Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([CH:13]=[CH:12][CH:11]=[C:9]([OH:10])[CH:8]=1)[OH:7].C([O:16][C:17](=O)[CH:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[C:24]=1[F:32])[C:19](=O)[CH3:20])C>O>[F:32][C:24]1[C:25]([N+:29]([O-:31])=[O:30])=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][C:18]1[C:17](=[O:16])[O:7][C:6]2[CH:8]=[C:9]([OH:10])[CH:11]=[CH:12][C:13]=2[C:19]=1[CH3:20]
Reactant: CCOC(=O)C(Cc1cccc([N+](=O)[O-])c1F)C(C)=O
Reactant: Oc1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(Cc2cccc([N+](=O)[O-])c2F)c(=O)oc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
Concentrated sulfuric acid (21.5 mL) was added at 0° C. to a mixture of resorcinol (14.8 g, 135 mmol) and 2-(2-fluoro-3-nitrobenzyl)-3-oxobutanoic acid ethyl ester (38.2 g, 135 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into water, and the solid was filtered off. It was washed with water and methanol to yield the title compound (28.3 g, 64%) as a pale yellow powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS[C:20]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][N:28]=2)[N:23]=[CH:22][N:21]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:20]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][N:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1ncnc2nccnc12
Reactant: NCC1CCN(C(=O)OCc2ccccc2)C1
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncnc3nccnc23)C1

Procedure:
EXAMPLE 101 was prepared from 3-aminomethyl-pyrrolidine-1-carboxylic acid benzyl ester (EXAMPLE 79, Step 3) and 4-methylthio-pteridine (A. A. Brown, D. J. Brown,h. C. S. Wood, J. Chem. Soc., 1954, 3832–3839): MS (m+1)=365.4.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([CH:19]=[O:20])=[CH:12][C:11]=1[O:21][CH3:22].CCOC(C)=O>C1COCC1>[CH3:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([CH2:19][OH:20])=[CH:12][C:11]=1[O:21][CH3:22]
Reactant: COC(=O)CCCOc1cc([N+](=O)[O-])c(C=O)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCCOc1cc([N+](=O)[O-])c(CO)cc1OC
Yield: 64.2 %

Procedure:
Sodium borohydride (2.69 g, 71.3 nmol) was added to a stirred solution of the ester (49)(10.0 g, 33.6 mmol) in THF (50 mL) under an N2 atmosphere at room temperature. Effervescence was observed upon addition of the reducing agent. TLC (EtOAc) after 16 hours revealed the complete loss of starting material. The solution was concentrated and redissolved in EtOAc (100 mL). The organic layer was washed with sat. NH4Cl (5×100 mL) and concentrated in vacuo. Purification by flash chromatography (1% MeOH/CHCl3) yielded the product (50) as a yellow solid (6.46 g, 64%). MP=98-102° C. 1H NMR (250 MHz, CDCl3) δ 7.70 (s, 1H), 7.16 (s, 1H), 4.95 (d, J=6.5 Hz, 2H), 4.12 (t, J=6.2 Hz, 2H), 3.98 (s, 3H), 3.70 (s, 3H), 2.71 (t, J=6.5 Hz, 1H), 2.56 (t, J=7.1 Hz, 2H), 2.19 (pent, J=6.7 Hz, 2H). 13C NMR (67.8 MHz, CDCl3) 173.9 (C12), 154.6 (Cquat.), 147.3 (Cquat.), 139.6 (Cquat.), 133.2 (Cquat.), 111.0 (C6), 109.8 (C3), 68.6 (C9), 62.7 (C1), 56.7 (C8), 52.1 (C13), 30.7 (C11), 24.6 (C10). IR (cm−1) 3286, 2937, 2881, 1737, 1577, 1533, 1368, 1332, 1282, 1162, 1008, 979, 950, 872, 821, 755, 651. MS (M+) 299.0. Anal. Calcd for C13H17NO7: C, 52.17; H, 5.73; N, 4.68. Found: C, 52.41; H, 5.86; N, 4.67.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:25])([F:24])[C:5]([C:11]1[CH:12]=[N:13][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]2[CH3:23])=[N:15][CH:16]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(Cl)Cl.C(N(CC)CC)C.[Br:36][C:37]1[S:41][C:40]([S:42](Cl)(=[O:44])=[O:43])=[CH:39][CH:38]=1>O>[Br:36][C:37]1[S:41][C:40]([S:42]([N:20]2[CH2:21][CH2:22][N:17]([C:14]3[N:15]=[CH:16][C:11]([C:5]([OH:10])([C:6]([F:9])([F:8])[F:7])[C:4]([F:3])([F:24])[F:25])=[CH:12][N:13]=3)[C@@H:18]([CH3:23])[CH2:19]2)(=[O:44])=[O:43])=[CH:39][CH:38]=1
Reactant: C[C@H]1CNCCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C[C@H]1CN(S(=O)(=O)c2ccc(Br)s2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
A 250-mL round-bottomed flask was charged with (1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-2-propanol dihydrochloride (1.48 g, 3.55 mmol), 25 mL of CH2Cl2, and triethylamine (1.48 mL, 10.7 mmol). After cooling to 0° C., 5-bromothiophenesulfonyl chloride (0.93 g, 3.55 mmol. Sigma-Aldrich, St. Louis, Mo.) was added and the solution was stirred for 15 min at 0° C. 100 mL of water was then added and the layers were separated. The organics were dried (MgSO4), filtered, and concentrated to give a tar that was purified by column chromatography on silica gel (0-60% EtOAc in hexanes) to give 2-(2-((2S)-4-((5-bromo-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (2.01 g) as an off-white foam.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[CH2:13]([OH:16])[CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[O:15]1[CH2:14][CH2:13][O:16][CH:1]1[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(C2OCCO2)c1
Yield: 97.6 %

