Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][C:11]([CH3:22])=[CH:12][CH2:13][CH:14]=[C:15]([CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[H][H]>S([O-])([O-])(=O)=O.[Ba+2].[Pd+2].S([O-])([O-])(=O)=O.N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH:9][CH2:10][C:11]([CH3:22])=[CH:12][CH2:13][CH:14]=[C:15]([CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: [H][H]
Reactant: CCCCCC(C)=CCC=C(C)CC#CCCCCCCCl
Agent: [Pd+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: c1ccncc1
Product: CCCCCC(C)=CCC=C(C)CC=CCCCCCCCl

Procedure:
A mixture of 5.0 g. of 1-chloro-10,14-dimethylnonadeca-10,13-dien-7-yne 500 mg. of 5% palladium-barium sulfate catalyst and 40 ml. of pyridine is shaken under hydrogen for about 2 hrs. (until the uptake of hydrogen practically ceases). The mixture is then filtered, diluted with water, and extracted with ether. The ether extract is washed with water, dilute hydrochloric acid, and aqueous sodium bicarbonate, then is dried over sodium sulfate and evaporated to leave a residue comprising 1-chloro-10,14-dimethylnonadeca-7,10,13-triene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18](S(C)(=O)=O)[N:17]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.[NH2:26][CH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30].C(N(C(C)C)CC)(C)C>CS(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:26][CH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30])[N:17]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1
Reactant: CC(C)(CN)CO
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)nc3occn23)n1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO)CNc1nccc(-c2c(-c3ccc(F)cc3)nc3occn23)n1
Temperature: 100 °C
Yield: 86.1 %

Procedure:
To a solution of 6-(4-fluorophenyl)-5-[2-(methylsulfonyl)pyrimidin-4-yl]imidazo[2,1-b][1,3]oxazole (F) (0.5 g, 1.4 mmol) in dimethylsulfoxide is added 3-amino-2,2-dimethyl propanol (0.430 mg, 3.8 mmol) followed by the addition of diisopropylethylamine (0.631 g, 5.0 mmol). The mixture is heated at 100° C. overnight. After cooling to room temperature the reaction is diluted with water and extracted with dichloromethane (2×50 ml). The combined organic phase is dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. The residue is purified by silica gel column chromatography eluting with ethyl acetate/hexane (3:1) to provide 3-({4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)-2,2-dimethylpropan-1-ol (G) (0.46 g, 86%), m.p. 149° C.;
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]2[NH:7][C:8]3[C:9]([N:16]=2)=[N:10][C:11]([CH3:15])=[CH:12][C:13]=3[CH3:14])[CH2:5][CH2:4]1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][N:19]=1>CS(C)=O.O>[CH:3]1([C:6]2[N:16]([CH2:24][C:21]3[CH:20]=[N:19][C:18]([Br:17])=[CH:23][CH:22]=3)[C:9]3=[N:10][C:11]([CH3:15])=[CH:12][C:13]([CH3:14])=[C:8]3[N:7]=2)[CH2:5][CH2:4]1
Reactant: BrCc1ccc(Br)nc1
Reactant: Cc1cc(C)c2[nH]c(C3CC3)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C)c2nc(C3CC3)n(Cc3ccc(Br)nc3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
255 mg (6.4 mmol) of sodium hydride and 994 mg (5.3 mmol) of 2-cyclopropyl-5,7-dimethylimidazo[4,5-b]pyridine are stirred at 0° C. for 2 h in 15 ml of dimethyl sulphoxide. After adding 2 g (7.97 mmol) of 2-bromo-5-bromomethylpyridine, the mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and washed twice with ethyl acetate; the combined organic phases are washed with water and sodium chloride solution, dried over sodium sulphate and then chromatographed on 150 g of silica gel using ethyl acetate/petroleum ether mixtures 1:2→1:0 to yield 1.32 g of the title compound.
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[C@@:8]2([CH3:24])[CH2:9][CH2:10][C@@H:11]3[C@:21]4([CH2:22][OH:23])[C:15](=[CH:16][C:17]([CH2:19][CH2:20]4)=[O:18])[CH2:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].[C:25](OC(=O)C)(=[O:27])[CH3:26].CO>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:25]([O:23][CH2:22][C@@:21]12[C@@H:11]3[C@H:12]([C@H:7]4[C@:8]([CH3:24])([CH2:9][CH2:10]3)[C@@H:4]([C:2](=[O:3])[CH3:1])[CH2:5][CH2:6]4)[CH2:13][CH2:14][C:15]1=[CH:16][C:17](=[O:18])[CH2:19][CH2:20]2)(=[O:27])[CH3:26]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(CO)[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3.5 g of 19-hydroxyprogesterone and 0.25 g of 4-dimethylaminopyridine in 8 ml of pyridine is treated with 4 ml of acetic anhydride and stirred for 18 hours at room temperature. The solution is chilled to 0° C. and treated with 4 ml of methanol to consume excess acetic anhydride. After stirring for 15 minutes, the solution is concentrated to a small volume at reduced pressure and the residue is taken up in ether. The ether solution is washed three times with dilute hydrochloric acid, once with sodium bicarbonate solution and finally with brine. Drying and concentration gives 19-acetoxypregn-4-ene-3,20-dione which is obtained as a colorless solid upon crystallization from aqueous ethanol.
Reaction SMILES: [CH3:1][C@@H:2]1[N:5]([P:6](=[O:11])([O-:10])[O:7][CH2:8][CH3:9])[C:4](=[O:12])[C@H:3]1[NH:13]C(OC(C)(C)C)=O.[K].[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>C1(OC)C=CC=CC=1.C1(C)C=CC=CC=1>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:13][C@H:3]1[C@H:2]([CH3:1])[N:5]([P:6](=[O:10])([OH:11])[O:7][CH2:8][CH3:9])[C:4]1=[O:12]
Reactant: CCOP(=O)([O-])N1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1C
Agent: [K]
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(O)N1C(=O)[C@@H](N)[C@@H]1C
Temperature: -24 °C
Reaction time: 3 h

