Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.[Cl-].[NH4+].O.C(O)C>C1COCC1.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19]
Reactant: O=[N+]([O-])c1cnc(Oc2ccc(F)cc2F)c(Br)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cnc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 50 °C
Yield: 46.4 %

Procedure:
A mixture of 3-bromo-2-(2,4-difluorophenoxy)-5-nitropyridine (1.9 g, 5.9 mmol), ammonium chloride (637 mg, 11.8 mmol), and iron powder (1.65 g, 30 mmol) suspended in THF (10 mL), water (3 mL) and ethanol (10 mL) was heated to 90° C. using microwave irradiation (normal) for 5 h. The crude reaction mixture was filtered through a short plug of celite; the celite plug was washed with warm (50° C.) MeOH (˜50 mL). The resulting filtrate was concentrated in vacuo. The resulting residue was diluted with EtOAc (100 ml) and washed with saturated bicarbonate solution (aq), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound, (824 mg, 46%). LCMS (M+H)+=302.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>>[Br:15][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2nccc(C)n2)cc1
Reactant: O=C1CCC(=O)N1Br
Product: Cc1ccnc(-c2ccc(CBr)cc2)n1

Procedure:
Reaction of this 2-(4-methylphenyl)-4-methylpyrimidine with N-bromosuccinimide, as described in Example 15, affords 2-(4-bromomethylphenyl)-4-methylpyrimidine with a melting point of 104°-106° C. after recrystallisation from ligroin. A mixture of 105 g of 2-(4-bromomethylphenyl)-4-methylpyrimidine and 265 g of triethylphosphite is slowly heated, with stirring, to 150° C., while simultaneously distilling off ethyl bromide, and then stirred for 5 hours at this temperature. After distilling off excess triethylphosphite, the phosphate is obtained in a yield of 125 g in the form of a light brown viscous oil.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[Br:9][C:10]1[S:14][C:13]([N:15]=[C:16]=[O:17])=[CH:12][CH:11]=1.O>CN(C=O)C.C1(C)C=CC=CC=1>[Br:9][C:10]1[S:14][C:13]([NH:15][C:16]([N:8]=[C:7]2[NH:6][C:4](=[O:5])[CH2:3][N:2]2[CH3:1])=[O:17])=[CH:12][CH:11]=1
Reactant: O=C=Nc1ccc(Br)s1
Reactant: CN1CC(=O)N=C1N
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1ccc(Br)s1
Temperature: 75 °C
Yield: 29.6 %

Procedure:
To a stirred suspension of 3.0 g (26 mM) of creatinine in 30 ml of anhydrous DMF was added a solution of 5.0 g (26.5 mM) of 5-bromo-2-thienyl isocyanate in 15 ml of toluene. The resulting mixture was heated at 75° C. for 3 hrs., cooled, and poured into 200 ml of water. The precipitate was collected, washed with ethanol and ether, and air-dried. The solid was dissolved in 250 ml hot acetone, treated with charcoal, filtered, and the filtrate diluted with water (250 ml). The resulting precipitate was collected, washed with acetone and then ether. Air-drying gave 2.3 g of the above urea as a buff powder, m.p. 192°-193° C. (dec.).
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=O)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH:1]1([S:4][C:5]2[CH:13]=[CH:12][C:8]([CH2:9][NH2:11])=[CH:7][CH:6]=2)[CH2:2][CH2:3]1
Reactant: NC(=O)c1ccc(SC2CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(SC2CC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4-cyclopropylsulfanyl-benzamide (preparation 31a, 137 mg, 0.71 mmol) in dry tetrahydrofuran (1.0 mL) is added at 0° C. to a solution of lithium aluminium hydride in tetrahydrofuran (1 M, 2.1 mL, 2.1 mmol). The mixture is stirred at 0° C. for 1 h and heated at reflux for 1 h. The mixture is cooled at room temperature and stirred for 1.5 h. Water is added, and the mixture is extracted twice with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure. Yield: 75 mg (60% of theory); ESI mass spectrum: [M+H]+=180; Retention time HPLC: 0.51 min (X011_S03).
Reaction SMILES: C(O[C:9](=[O:34])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([Cl:28])[CH:26]=3)[C:21]3=[N:29][O:30][C:31]([CH3:32])=[C:20]3[C:19]2=[O:33])[CH2:13]1)C1C=CC=CC=1.I[Si](C)(C)C.C(O)(=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[Cl:28][C:25]1[CH:26]=[C:27]2[C:22](=[N:23][CH:24]=1)[C:21]1=[N:29][O:30][C:31]([CH3:32])=[C:20]1[C:19](=[O:33])[N:18]2[CH:14]1[CH2:15][CH2:16][CH2:17][CH:12]([CH2:11][NH:10][C:9](=[O:34])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:13]1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)OCc3ccccc3)C1)c1cc(Cl)cnc21
Agent: CCN=C=NCCCN(C)C
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)c3ccccc3)C1)c1cc(Cl)cnc21
Temperature: 25 °C
Yield: 38.4 %

