Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:13]([CH2:23]O)=[C:12]2[CH2:25][CH2:26][CH2:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[C:41]1(=[O:51])[NH:45][C:44](=[O:46])[C:43]2=[CH:47][CH:48]=[CH:49][CH:50]=[C:42]12.[K]>O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:13]([CH2:23][N:45]1[C:41](=[O:51])[C:42]3[C:43](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:44]1=[O:46])=[C:12]2[CH2:25][CH2:26][CH2:27][CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCc1c(CO)c(CC(C)C)nc2ccc(OCc3ccccc3)cc12
Agent: CS(=O)(=O)Cl
Agent: [K]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCc1c(CN2C(=O)c3ccccc3C2=O)c(CC(C)C)nc2ccc(OCc3ccccc3)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of [6-(benzyloxy)-4-butyl-2-isobutylquinolin-3-yl]methanol (1.43 g, 3.8 mmol) in tetrahydrofuran (20 ml) were added triethylamine (0.64 ml, 4.6 mmol) and methanesulfonyl chloride (0.36 ml, 4.6 mmol) and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in N,N-dimethylformamide (30 ml). Potassium phthalimide (1.41 g, 7.6 mmol) was added, and the mixture was stirred at room temperature for 6 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give 2-{[6-(benzyloxy)-4-butyl-2-isobutylquinolin-3-yl]methyl}-1H-isoindole-1,3(2H)-dione (1.81 g, yield 94%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[C:10]([CH:20]=[N:21][O:22][CH3:23])=[CH:9]2.[N:29]([Si](C)(C)C)=[N+:30]=[N-:31].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:23][O:22][N:21]=[CH:20][C:10]1[N:11]([CH2:15][CH2:16][CH2:17][C:18]2[NH:31][N:30]=[N:29][N:19]=2)[C:12]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH2:4][C:3]1[C:24]([Cl:28])=[CH:25][CH:26]=[CH:27][C:2]=1[Cl:1])=[CH:14][CH:13]=2
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CON=Cc1cc2cc(OCc3c(Cl)cccc3Cl)ccc2n1CCCC#N
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CON=Cc1cc2cc(OCc3c(Cl)cccc3Cl)ccc2n1CCCc1nnn[nH]1
Yield: 57.6 %

Procedure:
To a solution of 4-[5-(2,6-dichlorobenzyloxy)-2-(methoxyiminomethyl)indol-1-yl]butyronitrile (0.07 g, 0.17 mmol) in toluene (3 mL) was added azidotrimethylsilane (0.067 mL, 0.55 mmol) and dibutyltin oxide (0.014 g, 0.055 mmol). The reaction was refluxed for 16 h. The solvent was removed under reduced pressure and the crude product was purified by HPLC to yield a yellow foaming solid (0.045 g, 58%). MS(ES) m/e 459.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[C:21](F)[CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:16][C:17]1[CH:22]=[C:21]([N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:11]=[C:12]2[CH3:15])[CH:20]=[CH:19][N:18]=1
Reactant: Fc1ccnc(Cl)c1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ccnc(Cl)c1
Temperature: 100 °C
Yield: 87.6 %