Procedure:
A suspension of (3S-trans)-[4-methyl-2-oxo-3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-azetidinyl]phosphonic acid, ethyl ester, potassium salt (500 mg) in anisole (5 ml) was cooled to -24° C. in an ice-methanol bath, and trifluoroacetic acid (10 ml) was added. The mixture was stirred at -24° C. to -12° C. for 3 hours, diluted with dry toluene (25 ml), and solvent was removed in vacuo at or below 19° C. The residual oil was solidified and triturated several times with ether giving 815 mg of the title compound as a powder.
Reaction SMILES: [OH-].[Na+].O.[CH3:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]Cl.[CH:13](=[O:17])[CH:14]([CH3:16])[CH3:15]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.C1(C)C=CC=CC=1>[CH3:15][C:14]([CH3:16])([CH2:8][C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([CH3:4])[CH:6]=1)[CH:13]=[O:17]
Reactant: CC(C)C=O
Reactant: Cc1cccc(CCl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(CC(C)(C)C=O)c1
Temperature: 70 °C

Procedure:
A pre-mix of 23.3 g of NaOH, 2.5 g of tetrabutylammonium iodide, 107 ml of water, 25 ml of toluene and 9 ml of tetrahydrofuran under argon was heated to 70° C. A mixture of 70 g (0.5 moles) of 3-methylbenzyl chloride and 50.4 g (0.7 moles) of isobutyraldehyde was added dropwise to this pre-mix within a period of 2 hours while stirring vigorously. The reaction mixture was then maintained at a temperature of 75° C. for 3 hours. After separating the phases and removing the solvents, 66.5 g of end product were obtained by fractional distillation at 0.12 mbar in a temperature range of from 50° C. to 52° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]([N+:35]([O-:37])=[O:36])([CH3:34])[CH2:32]O.[K+].[Br-].Cl>>[CH3:30][C:31]([N+:35]([O-:37])=[O:36])([CH3:34])[CH2:32][O:24][C:23]([C:18]1([C:20]([O:22][CH2:30][C:31]([CH3:34])([N+:35]([O-:37])=[O:36])[CH3:32])=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25]
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: CC(C)(CO)[N+](=O)[O-]
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC(C)(C)[N+](=O)[O-])(C(=O)OCC(C)(C)[N+](=O)[O-])O2)NC[C@H](O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-methyl-2-nitropropanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d6,400 MHz) δ 0.78 (s, 12H, 4×CH3), 0.8-1.0 (m, 4H, CH2), 1-1.2 (m, 11H, cyclohexyl, CH3), 1.5-1.65 (m, 10 H, cyclohexyl), 2.6 (m, 1H, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, 1H, CH), 4.04 (s, 4H, OCH2, OCH2), 5.05 (m, 1H, CH), 6.35 (d, J=4.17 Hz, 1H, OH), 6.83 (dd, J=7.9, 1.32 Hz, 1H, Ar--H), 7.06 (s 1H, Ar--H), 7.09 (d, J=8.35 Hz), 7.38-7.42 (m, 3H, Ar--H), 7.5 (s, 1H, Ar--H), 8.8 (brs, 1H, NH), 9.4 (brs, 1H, NH); IR (KBr, cm-1) 3400 (OH), 2900 (NH), 1760 (CO); Analysis for: C28H34ClN3O11 ×HCl: Calc'd: C, 50.92; H, 5.34; N, 6.36; Found: C, 50.72; H, 5.42; N, 5.96.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:9]>[O-2].[Cr+3].[Cu+2]>[C:1]([NH2:8])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: N#Cc1ccccc1
Agent: [Cr+3]
Agent: [Cu+2]
Agent: [O-2]
Product: NC(=O)c1ccccc1
Yield: 20 %

Procedure:
Watanabe et al., in Bull. Chem. Soc. Japan, 39, 8 (1966) also show the use of a copper chromium oxide catalyst, Cu--CrO2, to convert benzonitrile to benazmide. Although the preparation is not disclosed, Watanabe's catalyst apparently was not prepared according to the present invention since benzonitrile in water reacted in the presence of the catalyst for 8 hours gave only a 20% yield of benzamide.
Reaction SMILES: [C:1]([O:11]CC(N)CC)(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]>O>[C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: CCC(N)COC(=O)[C@H](O)c1ccccc1
Solvent: O
Product: O=C(O)[C@H](O)c1ccccc1
Temperature: -5 °C
Yield: 72.6 %

