27])([O-:24])=[O:23].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C(O)C>[F:9][C:2]1([F:1])[CH2:3][CH:4]([C:6]([NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[N+:22]([O-:24])=[O:23])=[O:8])[CH2:5]1
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=C(O)C1CC(F)(F)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1[N+](=O)[O-])C1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
[step 1] 3,3-Difluorocyclobutanecarboxylic acid (500 mg, 3.67 mmol) was dissolved in DMF (18 mL), 1,1′-carbonyldiimidazole (1.19 g, 7.35 mmol) was added, and the mixture was stirred at room temperature for 1 hr. To the mixture were added 2-nitroaniline (1.02 g, 7.35 mmol) and triethylamine (1.02 mL, 7.35 mmol), and the mixture was stirred at 80° C. for 13 hr. To the mixture were added 5% aqueous citric acid solution and ethanol (5 mL), and the mixture was stirred for 1 hr. The precipitated crystals were collected by suction filtration to give 3,3-difluoro-N-(2-nitrophenyl)cyclobutanecarboxamide (527 mg, 56%).
Reaction SMILES: BrC1[C:10]2[C:5](=[CH:6][C:7](F)=[CH:8][CH:9]=2)C(=O)C1.BrC1C2C(=CC=C(F)C=2)C(=O)C1.Br[CH:26]1[C:34]2[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=2)[C:28](=[O:36])[CH2:27]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[C:5]1([CH:26]2[C:34]3[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=3)[C:28](=[O:36])[CH2:27]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C1CC(Br)c2ccc(F)cc21
Reactant: O=C1CC(Br)c2ccc(Cl)cc21
Agent: Cl
Agent: O=C1CC(Br)c2cc(F)ccc21
Agent: [Al+3]
Solvent: c1ccccc1
Product: O=C1CC(c2ccccc2)c2ccc(Cl)cc21

Procedure:
In a corresponding manner was made 3-bromo-6-fluoro-1-indanone melting at 62-64 degrees Centigrade, and 3-bromo-5-fluoro-1-indanone melting at 44-47 degrees Centigrade. To a solution of 113 grams of 3-bromo-6-chloro-1-indanone in 1400 milliliters of dry benzene were added over 10 minutes 230 grams of aluminiumchloride in portions. The reaction mixture was then refluxed for 3 hours, cooled and treated with crushed ice and concentrated hydrochloric acid. The organic phase was separated and extracted with 1 N sodium hydroxide and water, dried over anhydrous magnesium sulfate, treated with active carbon and concentrated in vacuo. The residue was taken up to 450 milliliters of hot n-hexane, cooled and filtered to give 96 grams of 3-phenyl-6-chloro-1-indanone melting at 84-92 degrees Centigrade.
Reaction SMILES: C([O:5][C:6](=[O:40])[C@@H:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]3[O:31][C:32]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:33]=4[N:34]=3)=[O:29])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:9][CH:8]([CH3:10])[C@H:7]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28]([C:30]3[O:31][C:32]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:33]=4[N:34]=3)=[O:29])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)(=[O:14])=[O:13])[C:6]([OH:40])=[O:5]
Reactant: Cc1ccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C)cc4)cc3)nc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.8 %

Procedure:
To (S)-3-methyl-2-{4′-[(5-methyl-benzooxazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid tert-butyl ester (30 mg) was added 2 mL of TFA/CH2Cl2 (1:1). The solution was stirred at room temperature for 3 h. The solvents were removed under vacuum and the residue was triturated with ether. Filtration gave 14 mg of (S)-3-methyl-2-{4′-[(5-methyl-benzooxazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.76-0.93 (m, 6 H) 1.84-2.07 (m, 6 H) 3.56 (dd, 1 H) 7.70-7.95 (m, 8 H) 7.98-8.14 (m, 3 H) 11.32-11.41 (m, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH2:12]([N:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][OH:18])[CH3:13]>>[CH2:12]([N:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][O:18][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[F:1])[CH3:13]
Reactant: CCN(CC)CCCO
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Product: CCN(CC)CCCOc1ccc([N+](=O)[O-])cc1F