Procedure:
A mixture of methyl 3-formylbenzoate (2.5 g, 15.2 mmol), ethylene glycol (4.2 mL, 75 mmol) and para-toluenesulfonic acid monohydrate (0.29 g, 1.52 mmol) in toluene (60 mL) was heated at reflux under Dean and Stark conditions for 4 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated sodium hydrogen carbonate and brine. The organic phase was dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure to afford the title compound (3.09 g, 98%).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O.[Li+].[B-](CC)(CC)CC>C1COCC1>[C:21]([O:20][C:18]([N:6]1[CH2:7][CH2:8][C@@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C@H:5]1[CH2:3][OH:2])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
To (2S,3R)-3-(tert-butyldimethylsilanyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (7A) (8.05 g, 22.4 mmol) in THF (90 mL) at −78° C. was added a 1 M THF solution of Super-Hydride® (112 mL, 112 mmol) in five portions over 15 min The cold bath was removed and the reaction was allowed to warm to rt. After 3 h, the reaction was poured into a 1-L Erlenmeyer flask and was carefully quenched with ice while stirring and then diluted with EtOAc. The layers were separated and the organic layer washed with 1 M H3PO4, NaHCO3 and brine, dried (MgSO4), filtered and concentrated. The residue was diluted with CH2Cl2, stirred with silica gel overnight, then concentrated and purified via flash chromatography eluting with 30% EtOAc/hexane to obtain compound 7B (6.70 g) as a clear oil.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19]([OH:21])=O)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:22]1[CH:23]=[CH:24][C:25]2[N:30](O)[N:29]=[N:28][C:26]=2C=1.CC[N:34]=C=NCCCN(C)C.CN1CCOCC1.OS([O-])(=O)=O.[K+]>CN(C=O)C.C(OCC)(=O)C>[N:28]([CH2:26][CH:25]1[CH2:24][CH2:23][CH2:22][N:30]1[C:19](=[O:21])[CH:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[N+:29]=[N-:34]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(COCc1ccccc1)C(=O)N1CCCC1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
Example 1a Part A compound (2.13 g, 9.4 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (7 mL) and stirred at RT 3 hours. The TFA and dichloromethane were removed by distillation under reduced pressure and by coevaporation with toluene to give the amine as a TFA salt. This and N-BOC-O-benzyl-L-serine (2.95 g, 10 mmol) were dissolved in DMF (50 mL). HOBT (1.35 g, 10 mmol), WSC (1.91 g, 10 mmol) and NMM (3.3 mL, 30 mmol) were added. The reaction was stirred for 8 h at room temperature, diluted with ethyl acetate (50 mL) and satd. KHSO4 solution (30 mL). The layers were separated and the aqueous layer was reextracted with ethyl acetate (50 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (30 mL)) and 10% lithium chloride solution (30 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated in vacuo to provide title compound (3.87 g, 100%) as an oil which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=[O:3])[CH3:2].COC1C=C(C=CC=1OC)C=O.[CH3:28][O:29][C:30]1[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O>>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[CH:4]([C:1](=[O:3])[CH:2]=[CH:32][C:31]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:30]=2[O:29][CH3:28])[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: COc1cccc(C=O)c1OC
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Agent: COc1ccc(C=O)cc1OC
Product: COc1cccc(C=CC(=O)C2C(=O)OC(=O)C(C(C)=O)=C2O)c1OC