Procedure:
A portion of the (-)-2-amino-1-butanol D-(-)-mandelate wet cake (155 grams "as is"--90.3% pure; 0.58 mole) from resolution A is dissolved in water (125 mls) at 50°-55° C. and the resulting solution is distilled under vacuum to remove 48.5 mls of methanol and water. The concentrated solution is treated with 37% hydrochloric acid (60 mls) and the acidified solution is cooled to -5° C. over about 5 hours to crystallize D-(-)-mandelic acid from the solution. The crystals are isolated by filtration, washed twice with ice cold (0°-5° C.) water (20 mls), twice with hexane (20 mls), and dried at 60° C. to obtain 64.1 grams of D-(-)-mandelic acid (72.6% of theoretical; m.p. 131°-133° C.; [α]D25 =-154.1° (C=2. H2O)).
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:12][C:13]1[C:18]2[N:19]=[C:20]([C:22]3[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=3)[O:21][C:17]=2[CH:16]=[CH:15][CH:14]=1>C(O)(C(F)(F)F)=O>[NH2:28][C:23]1[C:22]([C:20]2[O:21][C:17]3[C:18](=[C:13]([OH:12])[CH:14]=[CH:15][CH:16]=3)[N:19]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: COc1ccc(COc2cccc3oc(-c4cccnc4N)nc23)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncccc1-c1nc2c(O)cccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
TFA (10 ml) was added to 3-[4-[(2,4-dimethoxyphenyl)methoxy]-1,3-benzoxazol-2-yl]pyridin-2-amine (1.4 g). The resulting solution was stirred at 25° C. for 2 hours. The TFA was evaporated under reduced pressure. Toluene was added and the mixture was evaporated. The solid was triturated with water. The pH was adjusted to 7 with a 30% solution of ammonia. The solid was filtered and washed with water, diethyl ether and dried under reduced pressure to afford 2-(2-amino-3-pyridyl)-1,3-benzoxazol-4-ol (617 mg) as a solid. NMR Spectrum: (DMSOd6): 6.74-6.83 (m, 2H), 7.18 (d, 1H), 7.23 (dd, 1H), 7.84 (bs, 2H), 8.20 (d, 1H), 8.26 (d, 1H), 10.43 (s, 1H); Mass spectrum: M+H+ 228
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][OH:6])[CH3:2].[H-].[Na+].[N:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:22]=3[NH:23][N:24]=2)=[CH:16][CH:15]=1)=[C:12]=[O:13]>C1COCC1>[NH:23]1[C:22]2[C:25]3[C:30]([CH2:31][C:21]=2[C:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:11][C:12](=[O:13])[O:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[CH:19][CH:18]=2)=[N:24]1)=[CH:29][CH:28]=[CH:27][CH:26]=3
Reactant: O=C=Nc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Reactant: CCN(CC)CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCOC(=O)Nc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of N,N-diethyl ethanol amine (0.368 mL, 2.75 mmol) in THF (5 mL) was added NaH (60% in mineral oil, 113 mg, 2.75 mmol). The reaction mixture was stirred at about 20° C., for about 1 hour then solid 3-(4-isocyanatophenyl)-1,4-dihydroindeno[1,2-c]pyrazole, 2 (58 mg, 0.22 mmol) was added. The reaction mixture was heated to about 45° C., for about 3 hours. The reaction mixture was quenched by addition of H2O and the product was extracted into EtOAc. The crude material was purified by flash chromatography on SiO2 (MeOH/CH2Cl2, 10/90) to give 51 mg (62%) of pure product. LC/MS 391 (M+1); LC retention time 2.68 minutes.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[Cl:7][C:8]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]>>[Cl:7][C:8]1[CH:15]=[C:14]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: OCCCCO