Procedure:
Dissolve [3-(7-chloro-3-methyl-4-oxo-5H-2-oxa-1,5,9-triaza-cyclopenta[a]naphthalen-5-yl)-cyclohexylmethyl]-carbamic acid benzyl ester(70 mg, 0.15 mmol) in dry dichloromethane (5 mL). Add iodotrimethylsilane (0.05 mL, 0.35 mmol) and stir overnight at ambient temperature. Quench with methanol (5 mL) and concentrate in vacuo. Concentrate the resulting residue twice from diethyl ether and use directly without purification. Combine this amine salt with benzoic acid (22 mg, 0.18 mmol), 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (34 mg, 0.18 mmol), 1-hydroxy-7-azabenzo-triazole (24 mg, 0.18 mmol), and N,N-diisopropylethyl amine (0.10 mL, 0.57 mmol) in N,N-dimethylformamide (5 mL) and stir over a weekend at ambient temperature. Concentrate in vacuo and take up in water and extract with ethyl acetate. Dry the combined extracts over sodium sulfate and concentrate in vacuo. Elute the resulting residue over silica gel using ethyl acetate/dichloromethane to give 26 mg (38%) of the desired product as a white solid. MS(ES): (M+1)+ Exact Mass Calc'd: 451.1537. Found: 451.1554 m/z.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:25]=[CH:24][C:7]([CH2:8][CH2:9][C:10]([NH:12][CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11])=[CH:6][CH:5]=1)[CH3:2].I[CH2:27][CH2:28][CH3:29].N12CCCC1=NCCC2>O1CCCC1>[CH2:1]([N:3]([CH2:27][CH2:28][CH3:29])[C:4]1[CH:25]=[CH:24][C:7]([CH2:8][CH2:9][C:10]([NH:12][CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCNc1ccc(CCC(=O)NC(C(=O)OCC)C(=O)OCC)cc1
Reactant: CCCI
Agent: C1CN=C2CCCN2C1
Solvent: C1CCOC1
Product: CCCN(CC)c1ccc(CCC(=O)NC(C(=O)OCC)C(=O)OCC)cc1
Reaction time: 36 h

Procedure:
Working as in Example F, but starting with 10 g of diethyl 4-ethylaminobenzylacetamidomalonate, 5.6 ml of 1-iodopropane and 7.2 ml of 1,5-diazabicyclo-[4.3.0] non-5-ene in 70 ml of tetrahydrofuran, and after reacting for 36 hours followed by purification by flash chromatography (eluent: 97/3 CH2Cl2/MeOH by volume), 2.8 g of a solid are obtained, which solid is recrystallized from 26 ml of cyclohexane. 2.9 g of diethyl 4-(ethylpropylamino)benzylacetamidomalonate are thus obtained in the form of a white solid melting at 84-86° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:24]C(=O)C(F)(F)F)[CH:21]=[CH:22][CH:23]=3)=[N:10][N:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[Li+].[OH-].O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=3)=[N:10][N:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc2c(-c3ccnc(Cl)n3)c(-c3cccc(NC(=O)C(F)(F)F)c3)nn2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(-c3ccnc(Cl)n3)c(-c3cccc(N)c3)nn2c1

