Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[OH:14].I[CH3:16]>CN(C=O)C.C1COCC1>[F:10][C:9]1[CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=[C:5]([O:14][CH3:16])[C:4]=1[F:3]
Reactant: O=[N+]([O-])c1cc(O)c(F)c(F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])cc(F)c1F
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 49.1 %

Procedure:
Step M (4): Sodium hydride (120 mg, 5 mmol) was added to a solution of 2,3-difluoro-5-nitrophenol (250 mg, 1.4 mmol) in DMF/THF (4 mL/4 mL). After 10 min, iodomethane (0.2 mL, 5 mmol) was added. The mixture was heated at 80° C. for 2 h. The reaction mixture was quenched with 1 N HCl. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 1,2-difluoro-3-methoxy-5-nitrobenzene (130 mg, 48% yield).
Reaction SMILES: [N:1]([CH2:4][C:5]([OH:7])=[O:6])=[N+:2]=[N-:3].B(F)(F)F.CCOCC.[CH:17]#[C:18][CH3:19]>C(Cl)Cl>[N:1]([CH2:4][C:5]([O:7][C:18]([CH3:19])=[CH2:17])=[O:6])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCC(=O)O
Reactant: C#CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: C=C(C)OC(=O)CN=[N+]=[N-]

Procedure:
Azidoacetic acid (5.35 g, 0.05 mole) and mercuric acetate (1.82 g, 5.7 mMoles) are added to 50 ml of methylene chloride containing 0.1 ml of boron trifluoride etherate. Propyne, which had been passed through Linde Co. Molecular Sieves 4A, is bubbled slowly through the mixture for 3 hours. Sodium bicarbonate (0.5 g) is added and the mixture is filtered through a short Florisil column. The eluent is concentrated in vacuo and the residue obtained is purified by vacuum distillation to give isopropenyl azidoacetate.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][CH:6]1[CH:11]=[C:10]([CH3:12])[CH2:9][CH2:8][CH:7]1[CH:13]=[O:14]>O1CCCC1>[CH3:5][CH:6]1[CH:11]=[C:10]([CH3:12])[CH2:9][CH2:8][CH:7]1[CH:13]([OH:14])[CH2:1][CH3:2]
Reactant: CC1=CC(C)C(C=O)CC1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)C1CCC(C)=CC1C
Temperature: 0 °C

Procedure:
A reaction flask was charged with ethylmagnesium bromide solution (CH3CH2MgBr) (3 M, 2.4 L) in tetrahydrofuran (THF) and cooled to 0° C. 2,4-Dimethyl-cyclohex-3-enecarbaldehyde (905 g) was added slowly while the temperature was kept at 0° C. The reaction mixture was stirred for an additional hour and then quenched with hydrochloric acid (HCl). The reaction mixture was washed with sodium carbonate (Na2CO3) and brine. Further distillation provided 1-(2,4 -dimethyl-cyclohex-3-enyl)-propan-1-ol (1.021 Kg).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]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.C(N(CC)CC)C.[NH2:53][C:54]1[CH:63]=[CH:62][C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[N:55]=1>CN(C)C=O.O.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:53][C:54]2[CH:63]=[CH:62][C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[N:55]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccc2ccccc2n1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2ccccc2n1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Yield: 49.8 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 1, 100 mg, 0.34 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (166 mg, 0.38 mmol), triethylamine (0.096 mL, 0.68 mmol), and 2-aminoquinoline (75 mg, 0.52 mmol) in dry N,N-dimethylformamide (2 mL) was stirred at 25° C. for 14 h. The reaction mixture was then diluted with water and ethyl acetate, and the layers were separated. The organic layer was sequentially washed with a saturated aqueous sodium bicarbonate solution, water, and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 4/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-quinolin-2-yl-propionamide (70 mg, 50%) as a white foam: mp 172-173° C.; EI-HRMS m/e calcd for C23H22Cl2N2O (M+) 412.1109, found 412.1108.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Br:10][C:11]1[CH:12]=[C:13]([N:23]([CH3:25])[CH3:24])[C:14]([O:21][CH3:22])=[C:15]([C:17](O)([CH3:19])[CH3:18])[CH:16]=1.O>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[C:15]([C:17]([F:7])([CH3:19])[CH3:18])[C:14]([O:21][CH3:22])=[C:13]([N:23]([CH3:25])[CH3:24])[CH:12]=1
Reactant: COc1c(N(C)C)cc(Br)cc1C(C)(C)O
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1c(N(C)C)cc(Br)cc1C(C)(C)F
Yield: 67.5 %