Reactant: N#Cc1ccc(F)cc1Cl
Product: N#Cc1ccc(OCCCCO)cc1Cl
Yield: 4.4 %

Procedure:
Following the procedure described for Example 29, 1,4-butanediol (1 mL, 10 mmol) was reacted with 2-chloro-4-fluoro-benzonitrile (159 mg, 1.0 mmol) for 24 hours at room temperature. Purification by reverse phase high pressure chromatography eluting with a solvent gradient (15% of 0.1% formic acid/CH3CN in 0.1% formic acid/water to 100% of 0.1% formic acid/water) provided 10 mg of 2-chloro-4-(4-hydroxy-butoxy)-benzonitrile. 1H NMR (CDCl3) δ 7.54 (d, 1H), 6.98 (d, 1H), 6.83 (dd, 1H), 4.03 (t, 2H), 3.71 (t, 2H), 1.90 (m, 2H), 1.72 (m, 2H); MS 226.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:17]([O:19][C:20](=[O:43])[C@H:21]([NH:26][C:27](=[O:42])[C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][CH:37]([CH:40]=O)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1)[CH2:22][CH:23]([CH3:25])[CH3:24])[CH3:18].C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C1COCC1>[CH2:17]([O:19][C:20](=[O:43])[C@@H:21]([NH:26][C:27](=[O:42])[C:28]1[CH:29]=[CH:30][C:31]([N:34]2[CH2:35][CH2:36][CH:37]([CH2:40][NH:1][CH2:2][C@H:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:38][CH2:39]2)=[CH:32][CH:33]=1)[CH2:22][CH:23]([CH3:25])[CH3:24])[CH3:18]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCOC(=O)[C@@H](CC(C)C)NC(=O)c1ccc(N2CCC(C=O)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CCC(CNC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
A solution of N-[5-(2-amino-1-{R}-hydroxyethyl)-2-hydroxyphenyl]-methane-sulfonamide (0.098 g, 0.4 mmol), (2R)-2-{[4-(4-(formyl)piperidin-1-yl)benzoyl]amino}4-methylpentanoic acid ethyl ester (0.4 mmol) and glacial acetic acid (0.023 g, 0.4 mmol) in 5 mL of methanol-THF (4:1, v/v) was stirred for 1 hour over 4A molecular sieves. In one portion sodium cyanoborohydride (0.026 g, 0.4 mmol) was added and the mixture stirred overnight at ambient temperature. The sieves were filtered and the filtrate was preabsorbed on silica gel. The solids were purified by flash chromatography (CH2Cl2—CH3OH, 20:1). to give the product (0.072 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N+:27]([C:30]1[O:34][C:33]([CH:35]=O)=[CH:32][CH:31]=1)([O-:29])=[O:28]>CC(O)=O.CO>[CH2:20]([N:16]1[N:15]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2](/[N:1]=[CH:35]/[C:33]4[O:34][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=4)=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)[O:18][C:17]1=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccc(N2CCC(c3nn(Cc4ccccc4)c(=O)o3)CC2)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Solvent: CC(=O)O
Solvent: CO
Product: O=c1oc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3)CC2)nn1Cc1ccccc1
Yield: 88 %