Procedure:
To a solution of 400 mg (1.85 mmol) of 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 1.12 ml (1.46 g, 11.1 mmol) of 2-chloro-4-fluoropyridine in 5 ml of DMF were added 1.2 g (3.69 mmol) of cesium carbonate. The mixture was heated to 100° C. for 4 h, allowed to cool and concentrated in vaccuo. The residue was taken up in 20 ml ethyl acetate and the organic phase was washed twice with 20 ml of water and dried over magnesium sulfate. After treatment with charcoal, the solution was filtered and concentrated to yield 531 mg (1.62 mmol, 88%) of the title compound as an off-white crystalline solid, MS: m/e=328.1, 330.1 (M+H+).
Reaction SMILES: C[N:2](C)[CH:3]=[N:4][C:5]([C:7]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][C:10](=[O:20])[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:8]=1)=O.O=C1[N:34](C2C=CC=CC=2)C=C(C(N)=O)C(OC2C=CC=CC=2)=C1.COC(OC)N(C)C>>[O:13]([C:12]1[C:7]([C:5]2[N:4]=[CH:3][NH:2][N:34]=2)=[CH:8][N:9]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:10](=[O:20])[CH:11]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(=O)c1cn(-c2ccccc2)c(=O)cc1Oc1ccccc1
Reactant: CN(C)C=NC(=O)c1cn(-c2ccccc2)c(=O)cc1Oc1ccccc1
Agent: COC(OC)N(C)C
Product: O=c1cc(Oc2ccccc2)c(-c2nc[nH]n2)cn1-c1ccccc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
Preparation of N,N-dimethyl-N′-[(6-oxo-4-phenoxy-1-phenyl-1,6-dihydropyridin-3-yl)carbonyl]formamidine: A mixture of 6-oxo-4-phenoxy-1-phenyl-1,6-dihydropyridine-3-carboxamide (195 mg, 0.64 mmol) and N,N-dimethylformamide dimethyl acetal (270 mg, 2.3 mmol) was stirred at 120° C. for 90 min. Then the mixture was cooled down to room temperature and evaporated in vacuo. The residue was crystallized on treatment with Et2O (15 mL). The solid product was filtered and washed with Et2O (2×10 mL) to yield the title compound as beige crystals (190 mg, 82%).
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([F:18])=[C:6]([CH:14]=[CH:15][C:16]=1[F:17])[O:7][CH2:8][CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[O:3].C([O-])([O-])=O.[K+].[K+].[CH2:25](Br)[CH2:26][CH2:27][CH3:28]>CN(C=O)C.O>[NH2:1][C:2]([C:4]1[C:5]([F:18])=[C:6]([CH:14]=[CH:15][C:16]=1[F:17])[O:7][CH2:8][CH:9]=[CH:10][C:11]([O:13][CH2:25][CH2:26][CH2:27][CH3:28])=[O:12])=[O:3]
Reactant: NC(=O)c1c(F)ccc(OCC=CC(=O)O)c1F
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)C=CCOc1ccc(F)c(C(N)=O)c1F
Temperature: 50 °C
Yield: 57 %

Procedure:
4-[3-(Aminocarbonyl)-2,4-difluorophenoxy]-2-butenoic acid, mixture of isomers (3:2) E:Z, (526 mg, 2 mmol, 1 equiv.) was dissolved in dry DMF (5 ml). K2CO3 (850 mg, 6 mmol, 3 equiv.) and n-butylbromide (0.23 ml, 2.1 mmol, 1.05 equiv.) were added and the reaction mixture was heated for 70 h at 50° C. and for 1.5 h at r.t. After cooling at r.t., the mixture was diluted with H2O (50 ml) and extracted with EtOAc (3×40 ml). The combined organic extracts were washed with H2O (6×30 ml), dried (MgSO4) and evaporated to dryness under reduced pressure. The oily residue was purified by column chromatography on silica, eluted with CH2Cl2 and MeOH/CH2Cl2 (1%), to give 364 mg, 57% yield, mp<40° C. HPLC-MS (method 1): m/z 314 [M+H]+, Rt=3.88 min. By 1H-NMR analysis it was determined to be a mixture of isomers in a ratio (5:7) E:Z. When the same reaction was performed on the acid (3:40) E:Z mixture of isomers, the product obtained was determined to be a mixture of isomers in a ratio (1:4) E:Z.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]([CH:14]1[CH2:19][CH2:18][N:17]([CH:20]2[CH2:25][CH2:24][N:23](CC3C=CC=CC=3)[CH2:22][CH2:21]2)[CH2:16][CH2:15]1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:2].[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]([CH:14]1[CH2:19][CH2:18][N:17]([CH:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)[CH2:16][CH2:15]1)[C:7]([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CN(C(=O)OC(C)(C)C)C1CCN(C2CCN(Cc3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CN(C(=O)OC(C)(C)C)C1CCN(C2CCNCC2)CC1
Reaction time: 5 h

Procedure:
A suspension of 1.30 g (2.83 mmol) ethyl[(1′-benzyl-[1,4′]bipiperidinyl-4-yl)-tert-butoxycarbonyl-amino]-acetate and 0.16 g 10% Pd/C in 25 mL EtOH was hydrogenated for 5 h at 50° C. and 50 psi hydrogen pressure. The catalyst was removed by suction filtering and the filtrate was evaporated to dryness. The product was obtained as a colourless oil, which was reacted further without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([NH2:19])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1.C([O:23][C:24](=O)[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:34]Br)C.C(N(CC)CC)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:14])[F:15])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1)[N:19]1[CH2:34][C:26]2[C:25](=[C:30]([N+:31]([O-:33])=[O:32])[CH:29]=[CH:28][CH:27]=2)[C:24]1=[O:23]
Reactant: CCOc1cc(C(N)CC(=O)OC)ccc1OC(F)F
Reactant: CCOC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C(CC(=O)OC)N2Cc3cccc([N+](=O)[O-])c3C2=O)ccc1OC(F)F
Yield: 80.8 %