Procedure:
Diethylaminosulfur trifluoride (620 mg) was added to a solution of 2-[5-bromo-3-(dimethylamino)-2-methoxyphenyl]-2-propanol (1 g) in methylene chloride while stirring on ice. After stirring for an additional 30 minutes while cooling on ice, water was added, extraction was performed with ethyl acetate, and the organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (680 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[C:16]([CH2:23][CH3:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1>COC(OC)N(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:26])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:20]/[CH:11]=[N:12]\[O:13][CH3:9])=[O:19])=[C:16]([CH2:23][CH3:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Agent: COC(OC)N(C)C
Product: CCc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N/C=N\OC
Yield: 147.2 %

Procedure:
A mixture of 0.18 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-ethyl benzoic acid amide and 10 mL of N,N-dimethylformamide dimethylacetal was stirred under reflux with heating for 4 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 5 mL of 1,4-dioxane, and added dropwise in a solution of 0.10 g of methoxyamine hydrochloride and 0.10 g of sodium hydroxide in 4 mL of water and 4 mL of acetic acid. After the completion of the addition dropwise, it was continued to stir at room temperature further for 30 minutes. After the completion of the reaction, 10 mL of water was added in the reaction mixture, and extracted with ethyl acetate (40 mL×1). The organic phase was dehydrated with and dried over saturated sodium chloride and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (2:3) to obtain 0.15 g of the aimed product as colorless resinous substance.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Cc1sc2nc(Cl)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C
Product: Cc1sc2nc(-n3cncn3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6-dimethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6-dimethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].O.O.[Na+].[NH2:10][C:11]1[C:18]([F:19])=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[Cl:20]>C(O)(=O)C>[Cl:20][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:19])[C:11]=1[N+:10]([O-:6])=[O:5])[C:15]#[N:16]
Reactant: O
Reactant: N#Cc1cc(F)c(N)c(Cl)c1
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: N#Cc1cc(F)c([N+](=O)[O-])c(Cl)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Sodium perborate tetrahydrate (131 g, 851 mmol) in acetic acid (200 mL) was heated to 60° C. A solution of 4-amino-3-chloro-5-fluorobenzonitrile (29.0 g, 170 mmol) in acetic acid (500 mL) was added dropwise, and the resulting reaction was stirred at 60° C. for 18 h. LCMS analysis indicated ˜50% conversion. Additional sodium perborate tetrahydrate (14.4 g, 93.6 mmol) was added, and the reaction was stirred at 70° C. for 2 h followed by another addition of sodium perborate tetrahydrate (70.0 g, 455 mmol). The reaction was stirred at 80° C. for 5 h and then at rt for 2 d. The reaction was poured into ice water, and the product was extracted into EtOAc. The combined organics were washed with water and brine. Finally, the organics were dried over MgSO4, filtered, and concentrated to half volume. Addition of water resulted in precipitation of the desired product which was collected in a frit, washed with water, and dried in vacuo to provide an orange solid (27.5 g, 81% crude yield). 1H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 7.55 (d, 1H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C:28]1[CH:29]=[C:30]([C:34]2[CH:35]=[CH:36][C:37]3[N:38]([C:40]([CH3:48])=[C:41]([C:43]4[S:44][CH:45]=[CH:46][CH:47]=4)[N:42]=3)[CH:39]=2)[CH:31]=[CH:32][CH:33]=1)(C(C)(C)C)(C)C>O1CCCC1>[CH3:48][C:40]1[N:38]2[CH:39]=[C:34]([C:30]3[CH:29]=[C:28]([CH2:27][OH:26])[CH:33]=[CH:32][CH:31]=3)[CH:35]=[CH:36][C:37]2=[N:42][C:41]=1[C:43]1[S:44][CH:45]=[CH:46][CH:47]=1
Reactant: Cc1c(-c2cccs2)nc2ccc(-c3cccc(CO[Si](C)(C)C(C)(C)C)c3)cn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(-c2cccs2)nc2ccc(-c3cccc(CO)c3)cn12
Temperature: 25 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