Procedure:
5-[1-(4-Aminophenyl)-4-piperidyl]-3-benzyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7d, 0.35 g, 1 mmol) on reacting with 5-nitro2-furaldehyde in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 10 h and the obtained solid is filtered, washed with water and recrystallized in ethanol to obtain product 3-benzyl-5-[1-(4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9d, 416 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.C(O)(C(F)(F)F)=[O:10]>OO.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:10]
Reactant: O=C(O)C(F)(F)F
Reactant: Clc1cccc(Cl)n1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Product: [O-][n+]1c(Cl)cccc1Cl
Temperature: 95 °C
Reaction time: 7 h
Yield: 80 %

Procedure:
A mixture of 2,6-dichloropyridine (2 g, 13.6 mmol) in TFA (6 mL) and 30% H2O2 (2.5 mL) was prepared at 0° C., after which the mixture was heated to reflux at 90-100° C. After 7 hour at this temperature, the mixture was cooled to room temperature and neutralized with IN NaOH solution to pH 8-9. The aqueous layer was extracted with petroleum ether (200 mL×3) and the organic layer was dried over sodium sulfate, filtered, and concentrated to dryness under vacuum. The residue was purified by column chromatography over 100-200 mesh silica gel, eluting with 20:80 acetone: hexanes, to afford the pure compound as a colorless solid (1.75 g, yield 80%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:14]=2)=[CH:5][C:4]=1[N:28]=[CH:29][N:30](C)C)#[N:2].[CH:33]1(N)[CH2:35][CH2:34]1.CCCCCC.ClCCl.CO>CO>[CH:33]1([NH:2][C:1]2[C:3]3[C:4](=[CH:5][C:6]([O:11][CH2:12][C:13]4[CH:14]=[C:15]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:16]=[CH:17][CH:18]=4)=[C:7]([O:9][CH3:10])[CH:8]=3)[N:28]=[CH:29][N:30]=2)[CH2:35][CH2:34]1
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)c1
Reactant: NC1CC1
Solvent: CCCCCC
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(NC4CC4)c3cc2OC)c1
Yield: 68 %

Procedure:
According to GWP 5, reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (72 mg, 0.16 mmol) with cyclopropylamine (13 μL, 0.19 mmol) and chromatographic purification (silica gel, amino column, hexane, dichloromethane/methanol: 0→5% methanol) gives the desired product in 68% yield (50 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][NH2:10].CO.C(Cl)Cl>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][NH2:10])[CH:5]=[CH:4][N:3]=1
Reactant: NN
Reactant: Clc1ccnc(Cl)n1
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: NNc1ccnc(Cl)n1
Yield: 94.8 %

