Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[NH2:40][C:41]([NH:43][CH2:44][C@@H:45]([C:51](O)=[O:52])[NH:46][C:47]([O:49][CH3:50])=[O:48])=[O:42].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)CC)C>O1CCCC1>[CH3:50][O:49][C:47](=[O:48])[NH:46][C@@H:45]([CH2:44][NH:43][C:41]([NH2:40])=[O:42])[C:51](=[O:52])[NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[NH:19][C:20](=[O:21])[C@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[NH:27][C:28](=[O:31])[O:29][CH3:30]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: COC(=O)N[C@@H](CNC(N)=O)C(=O)O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)N[C@@H](CNC(N)=O)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 7 h
Yield: 56.2 %

Procedure:
A solution containing the product from Example 2C (0.025 g, 0.047 mmol) in tetrahydrofuran (0.5 mL) was treated with the product from Example 176A (0.014 g, 0.07 mmol), DEPBT (0.028 g, 0.094 mmol), and triethylamine (0.016 mL, 0.117 mmol), stirred at 25° C. for 7 hours, and partitioned between ethyl acetate and 10% NaHCO3 solution. The organic phase was washed with additional 10% NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated. The product was purified by chromatography on silica gel eluting with 7% methanol/dichloromethane to give the title compound (0.019 g, 55% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.79 (s, 9H), 1.33-1.60 (m, 2H), 2.63-2.86 (m, 4H), 2.99-3.28 (m, 2H), 3.49 (s, 3H), 3.55 (s, 3H), 3.81 (d, J=9.56 Hz, 1H), 3.89-4.22 (m, 3H), 4.89 (d, J=6.62 Hz, 1H), 5.63 (s, 2H), 5.97 (s, 1H), 6.61 (d, 1H), 7.09-7.37 (m, 9H), 7.49 (d, J=9.19 Hz, 1H), 7.69-7.96 (m, 5H), 8.63 (d, J=4.41 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([Cl:10])[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]1=[O:24].[N:25]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[Cl:10][C:6]1[CH:5]=[C:4]([F:11])[C:3]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:2]([NH:1][NH2:25])[C:7]=1[O:8][CH3:9]
Reactant: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1NN
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
3-(2-Amino-4-chloro-6-fluoro-3-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.9 g, 2.4 mmol) was dissolved in conc. hydrochloric acid (5 ml) and the mixture cooled to −15° C., a solution of NaNO2 (0.2 g in 2 ml of H2O) was added slowly. After stirred for 20 min, a solution of SnCl2.2H2O (1.5 g in 4 ml of conc. hydrochloric acid) was added and the reaction continued at −15° C. for 30 min, then at room temperature for 30 min. The aqueous mixture was extracted with ethyl acetate (5 ml×3) and the organic phase washed with brine and dried over Na2SO4. Column chromatography was used to purify the product (silica gel, hexane/ethyl acetate=6/4). Yield: 0.5 g, 1.3 mmol.
Reaction SMILES: [CH:1]([C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:6]=1N)([CH2:3][CH3:4])[CH3:2].N([O-])=[O:16].[Na+].NC1C=CC=CC=1>OS(O)(=O)=O.O.[O-]S([O-])(=O)=O.[Cu+2]>[CH:1]([C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1cccc(C(C)C)c1N
Reactant: O=N[O-]
Agent: [Cu+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: Nc1ccccc1
Product: CCC(C)c1cccc(C(C)C)c1O
Temperature: 0 °C

