Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][C@H:9]1[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][CH2:25][NH:26]2)=[CH:22][CH:21]=1.C(N(CC)CC)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:26]2[C:27]3[C:23](=[CH:22][CH:21]=[C:20]([Br:19])[CH:28]=3)[CH2:24][CH2:25]2)=[O:17])[CH2:10][C@H:9]1[CH3:18])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H]1CN(CC(=O)O)CCN1C(=O)OC(C)(C)C
Reactant: Brc1ccc2c(c1)NCC2
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(CC(=O)N2CCc3ccc(Br)cc32)CCN1C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 56.7 %

Procedure:
(R)-4-Carboxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.39 mmol), 6-bromo indoline (100 mg, 0.43 mmol) and triethylamine (0.148 mL, 1.06 mmol) were dissolved in DCM (1.94 mL) at ambient temperature. PyBrop (199 mg, 0.43 mmol) was added and the reaction stirred for 18 h. The solvent was removed in vacuo and the residue purified by column chromatography on silica gel (gradient elution, 0-100% EtOAc/petrol), to give the title compound (97 mg, 52%) as a pale yellow oil. 1H NMR (Me-d3-OD): 8.32 (1H, s), 7.24-7.10 (2H, m), 5.50 (1H, s), 4.38-4.17 (3H, m), 3.83 (1H, d), 3.31 (1H, s), 3.17 (2H, t), 2.91 (1H, d), 2.81 (1H, d), 2.33 (1H, dd), 2.20-2.09 (1H, m), 1.48 (9H, s), 1.30 (3H, d).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]1C=CC=C[C:10]=1C>C1C=CC=CC=1>[CH:5]1[C:6]2[C:1](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:2]=[CH:3][CH:4]=1
Reactant: Cc1ccccc1
Reactant: Cc1ccccc1C
Solvent: c1ccccc1
Product: c1ccc2ccccc2c1

Procedure:
The substitution of (6) toluene, (7) dimethylbenzene and (8) naphthalene, respectively, for the benzene of Example 1 both as a charge material and an extractant, resulted in the production of the corresponding mononitro compound in yields comparative thereto.
Reaction SMILES: [CH3:1][C:2]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([OH:10])[CH2:5][CH2:4][CH:3]=1.CCCCCCCCCCCCCCCC.O=[Si]=O.[Na]>C1CCCCC1>[CH3:11][C:6]([OH:10])([CH2:7][CH2:8][CH:9]=[C:2]([CH3:3])[CH3:1])[CH:5]=[CH2:4]
Reactant: CC1=CCCC(C)(O)CCC1
Agent: O=[Si]=O
Agent: [Na]
Solvent: CCCCCCCCCCCCCCCC
Solvent: C1CCCCC1
Product: C=CC(C)(O)CCC=C(C)C

Procedure:
A mixture of 1,5-dimethylcyclooct-1-en-5-ol (prepared as in Example II (b) 100, cyclohexane and n-hexadecane in the volume ratio 1:2:1 was passed at a rate of 12 ml/hour together with nitrogen gas at one 1/hour through a 30 cm quartz glass tube filled with 3 mm sodium glass beads at 540° C. It was shown by GLC that under these conditions the conversion of starting material was 39% and the selectivity to the required product was 87%. The alpha-linalool was recovered by distillation b.p. 91°-92° C. at 20 mm Hg.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=O)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].Cl.[CH3:14][NH:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCCCCCC>ClC(Cl)C.CCOC(C)=O>[C:9]([O:8][CH2:7][CH:6]([N:15]([CH3:14])[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: CC(=O)OCC(=O)COC(C)=O
Reactant: CNCC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(=O)OCC(COC(C)=O)N(C)CC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 17 %