Procedure:
N-{3-[3-(2-Chloro-4-pyrimidinyl)-6-methylpyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (1.70 g, 3.94 mmol) and LiOH (0.50 g, 11.8 mmol) were combined in THF (30 mL) and water (5 mL) and stirred at 40° C. for 3 h. The mixture was cooled, concentrated to remove the THF, and extracted with DCM. The organic phase was concentrated to afford {3-[3-(2-chloro-4-pyrimidinyl)-6-methylpyrazolo[1,5-a]pyridin-2-yl]phenyl}amine which was carried on crude to Step C. ES-LC/MS m/z=336 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1.Cl.CC1CC[C@@H](C(C)=C)CC=1.N(Cl)=[O:23].CN(C)C=O>C(O)(C)C.N([O-])=O.[Na+]>[CH3:1][C:2]1[C:7](=[O:23])[CH2:6][C@H:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1
Reactant: O=NCl
Reactant: C=C(C)[C@H]1CC=C(C)CC1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: C=C(C)[C@@H]1CC=C(C)C(=O)C1

Procedure:
Synthesis of the exemplary Formula VI terpene compound L-Carvone (2-cyclohexen-1-one, 2-methyl-5-(1-methylethenyl)-(R); Millenium Chemicals) from D-limonene is described in Ikan, Natural Products—A Laboratory Guide pp. 151-155 (Academic Press, 1969), incorporated herein by reference. Briefly, a solution of D-limonene in isopropanol is cooled to below 10° C. Solutions of HCl in isopropanol and concentrated aqueous sodium nitrite are added dropwise to the D-limonene solution to generate limonene nitrosochloride. The limonene nitrosochloride and dimethylformamide is refluxed with isopropanol. After cooling, crystallization is induced and the precipitate filtered and washed with water. The resulting L-carvoxime is refluxed with 0.5 M oxalic acid and the mixture is steam distilled. The distillate is extracted with ether, dried over anhydrous magnesium sulfate, and the excess ether evaporated to leave L-carvone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([S:17][C:18]3[N:19]([CH2:28][CH2:29][CH2:30][NH:31][CH:32]([CH3:34])[CH3:33])[C:20]4[C:25]([N:26]=3)=[C:24]([NH2:27])[N:23]=[CH:22][N:21]=4)=[CH:10][C:11]3[O:15][CH2:14][O:13][C:12]=3[CH:16]=2)=[CH:4][CH:3]=1.BrC1C=CC(B(O)O)=CC=1.CC(NCCCN1C(SC2C=[C:67]3[O:69]COC3=CC=2I)=NC2C(N)=NC=NC1=2)C.C([O-])(O)=O.[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CN(C=O)C>[CH:32]([NH:31][CH2:30][CH2:29][CH2:28][N:19]1[C:18]([S:17][C:9]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([O:69][CH3:67])=[CH:3][CH:4]=3)=[CH:16][C:12]3[O:13][CH2:14][O:15][C:11]=3[CH:10]=2)=[N:26][C:25]2[C:20]1=[N:21][CH:22]=[N:23][C:24]=2[NH2:27])([CH3:34])[CH3:33]
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2-c2ccc(Br)cc2)OCO3)nc2c(N)ncnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: OB(O)c1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cc3c(cc2Sc2nc4c(N)ncnc4n2CCCNC(C)C)OCO3)cc1
Temperature: 90 °C