Procedure:
(−)-2-Sec-butyl-6-isopropylaniline (3) (1.92 g, 10 mmol) was dissolved in 20 ml 15% H2SO4 at 60° C., and then cooled to 0° C. A solution of NaNO2 (0.76 g, 11 mmol) in 8 ml water was added to the reaction mixture rapidly (˜30 sec) with vigorous stirring keeping temperature below 0° C. The solution was stirred for an additional 2 minutes, and then added in one portion to the suspension of Cu2O (1.5 g), in aqueous CuSO4×5H2O (10 g in 220 ml) with vigorous stirring at 50° C. Reaction mixture was stirred 30 min. and cooled to room temperature. The reaction was repeated five times with the same scale (total 9.13 g of aniline was used), and all reaction mixtures were combined. Organic material was extracted twice with ether (400 ml). The solvent was evaporated, and the compound purified by silica gel chromatography. CombiFlash chromatography (Hexane/EtAc) was performed and final product distilled (105-110*C/˜3 mm) (4.1 g (45%). Optical rotation: α20D=−7.58° (c=5, pentane). 1H NMR (250 MHz, chloroform-d1) δ 0.84-0.90 (t. 3H), δ 1.21-1.26 (m. 11H), δ 2.85-2.89 (m. 1H), δ 3.11-3.16 (m. 1H), δ 4.74 (s, 1H), δ 6.87-6.90 (t, 1H) δ 6.987-7.05(m 2H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1.ClC1N=CN=C2C=1NC=N2.[OH:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1.C(N(C(C)C)C(C)C)C>C(O)CC>[OH:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)=[CH:29][CH:28]=1
Reactant: Clc1ncnc2c1ncn2C1CCCO1
Reactant: NCc1ccc(O)cc1
Agent: Clc1ncnc2nc[nH]c12
Solvent: CCCO
Solvent: CCN(C(C)C)C(C)C
Product: Oc1ccc(CNc2ncnc3c2ncn3C2CCCO2)cc1
Yield: 80 %

Procedure:
A mixture of 10 mmol (2240 mg) of 6-chloro-9-(tetrahydrofuran-2-yl)purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (1478 mg) of 4-hydroxybenzylamine, and 5 ml of N-ethyldiisopropylamine was refluxed in n-propanol for 3 hours. After removal of the n-propanol by vacuum evaporation, the resulting material was treated with water and extracted into ethyl acetate. The ethyl acetate phase was evaporated and the residuum subsequently washed with 30 ml of petroleum ether. The solid residue was filtered off and the crude product crystallized from methanol. Yield 80%, white solid. TLC (EtOAc:hexane (1:1 (v:v)): single spot; HPLC: purity>98%. 1H NMR (400 MHZ, DMSO): 1.36tt (2H, Ja=7.8 Hz, Jb=2.2 Hz); 2.23m (1H); 2.32m (1H); 3.62dd (1H, Ja=10.8 Hz, Jb=3.8 Hz); 3.87dd (1H, Ja=10.8 Hz, Jb=3.8 Hz); 4.62s (2H); 6.23dd (1H, Ja=5.3 Hz, Jb=1.5 Hz); 6.71 d (2H, J=8.3 Hz); 7.21 d (2H, J=8.3 Hz); 8.06bs (1H); 8.16s (1H); 8.28s (1H); 9.23s (1H). MS (ES): [M+H]+=312 (100).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19](F)=[C:20]([F:25])[CH:21]=2)[N:16]([CH2:27][CH3:28])[C:15]1=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:20]([F:25])[CH:21]=2)[N:16]([CH2:27][CH3:28])[C:15]1=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(F)cc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCCC3)cc21
Yield: 91.3 %

Procedure:
Pyrrolidine (0.06 mL, 0.72 mmol) was added to a solution of 3-benzyloxy-1-ethyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example C, 0.2 g, 0.6 mmol) and triethylamine (0.17 mL, 1.2 mmol) in 30 mL of acetonitrile. The solution was warmed to reflux for 3 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform, washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.21 g of the title compound as a solid, mp 174-176° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])C.[OH-].[K+]>O>[N:17]1([C:15]([C:8]2[N:9]3[C:10]([CH2:11][O:12][CH2:13][CH2:14]3)=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)=[O:16])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)c1cc(C(=O)N2CCCC2)n2c1COCC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(C(=O)N2CCCC2)n2c1COCC2
Yield: 88 %

Procedure:
A mixture of 6-(pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester (Comp. No. 6a) (0.95 g, 3.25 mmol) and potassium hydroxide (0.91 g, 16.3 mmol) in water (33 ml) was stirred at 100° C. until complete conversion according to LC/MS (ca. 1 h). Approximately half of the solvents were evaporated in vacuo and the mixture was acidified with excess hydrochloric acid. The forming precipitate was filtered off, washed once with water and dried in vacuo to give 0.76 g (88%) of 6-(pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid as white solid. LC/MS (method 4): Rt=0.92 min; m/z=265.17 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([N:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:7]2[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([N:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(N(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(N(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Reaction time: 18 h