Procedure:
To a solution of 3-(acetyloxy)-2-oxopropyl acetate (4.54 g, 26 mmol) in dichloroethane (75 ml) was added tert-butyl 2-(methylamino)acetate HCl. After stirring for 10 minutes sodium triacetoxyborohydride (8.3 g, 39 mmol) was added and stirring was continued for 18 hours and monitored by TLC (1:1 heptane:EtOAc). The reaction was quenched by the addition of saturated sodium hydrogen carbonate solution and the crude product was extracted into dichloromethane. The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo. The title compound was purified by silica column chromatography eluting with 0-20% EtOAc:Hept to yield the title compound (1.32 g, 17% yield). 1H NMR (250 MHz, CHLOROFORM-d) δ 4.07-4.33 (4H, m), 3.34 (2H, s), 3.23 (1H, t, 5.9 Hz), 2.49 (3H, s), 1.99-2.19 (6H, m), 1.33-1.55 (9H, m).
Reaction SMILES: CON(C)[C:4]([C:6]1([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].OS([O-])(=O)=O.[K+]>C1COCC1.O>[CH:4]([C:6]1([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:8]1)=[O:5]
Reactant: CON(C)C(=O)C1(NC(=O)OCc2ccccc2)CC1
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: O=CC1(NC(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a solution of benzyl 1-(methoxy(methyl)carbamoyl)cyclopropylcarbamate (1.34 g, 4.82 mmol) in THF (25 mL) at 0° C. was added LiAlH4 (366 mg, 9.64 mmol). After stirred at 0° C. for 30 min, it was poured to a solution of KHSO4 (1.9 g) in water (30 mL), extracted with EtOAc, organic layer was separated, washed with brine, dried and concentrated to give benzyl 1-formylcyclopropylcarbamate (820 mg).
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.S(=O)(=O)(O)[OH:13]>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]([NH2:7])=[O:13])=[C:4]([F:11])[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(C#N)c(F)cc1Br
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(N)=O)c(F)cc1Br
Temperature: 80 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of 4-bromo-2-fluoro-5-methylbenzonitrile (40 g, 190 mmol) in a mixture of sulfuric acid (98%) and TFA (v/v=4:1, 480 mL) was stirred at 80° C. for 16 h. After the mixture was cooled to room temperature, the resulting mixture was poured into ice-cold water. The resulting precipitate was collected by filtration, washed with water and dried under reduced pressure to give the title compound (41 g, 95% yield) as a white solid. MS (ESI) m/z 232.0 [M+1]+.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][C:6]=2[S:15]([N:18]2[CH2:24][CH:23]([OH:25])[CH2:22][O:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])[CH2:3][CH2:2]1.Cl>C1COCC1.O>[CH:1]1([O:4][C:5]2[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=2[S:15]([N:18]2[CH2:24][CH:23]([OH:25])[CH2:22][O:21][CH2:20][CH2:19]2)(=[O:16])=[O:17])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC2CC2)c(S(=O)(=O)N2CCOCC(O)C2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(OC2CC2)c(S(=O)(=O)N2CCOCC(O)C2)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
To a solution of methyl 4-(cyclopropoxy)-3-[(6-hydroxy-1,4-oxazepan-4-yl)sulfonyl]benzoate (620.00 mg, 1.67 mmol, 1.00 eq) in THF (5.00 mL) and H2O (1.00 mL). The formed mixture was stirred at 50° C. for 3 hr. The reaction mixture was neutralized with 1N HCl solution and extracted with EA, the combined organic layer was dried over Na2SO4, concentrated to afford crude product 4-(cyclopropoxy)-3-[(6-hydroxy-1,4-oxazepan-4-yl)sulfonyl]benzoic acid (510.00 mg, 1.43 mmol, 85.45% yield) as white solid.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([O:21]CC)=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCOCC1>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([OH:21])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1c(C)nc2c(OCC3CCCCC3)cccn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
50 g of ethyl 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 5A; 158 mmol, 1 equivalent) were dissolved in 600 ml of dioxane, 790 ml of 2 N aqueous sodium hydroxide solution (1.58 mol, 10 equivalents) were added and the mixture was stirred at RT for 16 h. Then 316 ml of 6 N aqueous hydrochloric acid were added, and the mixture was reduced to about ⅕ of the total volume. The resulting solid was filtered off, washed with water and tert-butyl methyl ether and dried under reduced pressure. This gave 35 g (74% of theory) of the title compound.