Procedure:
8-(6-(4-bromophenyl)benzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine [DZ3-6]. 4-Bromophenylboronic acid (17.6 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H2O (0.1 mL) and Pd(PPh3)2Cl2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90° C. for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH—NH3 (7N), 4:5:2:1) to give 13.9 mg (44%) of DZ3-6. 1H NMR (500 MHz, CDCl3) δ 8.23 (s, 1H), 7.44 (d, J=8.2 Hz, 2H), 7.13 (d, J=8.2 Hz, 2H), 7.01 (s, 1H), 6.81 (s, 1H), 6.05 (s, 2H), 5.69 (br s, 2H), 4.08 (t, J=6.0 Hz, 2H), 2.91 (m, 1H), 2.50 (t, J=5.9 Hz, 2H), 1.98 (m, 2H), 1.20 (d, J=6.4 Hz, 6H); 13C NMR (125 MHz, CDCl3/MeOH-d4) δ 154.2, 152.0, 151.2, 149.8, 149.1, 148.2, 139.8, 139.1, 131.2, 131.0, 122.0, 119.0, 117.9, 115.0, 111.1, 102.4, 50.1, 42.1, 40.2, 27.3, 20.2; HRMS (ESI) m/z [M+H]+ calcd. for C24H26BrN6O2S, 541.1021/543.1001; found. 541.1016/543.1004; HPLC: method A Rt=6.93, method B Rt=8.30.
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(C)=O.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([C:15]1[CH:16]=[C:17]([CH:21](Cl)[CH3:22])[CH:18]=[CH:19][CH:20]=1)=[O:14]>O>[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([C:15]1[CH:16]=[C:17]([CH:21]([C:1]#[N:2])[CH3:22])[CH:18]=[CH:19][CH:20]=1)=[O:14]
Reactant: [C-]#N
Reactant: CC(Cl)c1cccc(C(=O)c2cccs2)c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C#N)c1cccc(C(=O)c2cccs2)c1

Procedure:
To a stirred and hot mixture of 2.7 parts of sodium cyanide in 20 parts of dimethylsulfoxide is added dropwise a solution of 5.8 parts of α-chloro-α-methyl-m-tolyl 2-thienyl ketone in 10 parts of dimethylsulfoxide at 60° C. Another 5 parts of dimethylsulfoxide is added and the whole is stirred for 2.5 hours at 50°-55° C. The reaction mixture is poured onto 35 parts of water and the product is extracted with ether and ethyl acetate. The combined organic layers are washed with water, dried, filtered and evaporated in vacuo. The residue is dissolved in benzene. This solution is washed with water, dried and evaporated in vacuo, yielding m-(2-thenoyl)hydratroponitrile, also named α-cyano-α-methyl-m-tolyl 2-thienyl ketone, as a residue.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].C(N(C(C)C)CC)(C)C.[O:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH:34]=[C:33]1[CH:41]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[O:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH:34]=[C:33]1[CH2:41][NH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22]
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=Cc1cc2ccccc2o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1CCC(N2C(=O)c3ccc(CNCc4cc5ccccc5o4)cc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
To a mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol) in CH2Cl2 (20 mL), were added diisopropylethylamine (0.52 mL, 3.0 mmol), 2-benzofurancarboxaldehyde (0.36 mL, 3.0 mmol) and glacial acetic acid (0.17 mL, 3.0 mmol). The reaction mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (1.27 g, 6.0 mmol) was added, and the mixture was stirred at room temperature overnight. Water (20 mL) was added to quench the reaction, and the mixture was extracted with CH2Cl2 (2×50 mL). The organic layer was washed with dilute aqueous HCl (2×150 mL) and water (2×150 mL), and dried (MgSO4) and evaporated under vacuum. The residue was chromatographed using an ethyl acetate-hexanes gradient, eluting the 0.38 g of the product at 83:17 ethyl acetate-hexanes, in 30% yield; mp 133-135° C.; HPLC, Waters Xterra RP18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% HCO2(NH4), 5.11 min (98.22%); 1H NMR (DMSO-d6) δ 2.04-2.10 (m, 1H), 2.50-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.20 (br, 1H), 3.85 (s, 2H), 3.94 (s, 2H), 5.14 (dd, J=12.6 Hz, 5.1 Hz, 1H), 6.73 (s, 1H), 7.17-7.27 (m, 2H), 7.48-7.58 (m, 2H), 7.84 (t, J=7.8 Hz, 2H), 7.93 (s, 1H), 11.12 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 45.0, 48.9, 51.5, 103.6, 110.8, 120.7, 122.6, 123.2, 123.6, 128.2, 129.6, 131.4, 134.1, 148.8, 154.1, 157.3, 167.1, 167.2, 169.8, 172.7; Anal. Calcd for C23H19N3O5: C, 66.18; H, 4.59; N, 10.07. Found: C, 66.02; H, 4.27; N, 9.94.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]=[C:13]1[CH2:19][N:18]([C:20]2[N:21]([CH3:28])[N:22]=[CH:23][C:24]=2[N+:25]([O-:27])=[O:26])[CH2:17][CH2:16][C@H:15]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:14]1>C(Cl)Cl>[CH3:28][N:21]1[C:20]([N:18]2[CH2:19][C:13]3([CH2:12][O:9]3)[CH2:14][C@@H:15]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:16][CH2:17]2)=[C:24]([N+:25]([O-:27])=[O:26])[CH:23]=[N:22]1
Reactant: C=C1C[C@@H](NC(=O)OC(C)(C)C)CCN(c2c([N+](=O)[O-])cnn2C)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1ncc([N+](=O)[O-])c1N1CC[C@H](NC(=O)OC(C)(C)C)CC2(CO2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
MCPBA (335 mg, 1.49 mmol, 77 mass %) was added to a stirred solution of tert-butyl N-[(4R)-6-methylene-1-(2-methyl-4-nitro-pyrazol-3-yl)azepan-4-yl]carbamate (350 mg, 1.00 mmol) in DCM (12 mL). The mixture was stirred at room temperature overnight. The reaction was quenched with sat NaHCO3 and extracted with DCM 3×. The combined organic layers were concentrated and the residue was purified via silica gel column chromatography (0-100% EA/heptane) to give tert-butyl N-[(5S)-8-(2-methyl-4-nitro-pyrazol-3-yl)-2-oxa-8-azaspiro[2.6]nonan-5-yl]carbamate (316 mg, 86%).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH2:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])(=[O:18])=[O:17])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([N:47]=[N+:48]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1.Cl>ClCCl>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([C:19]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[N+:47]=[N-:48])(=[O:17])=[O:18])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccc(S(=O)(=O)CS(=O)(=O)c2ccc(OC(=O)c3ccccc3)cc2)cc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: [N-]=[N+]=C(S(=O)(=O)c1ccc(OC(=O)c2ccccc2)cc1)S(=O)(=O)c1ccc(OC(=O)c2ccccc2)cc1
Reaction time: 0.08 h
Yield: 37 %