Procedure:
Similarly, equimolar amounts of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one and 3,4-dimethoxybenzaldehyde or 2,3-dimethoxybenzaldehyde are reacted as above to yield the products, 5-acetyl-3-(3,4-dimethoxycinnamoyl)-4-hydroxy-2H-pyran-2,6(3H)-digne, m.p. 223°-225° C., and 5-acetyl-3-(2,3-dimethoxycinnamoyl)-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 175°-176° C., respectively.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.Cl.[CH3:7][N:8]1[C:17]2[NH:16][C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)=[C:26]([CH3:40])[CH:25]=3)=[O:23])[CH2:12][C:11]=2[CH:10]=[N:9]1>ClCCl.C(N(CC)CC)C>[CH3:40][C:26]1[CH:25]=[C:24]([C:22]([N:13]2[CH2:12][C:11]3[CH:10]=[N:9][N:8]([CH3:7])[C:17]=3[NH:16][C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]2=3)=[O:23])[CH:29]=[CH:28][C:27]=1[O:30][CH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][N:37]([C:1](=[O:3])[CH3:2])[CH2:36][CH2:35]1
Reactant: CC(=O)Cl
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCN1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(CCCOc2ccc(C(=O)N3Cc4cnn(C)c4Nc4ccccc43)cc2C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of acetyl chloride (0.39 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of (3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[3-methyl-4-(3-piperazin-1-yl-propoxy)-phenyl]-methanone dihydrochloride (Compound number 408) (2.67 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=503.2
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.C(N(CC)CC)C.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>ClCCl>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:6][C@H:3]2[CH2:4][CH2:5][O:1][CH2:2]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O[C@H]1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@H]2CCOC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a mixture of (S)-tetrahydrofuran-3-ol (1 g, 11.4 mmol) and triethylamine (TEA) (2.3 g, 22.8 mmole) in dichloromethane (DCM) (20 mL) at 0° C. was added 4-methylbenzene-1-sulfonyl chloride (2.2 g, 11.4 mmole). The resulting mixture was stirred at room temperature for 8 h. The mixture was washed with water, dried over MgSO4, filtered, and concentrated. The crude product was purified by ISCO (silica gel, 15% ethyl acetate in hexane) to give the title compound (2.5 g). MS (ESI) m/z: Found: 243.3 (M++1). Calc. 242.3 (M+).
Reaction SMILES: [OH-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][C:7]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)([O:12][CH3:13])[C:8]([O:10]C)=[O:9].O>C1COCC1.CO>[Cl:3][CH2:4][CH2:5][CH2:6][C:7]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)([O:12][CH3:13])[C:8]([OH:10])=[O:9]
Reactant: COC(=O)C(CCCCl)(OC)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(CCCCl)(C(=O)O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 81.5 %

Procedure:
A 4 N sodium hydroxide solution (0.2 mL) was added to a mixed solution of methyl 5-chloro-2-(4-fluorophenyl)-2-methoxyvalerate (141 mg) in THF (1 mL) and methanol (0.5 mL), and the reaction solution was stirred at room temperature for 3.5 hours. Methanol (0.5 mL) and a 4 N sodium hydroxide solution (0.1 mL) were added to the reaction solution, and the reaction solution was further stirred at room temperature for 1.5 hours. Water was added to the reaction solution which was then washed with diethyl ether. 1 N hydrochloric acid (1.4 mL) and ethyl acetate were added to the resulting aqueous layer, and the organic layer was separated. The resulting ethyl acetate layer was washed with brine and dried over anhydrous magnesium sulfate. The resulting ethyl acetate layer was concentrated under reduced pressure to obtain 109 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH2:12][CH2:11][N:10]([CH3:13])[S:9]2(=[O:15])=[O:14])=[CH:5][CH:4]=1.[N:18]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>Cl.O>[O:14]=[S:9]1(=[O:15])[N:10]([CH3:13])[CH2:11][CH2:12][N:8]1[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([NH:2][NH2:18])=[CH:17][CH:16]=1
Reactant: O=N[O-]
Reactant: CN1CCN(Cc2ccc(N)cc2)S1(=O)=O
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CN1CCN(Cc2ccc(NN)cc2)S1(=O)=O
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 35.2 %