Procedure:
4-chloro-N-(4-chlorophenyl)-N-(4-methoxyphenyl)aniline (68, 10.79 g, 31.3 mmol) was dissolved in anhydrous DCM (120 mL), and the BBr3 (1.0 M, 38 mL, 37.6 mmol) was added slowly over a period of −20 minutes. The reaction mixture was allowed to stir under an Argon atmosphere for 18 hours. The reaction mixture was slowly poured into water (500 mL) and stirred for 30 minutes. The purple organic layer was separated and the aqueous layer was extracted with DCM (100 mL). The combined organics were washed with water (500 mL), dried over MgSO4, filtered and solvent removed by rotary evaporation. Flash chromatography (15% EtOAc/hexanes) afforded 69 as a clear, light green viscous oil, 9.41 g (91%).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:22][C:23]1[N:24]=[C:25]([CH:28]=[CH:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([C:38]([F:41])([F:40])[F:39])=[O:37])=[CH:32][CH:31]=2)[O:26][CH:27]=1.O>CN(C=O)C>[F:41][C:38]([F:39])([F:40])[S:36]([C:33]1[CH:34]=[CH:35][C:30](/[CH:29]=[CH:28]/[C:25]2[O:26][CH:27]=[C:23]([CH2:22][O:20][C:17]3[CH:16]=[CH:15][C:14]([CH2:13][S:10]([CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)(=[O:12])=[O:11])=[CH:19][CH:18]=3)[N:24]=2)=[CH:31][CH:32]=1)=[O:37]
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Reactant: O=S(=O)(CCn1ccnn1)Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(c1ccc(/C=C/c2nc(COc3ccc(CS(=O)(=O)CCn4ccnn4)cc3)co2)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 3.9 %

Procedure:
13.0 mg (0.50 mmol) 95% sodium hydride were given to a solution of 134 mg (0.50 mmol) 4-(2-[1,2,3]triazol-1-yl-ethanesulfonylmethyl)-phenol in 4.0 ml DMF and stirred for 15 min. 168 mg (0.50 mmol) 4-Chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 10 ml water the resulting precipitate was purified by chromatography on silica gel (eluent: dichloromethane/acetone 20:1) to give 11 mg product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2)([O-:3])=[O:2].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[C:8]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Fc1ccccc1CBr
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1Cc1ccccc1F

Procedure:
The preparation is carried out as described for Example I using 940 mg (4.00 mmol) of ethyl 5-nitro-1H-indole-2-carboxylate and 780 mg (4.15 mmol) of 2-fluorobenzyl bromide, reaction time 6 h.
Reaction SMILES: C(OC(=O)C[N:6]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][C:9]=1[C:22](OCC)=[O:23])C.CC(C)([O-])C.[K+].[C:45]([O:48][CH2:49][CH3:50])(=[O:47])[CH3:46].[Cl-].[NH4+]>C1COCC1>[CH2:49]([O:48][C:45]([C:46]1[N:6]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[O:36][CH3:37])[CH2:7][C:8]2[C:9]([C:22]=1[OH:23])=[CH:10][CH:11]=[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:13]=2)=[O:47])[CH3:50]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1cc(OCc2ccccc2)ccc1C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(O)c2ccc(OCc3ccccc3)cc2CN1Cc1ccc(OC)cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 6.4 g (12.3 mmol) of N-(2,4-dimethoxy-benzyl),N-(5-benzyloxy-2-ethoxycarbonyl-benzyl)glycine ethyl ester in 140 mL of anhydrous THF was cooled in an ice bath. 24.6 mL of 1 N potassium tert-butoxide in THF was added slowly to the stirring cold solution. The reaction mixture was stirred at 0° C. for 1 hour and then allowed to warm to room temperature and stirred for 4 hours. The mixture was poured into a biphasic mixture of ethyl acetate and saturated aqueous ammonium chloride. The organic fraction was washed twice with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5.7 g of the title compound; MS (ESI+): 476.3 e/z (M+1)
Reaction SMILES: [NH3:1].[CH2:2]([CH:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10])[CH:3]=[CH2:4]>COCCOC>[OH:7][CH2:8][CH2:9][CH:5]([C:6]([NH2:1])=[O:10])[CH2:2][CH:3]=[CH2:4]
Reactant: N
Reactant: C=CCC1CCOC1=O
Solvent: COCCOC
Product: C=CCC(CCO)C(N)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
In an amount of 112 mg of 3-allyldihydrofuran-2-one (WO99/36419) was dissolved in 1 ml of 1,2-dimethoxyethane, added with 1.2 ml of 28% aqueous ammonia, and stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure to obtain 130 mg of 1-(2-hydroxyethyl)-3-butenecarboxamide. Physicochemical Properties of this Compound
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3C(=CC=C[CH:18]=3)C[C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(N[C@@H]2C[O:37]C[C@H]2O)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[CH2:12][O:20][CH2:18][C@H:19]2[OH:37])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(N[C@@H]2COC[C@H]2O)n1
Product: CCc1nc(N[C@@H]2COC[C@H]2O)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting trans-(+/−)-4-[(3,6-diethylpyrazin-2-yl)amino]tetrahydrofuran-3-ol and making non-critical variations provided the title compound as a light yellow solid. IR (diffuse reflectance) 3398, 2971, 2938, 1569, 1539, 1490, 1466, 1447, 1413, 1397, 1251, 1232, 1054, 969, 891 cm−1; OAMS supporting ions at: ESI+ 315.9 & ESI− 313.9; MS (EI) m/z 315 (M+); HRMS (FAB) calcd for C12H18BRN3O2+H1 316.0661, found 316.0656; Anal. Calcd for C12H18BrN3O2: C, 45.58; H, 5.74; N, 13.29. Found: C, 45.49; H, 5.84; N, 13.14.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12]([CH3:14])[C:11](=[O:15])[N:10]([CH2:16][C:17]2([CH2:20][OH:21])[CH2:19][CH2:18]2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)Cl.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>O>[CH3:33][S:34]([O:21][CH2:20][C:17]1([CH2:16][N:10]2[C:11](=[O:15])[C:12]([CH3:14])=[CH:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]2=[O:22])[CH2:18][CH2:19]1)(=[O:36])=[O:35]
Reactant: Cc1cn(Cc2ccccc2)c(=O)n(CC2(CO)CC2)c1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cn(Cc2ccccc2)c(=O)n(CC2(COS(C)(=O)=O)CC2)c1=O