Reaction SMILES: [CH3:1][C@:2]1([NH:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[NH:24]C(=O)OCC2C=CC=CC=2)[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3]1.I[Si](C)(C)C.Cl>C(Cl)Cl.CO>[CH3:1][C@:2]1([NH:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[NH2:24])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH2:3]1
Reactant: C[C@]1(N[C@@H]2CCCC[C@H]2NC(=O)OCc2ccccc2)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: C[C@]1(N[C@@H]2CCCC[C@H]2N)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
To a solution of benzyl (1R,2R)-2-((S)-3-methyl-1-(4-nitrophenyl)piperidin-3-ylamino)cyclohexylcarbamate (132 mg, 0.283 mmol) in CH2Cl2 (2 mL) cooled at 0° C. was added iodotrimethylsilane (0.058 mL, 0.424 mmol) dropwise. After addition, the orange colored suspension was stirred at 0° C. for 10 min, then at rt for 40 min. LCMS showed little reaction happened. Then more TMSI (0.060 mL) was added and the reaction was stirred for total 2 h. LCMS showed the reaction was about ˜20% completed. More TMSI (0.070 mL) was added and the reaction was stirred at rt for total 7 h. LCMS showed the reaction was about ˜60% completed. Additional amount of TMSI (0.060 mL, total 0.25 mL, 1.84 mmol) was added and the reaction was stirred at rt for total 9 h. LCMS showed the reaction was completed. The reaction was quenched by addition of 1.70 mmol of HCl (0.45 mL of 4N HCl in dioxane) in MeOH (3 mL), and then the mixture was concentrated. The dark reddish residue was partitioned between ether and water. The ether phase was extracted with 0.2 N aqueous HCl (3×). The combined acidic aqueous was cooled at 0° C. and then basified with 1N aqueous NaOH to pH ˜10. The aqueous phase was extracted with CH2Cl2 (3×). The combined CH2Cl2 extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified using RP prep-HPLC (Method A). The desired fractions was neutralized and concentrated to give the desired product (1R,2R)—N1-((S)-3-methyl-1-(4-nitrophenyl)piperidin-3-yl)cyclohexane-1,2-diamine (23 mg, 0.068 mmol, 24.21% yield) as a yellow oil. Anal. Calcd. for C18H28N4O2 m/z 332.4, found: 333.2 (M +H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.08 (d, J=9.34 Hz, 2H), 6.83 (d, J=9.34 Hz, 2 H), 3.35-3.46 (m, 1 H), 3.23-3.35 (m, 2 H), 3.16 (d, J=12.64 Hz, 1 H), 2.11-2.26 (m, 2 H), 1.88-2.00 (m, 2 H), 1.85 (ddd, J=8.11, 3.99, 3.85 Hz, 1 H), 1.65-1.75 (m, 4 H), 1.56 (ddd, J=17.31, 8.52, 8.25 Hz, 3 H), 1.21-1.33 (m, 3 H), 1.12 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.[NH:29]1[CH2:33][CH:32]=[CH:31][CH2:30]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC([O-])(C)C.[Na+]>O1CCOCC1.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].O>[N:29]1([C:6]2[CH:5]=[CH:4][C:3]([N:9]3[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]4[N:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[N:21]=[CH:20][CH:19]=4)=[N:10]3)=[C:2]([F:1])[CH:7]=2)[CH2:33][CH:32]=[CH:31][CH2:30]1
Reactant: C1=CCNC1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: O
Product: COc1cn(-c2ccc(N3CC=CC3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
A suspension of ±1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (244 mg, 0.5 mmol), 3-pyrroline (0.046 mL, 0.6 mmol), Pd2(dba)3 (18.3 mg, 0.02 mmol), Xantphos (46.3 mg, 0.08 mmol), and NaOtBu (67.3 mg, 0.7 mmol) in 1,4-dioxane (2.5 mL) was stirred for 2 h at 90° C. under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane/THF (1/2) and recrystallized from MeOH/H2O to give the title compound (109 mg, 51% yield) as a yellow solid: mp 204-207° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.89 (3H, s), 4.09 (4H, s), 5.97 (2H, t, J=4.1 Hz), 6.07 (1H, dd, J=2.6, 9.0 Hz), 6.19 (1H, dd, J=2.6, 14.3 Hz), 6.32 (1H, t, J=9.0 Hz), 7.24 (1H, d, J=1.9 Hz), 7.33-7.45 (5H, m), 7.72 (1H, d, J=2.3 Hz), 7.77 (1H, d, J=1.9 Hz). LC-MS (ESI) m/z 430 [M+H]+. Anal. Calcd for C24H20FN5O2: C, 67.12; H, 4.69; N, 16.31. Found: C, 67.03; H, 4.76; N, 16.16.
Reaction SMILES: [H-].[Na+].[CH2:3]([C@@H:10]([CH:25]=[CH2:26])[C@@H:11]([OH:24])[C@@H:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:28][CH2:29][O:30][CH3:31]>CN(C=O)C>[CH2:3]([C@@H:10]([CH:25]=[CH2:26])[C@@H:11]([O:24][CH2:28][CH2:29][O:30][CH3:31])[C@@H:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH3:13])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C=C[C@H](Cc1ccccc1)[C@@H](O)[C@H](C)OCc1ccc(OC)cc1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C[C@H](Cc1ccccc1)[C@@H](OCCOC)[C@H](C)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62 %