310 mg of tetrabutylammonium fluoride are introduced into a round-bottomed flask containing 260 mg of 6-[3-(tert-butyldimethylsilanyloxymethyl)phenyl]-3-methyl-2-thien-2-ylimidazo[1,2-a]pyridine in 6 ml of tetrahydrofuran. The reaction mixture is stirred at ambient temperature for 48 h and is concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a dichloromethane/methanol mixture. 140 mg of compound are obtained. M+H=321
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:15]2[CH:29]=[CH:28][C:18]([C:19]([NH:21][CH2:22][C:23](=[O:27])[O:24]CC)=[O:20])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH2:32][CH2:33][CH3:34])[C:5]=1[OH:35])(=[O:3])[CH3:2].[OH-].[Na+].O>C1COCC1>[C:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:15]2[CH:29]=[CH:28][C:18]([C:19]([NH:21][CH2:22][C:23]([OH:27])=[O:24])=[O:20])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH2:32][CH2:33][CH3:34])[C:5]=1[OH:35])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCS(=O)(=O)c2ccc(C(=O)NCC(=O)OCC)cc2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(OCCCS(=O)(=O)c2ccc(C(=O)NCC(=O)O)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of Example 3 (430 mg, 0.851 mmoles) was taken up in a mixture of THF (10 ml), 1N NaOH (1.8 ml) and water (8.2 ml). The reaction mixture was stirred at room temperature under nitrogen for two hours. The THF was then removed in vacuo and the residue was diluted with water and filtered. The aqueous solution was acidified with dilute HCl and extracted with chloroform. The combined chloroform extracts were dried and concentrated in vacuo to afford the title compound which was recrystallized from ethyl acetate/hexane, m.p. 171°-173°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[C@@H:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH3:27])[C:20]=3[CH3:28])[CH2:15][C:16](=O)[CH2:17][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.CO.FC(F)(F)S([O-])(=O)=O.[Zn+2].FC(F)(F)S([O-])(=O)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[C@@H:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH3:27])[C:20]=3[CH3:28])[CH2:15][CH2:16][CH2:17][C@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([C@H]2CC(=O)C[C@H]3CN(Cc4ccccc4)CCN32)c(C)c1C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc([C@H]2CCC[C@H]3CN(Cc4ccccc4)CCN32)c(C)c1C
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
(6R,9aS)-2-benzyl-6-(4-methoxy-2,3-dimethylphenyl)-octahydro-pyrido[1,2-a]pyrazin-8-one (9.48 g, 25.0 mmol) is stirred with p-toluenesulfonyl hydrazide (5.60 g, 30.0 mmol, 1.2 eq) in 40 mL anhydrous THF and 200 mL anhydrous MeOH for 20 h at ambient temperature under a nitrogen atmosphere. LC/MS analysis indicates complete conversion to the p-toluenesulfonyl hydrazone. The solution is sparged with argon for 30 min and then treated with 50 mL of a 1.5 M solution of NaCNBH3 in MeOH. Zinc trifluoromethanesulfonate (140 mg, 0.376 mmoles, 1.5%) is added and the solution is heated in a 65° C. oil bath for 5.5 h under an argon balloon. LC/MS analysis indicates consumption of the hydrazone. The mixture is allowed to cool and is quenched with 500 mL of saturated NaHCO3. After stirring vigorously for 30 min, the mixture is extracted with CH2Cl2 (4×200 mL). The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with 90%-80% hexanes/EtOAc to yield (6R,9aS)-2-Benzyl-6-(4-methoxy-2,3-dimethylphenyl)-octahydro-pyrido[1,2-a]pyrazine as an oil. LC/MS: 365 (M+1). 1H NMR (400 MHz, CDCl3): 7.34 (1H, d), 7.27 (5H, m), 6.72 (1H, d), 3.79 (3H, s), 3.47 (2H, dd), 3.28 (1H, d), 2.68 (3H, m), 2.28-2.04 (8H, bm), 1.98-1.88 (2H, bm), 1.75 (1H, m), 1.59 (1H, d), 1.50-1.30 (4H, bm).
Reaction SMILES: [BH4-].[CH3:2][N:3]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]1[SH:14].I[C:16]1[CH:35]=[CH:34][C:19]([CH2:20][NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][CH:23]=2)=[C:18]([O:36][CH2:37][CH2:38][CH3:39])[CH:17]=1>O1CCCC1.C(O)C>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][CH2:20][C:19]2[CH:34]=[CH:35][C:16]([S:14][C:4]3[N:3]([CH3:2])[C:7]([C:8]4[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=4)=[N:6][N:5]=3)=[CH:17][C:18]=2[O:36][CH2:37][CH2:38][CH3:39])=[CH:23][CH:24]=1)[CH3:33]
Reactant: CCCOc1cc(I)ccc1CNc1ccc(CC(=O)OCC)cc1
Reactant: Cn1c(S)nnc1-c1ccncc1
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCOc1cc(Sc2nnc(-c3ccncc3)n2C)ccc1CNc1ccc(CC(=O)OCC)cc1
Reaction time: 8 h