Procedure:
A solution of 2,4-dichloropyrimidine (2.0 g) in EtOH (25 mL) was cooled to 0-20° C. and treated with hydrazine (2.8 mL). The progress of the reaction was followed by TLC using 10% MeOH:CH2Cl2 as mobile phase and visualizing under UV light. The mixture was concentrated under reduced pressure to afford 3.1 g of crude 2-chloro-4-hydrazinyl-pyrimidine (yield=94.8%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][C:3]=1[C:7]([NH2:9])=[O:8].[H-].[Na+].[C:12]1([C:22]([C:24]2[C:31]([Cl:32])=[CH:30][C:27]([CH2:28]Br)=[CH:26][C:25]=2[Cl:33])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.C(O)(=O)C>CN(C)C=O.O>[NH2:1][C:2]1[N:6]([CH2:28][C:27]2[CH:26]=[C:25]([Cl:33])[C:24]([C:22]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)=[O:23])=[C:31]([Cl:32])[CH:30]=2)[N:5]=[N:4][C:3]=1[C:7]([NH2:9])=[O:8]
Reactant: O=C(c1c(Cl)cc(CBr)cc1Cl)c1cccc2ccccc12
Reactant: NC(=O)c1nn[nH]c1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)c1nnn(Cc2cc(Cl)c(C(=O)c3cccc4ccccc34)c(Cl)c2)c1N
Temperature: 45 °C
Reaction time: 0.75 h
Yield: 33.3 %

Procedure:
A solution of 5-amino-l,2,3-triazole-4-carboxamide (364 mg, 2.86 mmol) in 5 ml of dry dimethylformamide was treated with 50 % sodium hydride dispersion in mineral oil (137 mg, 2.86 mmol). The reaction mixture was warmed to 45° C. and then stirred for 45 minutes. A solution of 4-(1-naphthoyl)-3,5-dichlorobenzyl bromide (0.98 g, 2.49 mmol) in 5 ml of dry dimethylformamide was added. The reaction mixture was heated at 45° C. for an additional 20 minutes and then stirred at ambient temperatures for 1 hour. The mixture was slowly added to 100 ml of water containing two drops of glacial acetic acid. The precipitate was collected by filtration and thoroughly washed with water. The solid was dissolved in methylene chloride and washed with brine and dried with anhydrous sodium sulfate. Evaporation of the solvent afforded 1.11 g of crude product which was purified by column chromatography on silica gel (3g methanol in methylene chloride) to give 0.365 g of 5-Amino-1-[4-(l-naphthoyl)-3,5-dichlorobenzyl]1,2,3-triazole-4-carboxamide and 0.46 g of an isomer of undefined regiochemistry.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:32])=[N:5]1)([CH3:3])[CH3:2].[C:33]([O:37][C:38]([N:40]1[CH2:45][C:44](OS(C(F)(F)F)(=O)=O)=[CH:43][CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:33]([O:37][C:38]([N:40]1[CH2:41][C:42]([C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:18]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[C:6]([CH3:32])[N:7]=5)[S:10][C:11]=4[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)=[CH:43][CH2:44][CH2:45]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC=C(OS(=O)(=O)C(F)(F)F)C1
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(B4OC(C)(C)C(C)(C)O4)ccc2-3)n(C(C)C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(C4=CCCN(C(=O)OC(C)(C)C)C4)ccc2-3)n(C(C)C)n1
Temperature: 80 °C
Yield: 78.3 %

Procedure:
2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.496 g, 0.00110 mol), 5-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.550 g, 0.996 mmol) and sodium carbonate (0.317 g, 0.00299 mol) were dissolved in 1,2-dimethoxyethane (5.6 mL) and water (3.1 mL). The reaction was thoroughly degassed with N2. Tetrakis(triphenylphosphine)palladium(0) (0.115 g, 0.0000996 mol) was added and the reaction was heated to 80° C. for 3 hours. Water and dichloromethane were added and the mixture was extracted 3 times with dichloromethane. The organic layers were combined, dried with MgSO4 and concentrated. The crude was purified by flash chromatography to afford 5-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a yellow solid (396 mg). MS(ESI+) 508.2