Procedure:
To a suspension of NaH (0.088 g, 3.68 mmol) in DMF (10 mL) was added dropwise a solution of (2S,3R,4S)-4-benzyl-2-((4-methoxybenzyl)oxy)hex-5-en-3-ol (1 g, 3.06 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 20 min and then 1-bromo-2-methoxyethane (0.852 g, 6.13 mmol) was added. The reaction mixture was heated to 60° C. for 5 h. The reaction was cooled to room temperature and another portion of NaH (0.088 g, 3.68 mmol) and 1-bromo-2-methoxyethane (0.852 g, 6.13 mmol) were added, and the reaction mixture was heated to 60° C. and stirred overight. The reaction mixture was quenched with saturated NH4Cl and the phases were separated. The aqueous phase was extracted with EtOAc (2×40 mL), and the combined organic phases were dried over MgSO4, concentrated, and purified by column chromatography on SiO2 (EtOAc/hexanes) to furnish the title product as colorless oil (0.730 g, 62%): 1H NMR (400 MHz, CDCl3) δ 7.30-7.06 (m, 7H), 6.86 (dd, J=8.6, 0.9 Hz, 2H), 5.68-5.47 (m, 1H), 4.95-4.69 (m, 2H), 4.60-4.26 (m, 2H), 4.04-3.91 (m, 1H), 3.79 (s, 3H), 3.73-3.69 (m, 1H), 3.68-3.60 (m, 1H), 3.59-3.53 (m, 2H), 3.39 (d, J=0.8 Hz, 3H), 3.38-3.36 (m, 1H), 3.15 (d, J=10.4 Hz, 1H), 2.70-2.42 (m, 2H), 1.30-1.17 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 159.05, 140.67, 138.83, 130.95, 129.56, 129.11, 127.92, 125.60, 116.61, 113.74, 84.59, 76.46, 72.41, 71.76, 70.26, 58.96, 55.28, 48.55, 36.96, 14.01; ESIMS m/z 407.2 ([M+Na]+).
Reaction SMILES: [I:1][CH2:2][C:3]1([CH3:17])[CH2:7][C:6]2[C:8]([CH3:16])=[C:9]([NH:13][CH:14]=[O:15])[C:10]([CH3:12])=[CH:11][C:5]=2[O:4]1.[CH3:18][CH:19](O)[CH3:20].S(=O)(=O)(O)O>O>[I:1][CH2:2][C:3]1([CH3:17])[CH2:7][C:6]2[C:8]([CH3:16])=[C:9]([NH:13][CH:14]=[O:15])[C:10]([CH3:12])=[C:11]([CH:19]([CH3:20])[CH3:18])[C:5]=2[O:4]1
Reactant: CC(C)O
Reactant: Cc1cc2c(c(C)c1NC=O)CC(C)(CI)O2
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c2c(c(C(C)C)c(C)c1NC=O)OC(C)(CI)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
To a mixture of N-[2,3-dihydro-2-(iodomethyl)-2,4,6-trimethylbenzofuran-5-yl]formamide (6.9 g) and 2-propanol (10 mL) was added conc. sulfuric acid (20 mL) dropwise with water-cooling. The mixture was stirred for 1.5 hours at room temperature and poured into ice. The product was extracted twice with a mixture of tetrahydrofuran and diisopropylether (1:2). The combined organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate, filtrated and evaporated in vacuo. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) to afford 7.3 g of the title compound.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C@H:12]1([CH2:18][OH:19])[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]1>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:19][CH2:18][C@H:12]2[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OC[C@@H]1CC=CCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CC=CCC2)cc1
Reaction time: 64 h