Procedure:
A mixture of 1-(1-benzyl-5-methyl-2,4-dioxo-(1H,3H)-pyrimidin-3-ylmethyl)cycloprop-1-ylmethanol (1.95 g, 6.5 mmol), triethylamine (1.32 mL, 9.5 mmol) and methylene chloride (20 mL) was cooled to between 0° and 5° C. under argon and methanesulfonyl chloride (0.69 mL, 8.85 mmol) was added slowly. The mixture was stirred cooled 2 hours at 0° to 5° C., then diluted with water (20 mL) and extracted with methylene chloride. The extract was washed with 5% sodium bicarbonate, dried (MgSO4) and concentrated to give 1-(1-benzyl-5-methyl-2,4-dioxo-(1H,3H)-pyrimidin-3-ylmethyl)cycloprop-1-ylmethyl methanesulfonate.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][C:16]=3[CH3:23])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][C:16]=3[CH3:23])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]
Reactant: COCc1cc(-c2nc(-c3ccc(CO)cc3C)no2)ccc1-c1ccccc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: COCc1cc(-c2nc(-c3ccc(C=O)cc3C)no2)ccc1-c1ccccc1C
Temperature: 70 °C
Yield: 90.6 %

Procedure:
(4-(5-(2-(methoxymethyl)-2′-methylbiphenyl-4-yl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)methanol (401 mg, 1.0 mmol) was dissolved in dioxane (10 mL) and manganese dioxide (1.0 g, 11.6 mmol) was added. The mixture was heated at 70° C. overnight and then the solvent was removed in vacuo. The residue was triturated with a mixture of petrol and diethyl ether to give the title compound as a white solid (361 mg, 90%). 1H NMR (CDCl3, 400 MHz) δ 10.10 (1H, s), 8.45 (1H, s), 8.33 (1H, d, J=8.3 Hz), 8.19 (1H, dd, J=7.8, 1.9 Hz), 7.87 (2H, d, J=6.9 Hz), 7.38-7.24 (4H, m), 7.14 (1H, d, J=7.4 Hz), 4.24-4.21 (2H, m), 3.34 (3H, s), 2.81 (3H, s), 2.09 (3H, s).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][N:14]=1)[C:9](O)=O)[CH2:2][CH2:3][CH3:4].S(O)(O)(=O)=O.[NH2:20][NH:21][C:22]([NH2:24])=[NH:23].[OH-].[Na+]>O>[NH2:24][C:22]1[N:23]=[C:9]([C:8]2[CH:12]=[CH:13][N:14]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=2)[NH:20][N:21]=1
Reactant: CCCCNc1cc(C(=O)O)ccn1
Reactant: N=C(N)NN
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCNc1cc(-c2nc(N)n[nH]2)ccn1
Temperature: 200 °C
Yield: 18.6 %