Procedure:
3-(4-Difluoromethoxy-3-ethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester was prepared by the procedure of example 11 from 3-amino-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid methyl ester (7.3 g, 0.025 mol), 2-bromomethyl-6-nitro-benzoic acid ethyl ester (7.6 g, 0.028 mol) and triethyl amine (7 ml, 0.05 mol) in DMF (50 ml) to provide 3-(4-difluoromethoxy-3-ethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester as yellow oil (9.1 g, 81% yield). 1HNMR (CDCl3): δ 1.42 (t, J=7.5 Hz, 3H, OCH2CH3), 3.09 (dd, J=6.8, 15 Hz, 2H, CH2CO), 3.29 (dd, J=6.8, 15 Hz, 1H, CH2CO), 3.65 (s, 3H, OCH3), 4.10 (q, J=7.5 Hz, 2H, OCH2CH3), 4.26 (d, J=17 Hz, 2H, CH2N), 4.46 (d, J=17 Hz, 2H, CH2N), 5.80–5.86 (m, 1H, CHN), 6.55 (t, JH-F=75 Hz, 1H, OCF2H), 6.92 (dd, J=1.8, 8.2 Hz, 1H, Ar), 7.06 (d, J=1.8 Hz, 1H, Ar), 7.14 (d, J=8.25, 1H, Ar), 7.58–7.76 (m, 3H, Ar).
Reaction SMILES: B(F)(F)F.[CH3:5]COCC.[CH:10]1[CH2:14]C=[CH:12][CH:11]=1.[C:15]([O:18][CH2:19][CH:20]=[C:21]([CH:23]=[O:24])[CH3:22])(=[O:17])[CH3:16].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:15]([O:18][CH2:19][CH:20]1[C:21]([CH3:5])([CH:23]=[O:24])[CH:22]2[CH2:12][CH:11]1[CH:10]=[CH:14]2)(=[O:17])[CH3:16]
Reactant: CC(=O)OCC=C(C)C=O
Reactant: C1=CCC=C1
Reactant: CCOCC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OCC1C2C=CC(C2)C1(C)C=O
Temperature: -15 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
5 ml of boron fluoride etherate were added to 400 ml of methylene chloride and the mixture was cooled to -15° C. A solution of 132 g (2 moles) of freshly distilled cyclopentadiene and 256 g (1.8 moles) of 3-formylcrotyl acetate was added dropwise, whilst stirring, at a rate such that the reaction temperature did not rise above -10° C. The reaction was then allowed to continue for 2 hours at -10° C., whilst stirring. For working up, about 0.5 kg of ice was added, the mixture was neutralized with sodium bicarbonate solution, the aqueous phase was separated off and the methylene chloride was removed under reduced pressure (12 mm Hg/50° C.). The reaction product which remained was subjected to fractional distillation, giving 337 g of main fraction (yield: 90%).
Reaction SMILES: Cl[Ti:2](Cl)(Cl)Cl.[P:6](=[O:10])([OH:9])([OH:8])[OH:7].O.N>Cl.O>[P:6]([O-:10])([O-:9])([O-:8])=[O:7].[Ti+4:2].[P:6]([O-:10])([O-:9])([O-:8])=[O:7].[P:6]([O-:10])([O-:9])([O-:8])=[O:7].[P:6]([O-:10])([O-:9])([O-:8])=[O:7].[Ti+4:2].[Ti+4:2]
Reactant: Cl[Ti](Cl)(Cl)Cl
Reactant: O=P(O)(O)O
Agent: Cl
Agent: N
Solvent: O
Product: O=P([O-])([O-])[O-]
Product: [Ti+4]
Reaction time: 24 h