Procedure:
A solution of 10.48 g (55 mmol) of p-toluenesulphonyl chloride in 10 ml of pyridine is slowly added dropwise to a solution, cooled to -10°, of 5.6 g (50 mmol) of (S)-3-cyclohexene-1-methanol in 20 ml of pyridine. The solution is stirred at -10° for 64 hours, thereafter evaporated in a high vacuum and the residue is taken up in ether. The ether solution is washed in succession with 1N hydrochloric acid, water and saturated sodium bicarbonate solution and subsequently evaporated under reduced pressure. [(S)-3-Cyclohexen-1-yl]methyl p-toluenesulphonate is thereby obtained as a colourless oil; MS: 173 (M)+.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.N([O-])=[O:13].[Na+].FC(F)(F)C(O)=O.S(=O)(=O)(O)O.[OH-].[NH4+]>O>[NH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:10]=[CH:11][C:2]1=[O:13]
Reactant: O=N[O-]
Reactant: Nc1ccc2cccnc2n1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=c1ccc2cccnc2[nH]1

Procedure:
The 2-amino-1,8-naphthyridine (III) thus produced is converted to the diazonium salt with sodium nitrite in an acid, preferably trifluoroacetic acid or sulfuric acid. The diazonium salt is prepared at -5° C. or less during the addition, over a period of about 2 hours, of the sodium nitrite. The reaction mixture then is generally maintained at this temperature for an additional hour, and combined with a mixture of ice and water. The aqueous mixture is then made alkaline preferably with ammonium hydroxide, and the product 1,8-naphthyridine-2-(1H)-one (IV) isolated using known techniques.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[Br:12][C:13]1[N:17]2[N:18]=[C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>C(OCC)(=O)C>[Br:12][C:13]1[N:17]2[N:18]=[C:19]([N:22]3[CH2:23][CH2:24][N:25]([C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:26][CH2:27]3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Brc1cnc2ccc(N3CCNCC3)nn12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)N1CCN(c2ccc3ncc(Br)n3n2)CC1
Reaction time: 0.5 h

Procedure:
Hunig's base [7087-99-5] (1.8 mL, 10.3 mmol) was added to an ambient temperature stirred suspension of 3-bromo-6-piperazin-1-yl-imidazo[1,2-b]pyridazine dihydrochloride (907.1 mg, 2.6 mmol) in ethyl acetate (50 mL). After 30 minutes, pivaloyl chloride [3282-30-2] (0.3 mL, 2.5 mmol) was added and the suspension stirred under N2 blanket for 17 h then washed with brine, dried (MgSO4), and diluted with heptane. Chilling the stirred solution crystallized out a white powder which was isolated by filtration, 618.5 mg. LRMS (ESI) m/z 366.0/368.0 [(M+H)]+, calc'd for C16H20BrN6O: 366.26.
Reaction SMILES: C(OC([N:8]([CH2:18][C@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([S:29][C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=3)[C:33]([OH:35])=[O:34])[CH:25]=2)[O:20]1)[CH2:9][C@H:10]([OH:17])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C.Cl.C(O)(C(F)(F)F)=O>O1CCOCC1>[OH:17][C@H:10]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][NH:8][CH2:18][C@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([S:29][C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=3)[C:33]([OH:35])=[O:34])[CH:25]=2)[O:20]1
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(Sc3cccc(C(=O)O)c3)ccc2O1)C[C@H](O)c1cccnc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cccc(Sc2ccc3c(c2)CC[C@H](CNC[C@H](O)c2cccnc2)O3)c1
Temperature: 45 °C
Reaction time: 2 h
Yield: 5.2 %