Procedure:
265 mg (0.66 mmol, 3 eq) of resin-supported borohydride and 3 mg (0.01 mmol, 0.03 eq) of bis(bipyridine)dibromonickel (II) are added to a solution of 64 mg (0.33 mmol, 1.5 eq) of 4-methyl-5-pyridin-4-yl-4H-[1,2,4]-triazole-3-thiol in 1.5 ml of tetrahydrofuran/ethanol 5/5. To the suspension obtained there is added a solution of 100 mg (0.22 mmol, 1 eq) of ethyl [4-(4-iodo-2-propoxybenzylamino)phenyl]acetate in 1.5 ml of tetrahydrofuran/ethanol 5/5. The reaction mixture is stirred overnight under reflux. After returning to room temperature, the reaction medium is filtered and then concentrated. 0.111 g (97%) of the expected compound is recovered.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[CH:6][S:5][CH:4]=1)[CH3:2].C([Li])CCC.CCCCCC.CN([CH:22]=[O:23])C>CCOCC>[CH2:1]([C:3]1[CH:7]=[C:6]([CH:22]=[O:23])[S:5][CH:4]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCc1ccsc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCc1csc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-ethylthiophene (2 g, 17.7 mmol) in ether (20 ml) under N2 at room temp is added butyl lithium, 2.5M in hexane solution (8.15 ml, 21.4 mmol) and the resulting straw coloured solution is heated to reflux for 20 minutes. The resulting cloudy solution is then cooled to room temperature before the slow addition of DMF (2 ml) over 2 minutes and the resulting solution is stirred at room temp for 1 hour. The reaction is quenched with aqueous saturated ammonium chloride (100 ml) and extracted with chloroform (100 ml). The organic layer is washed with brine, dried over magnesium sulphate and concentrated to give 4-ethyl thiophene-2-carbaldehyde as a light brown oil (2.48 g).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[OH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:47][CH2:48][N:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[O:14][CH2:47][CH2:48][N:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1O
Reactant: OCCN1CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
To a solution of 1-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(2,4-difluoro-phenyl)-urea (0.35 g, 0.09 mmol) in anhydrous THF (2 mL), triphenyl phosphine (70.8 mg, 0.27 mmol) and 1-(2-hydroxyethyl)-pyrrolidine (0.032 mL, 0.27 mmol) were added followed by dropwise addition of diisopropyl azodicarboxylate (DIAD) (0.052 mL, 0.27 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated to give a crude product that was subjected to purification by preparative HPLC. The proper fractions were collected, neutralized with 1N NaOH and extracted with EtOAc four times. The solution was evaporated under reduced pressure to afford Compound 13 as an off-white solid in 52.8% yield. LCMS m/z (%)=476 (M+H35Cl, 100), 478 (M+H37Cl, 40). 1H NMR (400 MHz, DMSO-d6) δ: 9.10 (s, 1H), 8.55 (s, 1H), 8.17-8.09 (m, 1H), 7.69 (s, 1H), 7.61 (dd, J=8.97 and 2.72 Hz, 1H), 7.47 (d, J=2.70 Hz, 1H), 7.43-7.36 (m, 1H), 7.26 (d, J=9.04 Hz, 1H), 7.16-7.09 (m, 1H), 4.25-4.08 (m, 2H), 3.73 (s, 3H), 2.58-2.45 (m, 2H), 2.45-2.29 (m, 4H), 1.75-1.69 (m, 4H).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[Cl:5][C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[CH:8]=[CH:9][N+:10]([O-:12])=[O:11]>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[C@H:8]1[C@H:9]([N+:10]([O-:12])=[O:11])[CH2:4][CH:3]=[CH:2][CH2:1]1
Reactant: C=CC=C
Reactant: O=[N+]([O-])C=Cc1ccccc1Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])[C@@H]1CC=CC[C@H]1c1ccccc1Cl
Temperature: 110 °C
Reaction time: 72 h