Procedure:
Nineteen grams of TiCl4 were dissolved in 500 ml of 1N-HCl. Separately, 24 grams of 85 vol % phosphoric acid were diluted with 500 ml of distilled water. After which the two solutions were mixed at room temperature with stirring. The formation of precipitate began with the mixing of the two solutions. Next, the pH of the solution was adjusted to 5.0 by gradually adding concentrated ammonia water, followed by allowing the solution to stand for 24 hours. The precipitate was then separated by filtration, water-washed and dried at 300°C. for one hour. The so obtained titanium phosphate had a specific surface area of 169 m2 /gm. The mole ratio PO4 /Ti at the time of catalyst preparation was 2.0 in this case.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21].CCOC(C)=O>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:20](=[O:22])[CH3:21])[N:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)n1ncc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
Step 1) Dissolve commercially available 5-nitroindazole (100 g, 613 mmoles) in 2 L of THF and then add triethylamine (260 mL; 1.87 moles). Stir the solution at room temp until all the solid went into the solution, and then add acetic acid anhydride (94 g; 927 mmoles). After 2 h at room temperature, add 2 L of EtOAc and extract the mixture with 1 N HCl (2×800 mL). Wash the organic layer with aqueous sodium bicarbonate followed by saturated aqueous NaCl. Dry the organic layer with magnesium sulfate and concentrate to a thick slurry. Add t-Butyl methyl ether (300 mL) and filter the slurry. Collect the solid, rinse with t-butyl methyl ether, and dry under vacuum to afford 113 g (90%) of 1-(5-nitro-indazol-1-yl)-ethanone a pale yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.70 (d, 1H, J=2.0 Hz), 8.58 (d, 1H, J=9.5 Hz), 8.44 (dd, 1H J=7.0, 2.0 Hz), 8.31 (s, 1H), 2.84 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]([CH3:34])[C:9]([CH:11]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=1)[C:12]([NH:14][C@@H:15]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:16](O)=[O:17])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC(C)=CC=1C.[NH2:68][CH2:69][CH:70]1[CH2:75][CH2:74][CH:73]([C:76]#[N:77])[CH2:72][CH2:71]1>CN(C)C=O>[CH2:1]([N:8]([CH3:34])[C:9](=[O:10])[CH:11]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=1)[C:12]([NH:14][C@H:15]([C:16](=[O:17])[NH:77][CH2:76][CH:73]1[CH2:74][CH2:75][CH:70]([C:69]#[N:68])[CH2:71][CH2:72]1)[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C(=O)C(Cc1ccc(C#N)cc1)C(=O)N[C@H](C(=O)O)C1CCCCC1
Reactant: N#CC1CCC(CN)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: CN(Cc1ccccc1)C(=O)C(Cc1ccc(C#N)cc1)C(=O)N[C@H](C(=O)NCC1CCC(C#N)CC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103 %

Procedure:
To [2-(R,S)-(Benzyl-methyl-carbamoyl)-3-(4-cyano-phenyl)-propionylamino]-(S)-cyclohexyl-acetic acid (910 mg, 1.97 mmol) in dimethylformamide (150 ml) were added HATU (825 mg, 2.17 mmol) and collidine (263 mg, 2.17 mmol) at 0° C. After 30 minutes at 0° C. 4-aminomethyl-cyclohexanecarbonitrile (272 mg, 1.97 mmol) was added. The mixture was stirred for 1 hour, then allowed to warm to room temperature, and stand at room temperature for 72 hours. After evaporation the residue was stirred with Na2CO3 solution and the precipitate was sucked off to yield 1.18 g of the desired product which was used for further reactions without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].CC([O-])(C)C.[K+].Cl[CH2:16][C:17]1[C:18]([CH3:23])=[N:19][O:20][C:21]=1[CH3:22].O>CN(C=O)C>[CH3:23][C:18]1[C:17]([CH2:16][N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)=[C:21]([CH3:22])[O:20][N:19]=1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: Cc1noc(C)c1CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(C)c1Cn1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To 4-nitro-1H-pyrazole (Example 4-1d) (3.8 g, 34 mmol) in DMF (80 mL) cooled to 0° C., via an ice/water bath, was added t-BuOK (4.2 g, 38 mmol). After addition of the base the ice bath was removed and the mixture was stirred for 30 minutes followed by the addition of 4-(chloromethyl)-3,5-dimethylisoxazole (5 g, 34 mmol). The reaction was refluxed for 16 hours then cooled to ambient temperature. H2O was added to the reaction mixture and the precipitate formed was collected by filtration. The precipitate was washed with additional H2O then dried under high vacuum to afford 3,5-dimethyl-4-((4-nitro-1H-pyrazol-1-yl)methyl)isoxazole (5.8 g, 78%) as a light yellow solid. 1H NMR (CDCl3, 400 MHz): 2.23 (s, 3H), 2.46 (s, 3H), 5.08 (s, 2H), 8.02 (s, 1H), 8.08 (s, 1H).
Reaction SMILES: Br.[N:2]1[CH2:3][CH2:4][N:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[C:6]2[NH2:15].[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:2]1[CH2:3][CH2:4][N:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[C:6]2[NH:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1
Reactant: O=C(O)c1cccnc1
Reactant: NC1=Nc2ccccc2C2=NCCN12
Agent: Br
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1=Nc2ccccc2C2=NCCN12)c1cccnc1
Temperature: 80 °C
Yield: 82.6 %