Procedure:
To 670 mg (1.25 mmol) of crude 3-{[(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]sulfanyl}benzoic acid (Example 173) diluted in 5 mL 1,4-dioxane, was added 0.5 mL of 6N hydrochloric acid slowly. The resulting mixture was stirred at 45° C. for 2 hours. After this time the mixture was concentrated in vacuo, dissolved in 2 mL of 1:1 methanol to water, and purified by HPLC (0-70% acetonitrile/0.1% TFA) to afford 28.5 mg (5% yield) of the desired product as the bis TFA salt. MH+ 437.3. 1H NMR (CDCl3, δ): 8.91(br. S, 1 H), 8.63 (d, 1 H), 8.56 (dd, 1 H), 7.89 (m, 1 H), 7.72 (dt, 1 H), 7.62 (m, 1 H), 7.49 (m, 1 H), 7.39 (m, 1 H), 7.31 (m, 1 H), 7.27 (m, 1 H), 7.24 (dd, 1 H), 6.90 (d, 1 H), 6.35 (br. S, 1 H), 5.07 (m, 1 H), 4.48 (m, 1 H), 3.32 (m, 4 H), 3.16 (m, 1 H), 2.78 (m, 2 H), 2.04 (m, 1 H), 1.71 (m, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=[C:10]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])=[C:4]([CH3:24])[CH:3]=1.Cl.[NH2:26][OH:27]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C:10]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=3)([C:11]([F:14])([F:13])[F:12])[O:27][N:26]=2)=[C:4]([CH3:24])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(Br)ccc1C(=O)C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(Br)ccc1C1=NOC(c2cc(Cl)cc(Cl)c2)(C(F)(F)F)C1
Temperature: 25 °C
Yield: 24.5 %

Procedure:
To a stirred solution of 1-(4-bromo-2-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one (200 mg, 0.45 mmol) in pyridine (3 mL) at room temperature was added hydroxylamine hydrochloride (47 mg, 0.68 mmol). The reaction mixture was heated to reflux for 4 h. The resulting mixture was cooled to room temperature and then concentrated, and the residual oil was purified by chromatography on silica gel using 20:80 ethyl acetate/hexanes as eluent to afford the title product as a pale yellow oil (50 mg, 24% yield).
Reaction SMILES: C[N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.Cl.NC1[N:17]=[CH:18][NH:19][C:20]=1[C:21]([NH2:23])=[O:22].C(O)(C)C>C(O)(=O)C>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[N:17]3[CH:18]=[N:19][C:20]([C:21]([NH2:23])=[O:22])=[C:13]3[N:2]=[CH:3][CH:4]=2)[CH:8]=1
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: NC(=O)c1[nH]cnc1N
Agent: Cl
Solvent: CC(C)O
Solvent: CC(=O)O
Product: NC(=O)c1ncn2c(-c3cccnc3)ccnc12
Reaction time: 16 h
Yield: 53.9 %

Procedure:
A stirred mixture of 17.7 g of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (U.S. Pat. No. 4,281,000, Ex. 1) and 12.6 g of 4-amino-5-imidazolecarboxamide hydrochloride in 100 ml of glacial acetic acid was heated on a steam bath for 4 hours. The reaction mixture was then allowed to stand at room temperature for 16 hours. The mixture was evaporated to dryness in vacuo and the residual solid was partitioned between dichloromethane and saturated sodium bicarbonate. The two layers were separated, the organic layer was dried over anhydrous sodium sulfate and filtered and evaporation of the filtrate gave a dark yellow solid which was treated with isopropyl alcohol. This solid was collected by filtration and washed with hexane. The yellow solid was dried in vacuo to give 10.0 g of the product of the example, mp >260° C.