Procedure:
A mixture consisting of 2.5 g. (0.0108 mole) of 2-[N-mono(n-butyl)-amino]isonicotinic acid and 2.7 g. (0.0219 mole) of aminoguanidine sulfate was placed in a suitable reaction flask and heated at 200° C. for a period of three hours while under a nitrogen atmosphere. The melt was then cooled to room temperature (~25° C.), diluted with water and the pH of the resulting mixture adjusted to pH 8.0 with 1 N aqueous sodium hydroxide. The basified aqueous mixture was next filtered and the clear aqueous filtrate so obtained was subsequently concentrated in vacuo to afford a brown oil, which was thereafter triturated with methanol. After removal of the resultant solid by means of suction filtration, ethyl acetate was added to the filtrate and the latter solution was subsequently concentrated on a steam bath, followed by cooling to room temperature. In this way, there were ultimately isolated 1.04 g. of crude product (m.p. 218°-220° C.) in the form of a beige-colored precipitate. Recrystallization of the latter material from ethyl acetate/methanol then gave 467 mg (18%) of pure 3-amino-5-{2-[N-mono(n-butyl)amino]-4-pyridyl}-1,2,4-triazole, m.p. 268°-270° C. The final product was subsequently characterized by means of nuclear magnetic resonance data.
Reaction SMILES: [O:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(OC2CCNCC2)cc1
Reactant: Fc1ccc(OCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(OCCCN2CCC(Oc3ccccc3)CC2)cc1

Procedure:
A mixture of 4-phenoxypyridine and benzylbromide in acetone was stirred overnight at room temperature. After removal of the solvent, the residue was dissolved in methanol, cooled to -20° C. and treated portionwise with sodium borohydride, and warmed to 0° C. After a standard workup and purification, the resulting tetrahydropyridine adduct was dissolved in methanol and hydrogenated using 20% Pd-C as a catalyst to provide 4-phenoxypiperidine. A mixture of 4-phenoxypiperidine and 1-bromo-3-(4-fluorophenoxy)propane in acetone with excess potassium carbonate was heated at reflux for 12 hours to give the title compound.
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[C:8]([O:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[C:6]=2[CH:7]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[C:8]([O:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[C:6]=2[CH:7]=1
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(C=O)oc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(CO)oc2c1

Procedure:
To a solution of ethyl 2-formyl-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxylate (285b) (230 mg, 0.592 mmol) in MeOH (10 mL) was added NaBH4 (50 mg, 1.3 mmol). The mixture was stirred for half an hour. The solvent was evaporated, and the product was purified by gradient silica gel chromatography using CHCl3/MeOH (100/0 to 98/2). The desired compound was isolated as a white solid (170 mg, 74%). 1 H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.40 (t, J=7.16 Hz, 3 H) 1.99 (t, J=6.22 Hz, 1 H) 3.06 (s, 3 H) 4.39 (q, J=7.16 Hz, 2 H) 4.78 (d, J=6.22 Hz, 2 H) 6.52 (d, J=1.13 Hz, 1 H) 7.00-7.17 (m, 2 H) 7.64 (d, J=1.13 Hz, 1 H) 7.87-7.97 (m, 2 H) 8.06 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][C:9]1=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][CH:9]1[OH:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(O)CC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 3.00 g of 136 (6.61 mmol) in 15 ml of anhydrous CH2Cl2 was cooled to −78° C. in an annealed three-necked flask equipped with a dropping funnel and added dropwise with 12.5 ml of DIBAL-H (12.5 mmol, 2.2 eq., 1 M/hexane). After stirring for two hours at −78° C., the reaction was terminated by adding 1 ml of isopropanol, added with 20 ml of K—Na tartrate solution (1.77 M) and slowly thawed to room temperature. After separating the two phases, the aqueous phase was additionally extracted with 3×50 ml of MTBE, and the combined organic phases were dried over MgSO4. After filtration over a short silica gel column (eluted with EE/CH 1:3), the filtrate was concentrated to obtain 204 as a slightly yellowish oil which was further reacted without purification. Yield: 2.92 g (6.41 mmol, 97%).