Procedure:
In a manner similar to that described in Example 231 a, 3,4-difluoronitrobenzene (6.7 mL, 60.6 mmol, 1 equiv.) and 3-diethylamino-1-propanol (9 mL, 1 equiv.) are converted to the named compound as a brown oil (16.3 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH2:17][CH2:18][C:19](N1[C@@H](C3C=CC=CC=3)COC1=O)=[O:20])=[CH:11]2.CCOC(C)=O.[CH2:39]1[CH2:43]OC[CH2:40]1>[OH-].[Na+]>[CH3:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH2:17][C@H:18]([CH2:43][CH:39]=[CH2:40])[CH2:19][OH:20])=[CH:11]2
Reactant: C1CCOC1
Reactant: Cc1ccc2[nH]c(CCC(=O)N3C(=O)OC[C@@H]3c3ccccc3)cc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: C=CC[C@H](CO)Cc1cc2cc(C)ccc2[nH]1
Temperature: -78 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a stirred suspension of LiAlH4 (718 mg, 17.90 mmol) in THF (60 mL) was added a precooled solution of 8 (5.78 g, 14.9 mmol) in THF (50 mL) at −78° C. under argon. The mixture was stirred at −78° C. (1 h), then raised to 0° C. (1 h). After an additional 3 h at 0° C., the reaction mixture was cooled to −78° C. and EtOAc (20 mL) was added followed by 10% NaOH (aq) (30 drops). The reaction was quenched by the addition of ice-cold saturated NH4Cl solution (150 mL), extracted with Et2O, washed with brine and dried (Na2SO4). Evaporation provided a residue, which was purified by silica gel flash chromatography to yielded 10 as colorless oil. (3.14 g, 92% yield). H NMR (d6-DMSO) δ 7.32-7.30 (m, 2H), 7.25 (d, 1H, J=2.9 Hz), 6.94 (dd, 1H, J=1.3 Hz & 8.5 Hz), 6.31 (dd, 1H, J=0.8 Hz & 3.1 Hz), 5.78 (m, 1H), 5.04-4.98 (m, 2H), 4.63 (t, 1H, J=5.0), 4.16 (dd, 1H, J=6.9 Hz & 14.2 Hz), 4.02 (dd, 1H, J=6.3 Hz & 14.2 Hz), 3.30-3.23 (m, 2H), 2.36 (s, 3H), 2.09-1.92 (m, 3H). FABMS (+Ve) m/z 229 [M+], 230 [MH+]. Anal. Calcd for C15H19NO C, 78.56; H, 8.35; N, 6.11. Found C, 78.47; H, 8.50; N, 6.16.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[Br:18])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([SH:27])[CH:24]=[CH:25][CH:26]=1.[H-].[Na+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[O:10][C:4]1[C:5]([C:8]#[N:9])=[N:6][CH:7]=[C:2]([S:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=2)[CH:3]=1
Reactant: COc1cccc(S)c1
Reactant: N#Cc1ncc(Br)cc1Oc1ccc(F)cc1Br
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(Sc2cnc(C#N)c(Oc3ccc(F)cc3Br)c2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.4 %

Procedure:
A 500 mL flask was charged with 5-bromo-3-(2-bromo-4-fluorophenoxy)picolinonitrile (10 g, 26.9 mmol), 3-methoxybenzenethiol (3.34 mL, 26.9 mmol), and DMF (250 mL). The reaction was cooled to 0° C. and NaH (0.710 g, 29.6 mmol) was added slowly. The reaction stirred for 30 minutes at 0° C. The reaction was poured into saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo to afford 3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)picolinonitrile (12.0 g, 104% yield) as an amber oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.Cl[CH2:10][CH:11]=O>C(O)C.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[CH:11][N:1]=2)[CH:4]=1
Reactant: O=CCCl
Reactant: Nc1ccc(Br)cn1
Solvent: CCO
Solvent: O
Product: Brc1ccc2nccn2c1
Yield: 100 %

Procedure:
2.00 g of 2-amino-5-bromopyridine (3) is dissolved in ethanol (35 mL), and chloroacetaldehyde in water (2.52 mL, 6.1 mol/L) was added and the reaction mixture was heated at reflux for 3 hours. The reaction mixture was concentrated, and saturated aqueous NaHCO3 was added to the residue, and it is extracted with ethyl acetate. After conventional workup afford 2.30 g of the titled compound as a brown powder (yield: 100%).