Procedure:
The bis(4-benzoyloxyphenylsulfonyl)methane in Synthesis Example 6, 10 g (0.019 mol), was dispersed in 200 g of dichloromethane. To the dispersion was added 5.6 g (0.029 mol) of p-toluenesulfonylazide which had been separately prepared. With stirring under ice cooling, 4.0 g (0.026 mol) of DBU was added to the dispersion, and after 5 minutes, 100 g of a 0.2N aqueous hydrochloric acid was added to stop reaction. The organic layer was separated and washed with 100 g of water. The organic layer was concentrated and 15 g of the residue was purified by silica gel column chromatography using dichloromethane as an elute. The thus obtained oily product was combined with 40 g of hexane for crystallization, followed by filtration and vacuum drying. There was obtained 4.0 g (yield 37%) of fine yellow crystals.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12](C(O)=O)=[C:8]3[CH:7]=[C:6]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:3][CH2:2]1.CC([O-])=O.[Na+].[I:31]Cl.O>C(O)(=O)C>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([I:31])=[C:8]3[CH:7]=[C:6]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: ClI
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc(C3CC3)n3ncc(I)c3c2)cc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A mixture of 7-cyclopropyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyridine-3-carboxylic acid (example C.28 step 6) (1.03 g, 2.97 mmol) in acetic acid (40 mL) was refluxed for 20 h. Cooled to 23° C., added NaOAc (325 mg, 3.95 mmol) and ICl (2M in HOAc, 1.85 mL, 3.7 mmol) and the mixture was stirred at 23° C. for 2 h. Poured into water, filtered precipitate off, washed with water, dissolved in TBME, washed with sat. NaHCO3-sol.+little sat. Na2SO3-sol. and brine, dried over Na2SO4. Removal of the solvent in vacuum left the title compound as a light red solid (1.257 g, 99%). MS (ISP) 429.2 [(M+H)+].
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[Cl-].[Al+3].[Cl-].[Cl-].[CH:16]#[CH:17]>[N+](C)([O-])=O>[F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7](=[O:8])[C:16]#[CH:17]
Reactant: O=C(Cl)CCCCC(F)(F)F
Reactant: C#C
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: C#CC(=O)CCCCC(F)(F)F