Procedure:
To a cooled (-10° C.) and stirred suspension of the product from Step 2 (20 g, 72.0 mmol) in concentrated hydrochloric acid (100 ml) and water (10 ml) was added dropwise a solution of sodium nitrite (5.22 g, 75.6 mmol) in water (40 ml) at such a rate as to maintain the temperature below -5° C. (ca 20 minutes). After a further 10 minutes, the mixture was quickly filtered to remove solids and the filtrate was added portionwise to a cooled (-15° C.) and stirred solution of tin (II) chloride dihydrate (81.2 g, 360 mmol) in concentrated hydrochloric acid (60 ml) at such a rate as to maintain the temperature below -10° C. (ca 15 minutes). The mixture was allowed to warm to 0° C. and it was concentrated to 50% of the volume under vacuum. The remaining acid aqueous solution was basified with 10N potassium hydroxide (temperature maintained below 30° C.) and the resulting mixture was shaken with ethyl acetate (500 ml) and filtered through Hyflo supercel filter aid. The organic phase was decanted off and the basic aqueous solution was extracted with ethyl acetate (3×250 ml). The combined organic phases were washed with brine (1×100 ml), dried (Na2SO4) and concentrated. Crystallization of the remaining residue from ethyl acetate followed by flash chromatography purification of the mother liquors (silica gel, ethyl acetate-methanol, 98:2; and dichloromethane-methanol, 95:5) gave 6.5 g (35%) of the required title compound as a yellow solid; δH (250 MHz, DMSO-d6) 7.07 (2H, d, J=8.5 Hz, Ar--H), 6.74 (2H, d, J=8.5 Hz, Ar--H), 6.70 (1H, br s, --NH--), 3.94 (2H, s, Ar--CH2 --N), 3.91 (2H, br s, --NH2), 3.23--3.05 (4H, m, N--CH2CH2 --N), 2.60 (3H, s, --NMe); m/z (EI) 256 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH:13]1([C:16]2[C:17]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=2)[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:26]2[CH2:27][CH2:28][N:23]([C:17]3[C:16]([CH:13]4[CH2:15][CH2:14]4)=[CH:21][C:20]([CH3:22])=[CH:19][N:18]=3)[CH2:24][CH2:25]2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: Cc1cnc(N2CCNCC2)c(C2CC2)c1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C2CC2)c1
Yield: 54.6 %

Procedure:
Using 4-bromo-2-fluorobenzoyl chloride (2.6 g) and 1-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine hydrochloride (2.8 g) described in Preparation Example 85 and by the reaction and treatment in the same manner as in Preparation Example 108, the title compound (2.5 g) was obtained.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[C:11]([OH:14])=[N:12][CH:13]=1.[CH3:18][O:19][CH2:20][CH2:21]Br.O>CN(C)C=O>[Br:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[C:11](=[O:14])[N:12]([CH2:21][CH2:20][O:19][CH3:18])[CH:13]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1cc(Br)cc([N+](=O)[O-])c1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 58.4 %