Procedure:
A 10 mL solution of 1:1 1,3-butadiene and toluene stored at −20° C. and 2-chloro-β-nitrostyrene (2.0 g, 11 mmol) were added to a pressure tube and sealed. The solution was heated to 110° C. and stirred for three days. The reaction mixture was cooled to room temperature, concentrated, and the residue was crystallized from hexanes to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.35-7.38 (m, 1H), 7.15-7.29 (m, 3H), 5.71-5.84 (m, 2H), 5.09-5.16 (m, 1H), 4.04-4.13 (m, 1H), 2.76-2.84 (m, 2H), 2.54-2.60 (m, 1H), 2.19-2.28 (m, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:3]([OH:22])[CH2:4][N:5]([O:17][CH:18]([CH2:20][CH3:21])[CH3:19])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[OH:30][C:31]1[C:32]([CH3:40])=[C:33]([CH:37]=[CH:38][CH:39]=1)C(O)=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:18]([O:17][N:5]([CH2:4][C@@H:3]([OH:22])[C@@H:2]([NH:1][C:33]1[CH:37]=[CH:38][CH:39]=[C:31]([OH:30])[C:32]=1[CH3:40])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[S:6]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)(=[O:7])=[O:8])([CH2:20][CH3:21])[CH3:19]
Reactant: CCC(C)ON(C[C@@H](O)[C@@H](N)Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: Cc1c(O)cccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)ON(C[C@@H](O)[C@H](Cc1ccccc1)Nc1cccc(O)c1C)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 18 h
Yield: 31.5 %

Procedure:
N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(sec-butoxy)-4-methoxybenzenesulfon-amide (Step 1, Example 67)(0.12 mmol, 50 mg), 3-hydroxy-2-methylbenzoic acid (0.12 mmol, 18 mg), 1-hydroxybenzotriazole hydrate (0.12 mmol, 16 mg), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.13 mmol, 25 mg), diisopropylethylamine (0.14 mmol, 0.025 mL) and anhydrous N,N-dimethylformamide (0.5 mL) were combined at room temperature and stirred for 18 hours. The crude reaction mixture was concentrated to a residue, dissolved in ethyl acetate, washed with 1N HCl, 5% aq. potassium carbonate solution, brine and dried over magnesium sulfate. The solution was concentrated to a residue, purified by RPHPLC (water/acetonitrile) and lyophylized providing 20 mg (30%) of a white solid. H1-NMR (CDCl3): δ 7.76-7.73(2H,m), 7.32-7.23 (5H,m), 7.00-6.97 (3H,m), 6.78-6.76 (1H,m), 6.56-6.53 (1H,m), 5.90 (1H,bs), 4.42-4.27 (2H,m), 4.09-3.95 (1H,m), 3.87 (3H,s), 3.25-2.27 (5H,m), 2.05-1.95 (3H,m), 1.77-1.58 (1H,m), 1.55-1.22 (1H,m), 1.24-1.20 (3H,m), 0.93-0.86 (3H,m); MS (ESI): M+H=557.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][OH:15].[H-].[Na+].O>O1CCOCC1.C(OCC)(=O)C>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([O:10][CH3:9])[CH:12]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: COc1cccc(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(COc2cncc(Cl)n2)c1
Reaction time: 8 h
Yield: 114.4 %

Procedure:
To a solution of 2,6-dichloropyrazine (444 mg, 3.00 mmol) and 3-methoxybenzyl alcohol (455 mg, 3.30 mmol) in dioxane (5 mL) was added NaH (55% in oil, 144 mg, 3.30 mmol) at room temperature. The reaction mixture was stirred overnight. Water (0.5 mL) and ethyl acetate (10 mL) were added and the mixture was stirred for 15 min and then filtered. The filtrate was dried over K2CO3 and concentrated to give an oil (0.86 g) that was used directly in the next step. MS m/z 250 (M+H)+.
Reaction SMILES: C([N:4]1[C:8]2[C:9]3[C:14]([CH2:15][C:7]=2[C:6]([C:16]2[CH:25]=[CH:24][C:19]([NH:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:17]=2)=[N:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)(=O)C.[OH-].[Na+].[ClH:28]>CO>[ClH:28].[ClH:28].[NH:4]1[C:8]2[C:9]3[C:14]([CH2:15][C:7]=2[C:6]([C:16]2[CH:25]=[CH:24][C:19]([NH:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:17]=2)=[N:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CC(=O)Nc1ccc(-c2nn(C(C)=O)c3c2Cc2ccccc2-3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)Nc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4′-(1-acetyl-1,4-dihydroindeno[1,2-c]pyrazol-3-yl)acetanilide (1.0 g) was suspended in methanol (40 ml) and a 2N aqueous solution of sodium hydroxide (15 ml) added. The mixture was stirred at ambient temperature for about 20 minutes and then poured onto an aqueous solution of 2N hydrochloric acid (75 ml), a colourless solid precipitated which was collected by filtration and dried in vacuo at about 60° C. to give 4′-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)acetanilide dihydrochloride (0.96 g) m.p. 295-304° C.