Procedure:
The acetylenic ketones HC≡CCOCR2R3 (CH2)pQ can be prepared by several alternate routes analogous to those described for preparation of the corresponding vinyl ketones. For example (Method 1) propiolaldehyde is treated with the ##STR236## Grignard reagent derived from Q(CH2)pCR2R3X where X is halogen, preferably chlorine, affording an acetylenic carbinol which in turn is oxidized with chromic acid to the acetylenic ketone. Care must be taken that the aldehyde be added very slowly to cold Grignard reagent lest the aldehyde undergo extremely vigorous decomposition or polymerization. Method (2) involves addition of excess acetylene to an acyl chloride in the presence of a Friedel-Crafts catalyst such as aluminum chloride. Finally, in Method (3) sodium acetylide is allowed to react with a suitable aldehyde to afford an acetylenic carbinol, which in turn is oxidized by chromic acid to give the acetylenic ketone. Of these three methods (2) and (3) are usually the most satisfactory. Thus 6,6,6 trifluorohexanoic acid chloride (prepared via adipic acid monomethyl ester and SF4) reacts smoothly as its complex with aluminum chloride in nitromethane with excess acetylene (Method 2) to give a good yield of 8,8,8-trifluoro-1-octyn-3-one. Likewise, the acid chloride of 4 (p-chlorophenyl)butyric acid gives 6-(p-chlorophenyl)-1-hexyn-3-one. Hexaldehyde readily reacts with acetylene in glyme in the presence of powdered KOH to give an acetylenic carbinol which in turn is oxidized by a solution of CrO3 in water and sulfuric acid to 1-octyn-3-one (Method 3).
Reaction SMILES: C=O.[Cl:3][C:4]1[C:5]([F:34])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:32][CH3:33])=[C:18]([O:21][C@H:22]4[CH2:27][CH2:26][NH:25][C@H:24]([C:28]([NH:30][CH3:31])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O.C(Cl)Cl>[Cl:3][C:4]1[C:5]([F:34])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:32][CH3:33])=[C:18]([O:21][C@H:22]4[CH2:27][CH2:26][N:25]([CH3:35])[C@H:24]([C:28]([NH:30][CH3:31])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CNC(=O)[C@@H]1C[C@@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNC(=O)[C@@H]1C[C@@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C
Yield: 64.7 %

Procedure:
Molecular sieves (5 g) followed by aqueous formaldehyde (10 ml) were added to a stirred solution of (2S,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-methylpiperidine-2-carboxamide (3.0 g, 6.52 mmol) in DCM-AcOH (100:10 ml) at room temperature. The reaction mixture was stirred for 1-2 minutes before solid sodium triacetoxyborohydride (2.77 g, 13.1 mmol) was added portionwise over 5 minutes. The reaction was essentially complete after all the sodium triacetoxyborohydride reducing agent had been added. DCM was added (100 ml) and the reaction was carefully neutralised with saturated aqueous NaHCO3(aq). The organic extract was washed with brine, dried (MgSO4) and concentrated to a yellow foam. The residue was purified by flash chromatography (silica gel, DCM-NH3/MeOH 2%) to give the title product as a white solid (2 g, 65%): 1H NMR Spectrum: (DMSO d6) 1.85-1.96 (m, 3H), 2.07 (m, 1H), 2.15 (s, 3H), 2.45-2.50 (m, 1H), 2.59 (d, 3H), 2.71 (m, 1H), 2.84 (m, 1H), 3.96 (s, 3H), 4.81 (m, 1H), 7.23 (s, 1H), 7.28 (t, 1H), 7.47-7.53 (m, 2H), 7.81 (s, 2H), 8.37 (s, 1H), 9.59 (s, 1H); Mass Spectrum: (M+H)+ 474.1.