Procedure:
Cesium carbonate (14.88 g, 45.66 mmol) was added to a solution of 5-bromo-3-nitropyridin-2-ol (10.0 g, 45.7 mmol) and 2-bromoethyl methyl ether (4.29 mL, 45.66 mmol) in N,N-dimethylformamide (400 mL). After 3 h, additional 2-bromoethyl methyl ether (4.29 mL, 45.7 mmol) was added, and the reaction was heated to 60° C. After 4 h, water was added. The mixture was extracted with ethyl acetate (3×), and the combined organic extracts were washed with saturated brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→40% ethyl acetate/hexanes) gave the title compound (7.39 g). MS 277 (M).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15]1(O)[CH2:19][CH2:18][CH2:17][CH2:16]1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11]([O:13][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OC1CCCC1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 19 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-2-methylalanine (1.00 g, 4.92 mmol) in DCM (10 ml) at 0° C. was added cyclopentanol (0.83 ml, 9.84 mmol), EDCI (1.06 g, 5.42 mmol) and finally DMAP (60 mg, 0.49 mmol). The reaction mixture was warmed to RT and stirred for 18 hours. The DCM was removed in vacuo to give a clear oil. The crude residue was dissolved in EtOAc (100 ml) and washed with water, 1 M NaHCO3 and brine. The organic phase was dried (MgSO4) and concentrated in vacuo. The crude extract was purified by column chromatography (10% EtOAc in heptane) to yield the desired product as a clear oil (0.254 g, 20% yield).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].O[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[N:13]([CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7]
Reactant: Cc1ccccc1N1C(=O)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: OCCN1CCOCC1
Product: Cc1ccccc1N1C(=O)N(CCN2CCOCC2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=613.1 (M+), was prepared in accordance with the general method of example 121 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione and N-(2-hydroxyethyl)morpholine.
Reaction SMILES: [C:1]([CH:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:4])#[N:2].N[CH2:16][CH2:17][OH:18]>C(O)CCC.O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C>[CH3:4][CH:3]([C:1]1[O:18][CH2:17][CH2:16][N:2]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: NCCO
Reactant: CCCCCCCCCCC(C)C#N
Agent: CC(=O)[O-]
Agent: [Cd+2]
Solvent: CCCCO
Solvent: O
Product: CCCCCCCCCCC(C)C1=NCCO1

Procedure:
100 mmoles of 2-cyanododecane is treated with 120 mmoles of 2-aminoethanol in 50 ml of 1-butanol in presence of 2.5 mmoles of cadmium acetate dihydrate as outlined under Example 1 to give 2-(2-dodecyl)-2oxazoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14](O)[CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)O)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:33]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]2[CH2:15][CH2:16][CH:17]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)[S:33]2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1cc(C(O)CCC(O)c2cc(OC)c(OC)c([N+](=O)[O-])c2)cc(OC)c1OC
Solvent: c1ccncc1
Product: COc1cc(C2CCC(c3cc(OC)c(OC)c([N+](=O)[O-])c3)S2)cc(OC)c1OC
Temperature: 90 °C

Procedure:
1-(3,4-Dimethoxy-5-nitrophenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanediol (4.61 g, 10.55 mmole) and 6.57 g of P4S10 were suspended in 60 mL of pyridine and heated at 90° C. for 16 hours. The solvent was removed by distillation in vacuo. The residue was acidified with 10% HCl and extracted with dichloromethane. The organic layer was washed with 10% HCl, water and saturated aqueous sodium chloride, dried over MgSO4, filtered and evaporated to give a gummy residue that was purified by flash column chromatography using 3:1 hexane/ethyl acetate as the solvent (335.6 mg, 7.3%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]1([CH3:21])[CH2:20][O:19][CH2:18]1>CC#N>[CH3:16][C:17]1([CH2:21][N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)[CH2:20][O:19][CH2:18]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(Cn2cc([N+](=O)[O-])cn2)COC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
A mixture of 4-nitropyrazole (1.13 g, 10 mmol) and K2CO3 (3.4 g, 25 mmol) in MeCN (50 mL) was stirred at room temperature for 15 min prior to addition of 3-(bromomethyl)-3-methyloxetane (1.8 g, 11 mmol). The reaction mixture was stirred at room temperature for 18 hr, filtered and the filter cake washed with MeCN. The filtrate was concentrated under reduced pressure and the residue purified by silica gel column chromatography (0-100% EtOAc/isohexane) gradient to afford 1-((3-methyloxetan-3-yl)methyl)-4-nitro-1H-pyrazole as a colorless solid (1.43 g, 73%). A portion of this solid (206 mg, 1.04 mmol) dissolved in MeOH (20 mL) was treated with ammonium formate (260 mg, 4.13 mmol) and 10% palladium on carbon (50 mg). The mixture was heated at 80° C. for 1.5 hr, cooled, filtered through Celite® and the filtrate concentrated under reduced pressure to afford 1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-amine as a pale pink gum (160 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H), 6.97 (s, 1H), 4.66 (d, J=6.1 Hz, 2H), 4.37 (d, J=6.1 Hz, 2H), 4.19 (s, 2H), 2.91 (s, 2H), 1.23 (s, 3H).