Procedure:
To a suspension of 2,3-dihydroimidazo[1,2-c]quinazolin-5-ylamine hydrobromide (500 mg, 1.87 mmol) and nicotinic acid (346 mg, 2.81 mmol) in N,N-dimethyl-formamide (25 ml) at room temperature was added benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (1.46 g, 2.81 mmol) followed by N,N-diisopropylethylamine (1.30 ml, 7.49 mmol). The mixture was heated at 80° C. for 4 hours. After cooling to room temperature, the mixture was quenched with aqueous saturated NaHCO3 solution. The resulting precipitate was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give N-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (450 mg, 83% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:17]([CH2:18][C:19](O)=[O:20])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:17]([CH2:18][C:19](=[O:20])[N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cn1c(-c2ccc(Cl)c(Cl)c2)nc2cccnc21
Reactant: C1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)c(Cl)c2)nc2cccnc21)N1CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under nitrogen bubbling, a mixture of 2-(3,4-dichlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.5 g, 0.011 mole) and 1,1'-carbonyldiimidazole (1.95 g, 0.011 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 4 hrs. Piperidine (1.87 g, 0.022 mole) was added and the reaction was allowed to stir at room temperature overnight.
Reaction SMILES: C1COCC1.C[O:7][C:8](=[O:36])[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:17]=[CH:18][C:19]3[CH:24]=[C:23]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[N:22]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[C:20]=3[N:21]=2)=[N:11][CH:10]=1.[Li+].[OH-].Cl>CO.O>[CH:30]1([N:22]2[C:20]3[N:21]=[C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([C:8]([OH:36])=[O:7])=[CH:10][N:11]=4)[N:17]=[CH:18][C:19]=3[CH:24]=[C:23]2[C:25](=[O:29])[N:26]([CH3:27])[CH3:28])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COC(=O)c1ccc(Nc2ncc3cc(C(=O)N(C)C)n(C4CCCCC4)c3n2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCCC1
Temperature: 50 °C
Yield: 96.6 %

Procedure:
To a 25 mL solution of THF, water and MeOH (2:2:1) containing 6-(7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid methyl ester (860 mg, 2.04 mmol) was added solid LiOH (244 mg, 10.2 mmol). After stirring at 50° C. for 90 m, reaction was acidified to pH 6 with 1M HCl and then partitioned into two phases with a mixture of water, isopropyl alcohol and chloroform. The organic layer was removed and concentrated to yield 6-(7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (805 mg, 1.97 mmol) in 97% yield. MS m/z 409.6 (M÷H)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:27])[C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[C:12]([N+:24]([O-])=O)[CH:11]=2)=[CH:4][CH:3]=1.[NH4+].[Cl-]>[Fe]>[NH2:24][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[S:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:27]
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1

Procedure:
The product from Example 57b was reduced with Fe and NH4Cl following the procedure form Example 237E to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[S:13])[S-:12].C([NH+](CC)CC)C.[C:21]([O:24][CH2:25][C:26]([CH2:28]Cl)=[O:27])(=[O:23])[CH3:22]>C(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[S:12])[S:13][CH2:28][C:26](=[O:27])[CH2:25][O:24][C:21](=[O:23])[CH3:22]
Reactant: Fc1ccc(NC(=S)[S-])c(F)c1F
Reactant: CC(=O)OCC(=O)CCl
Agent: CC[NH+](CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)CSC(=S)Nc1ccc(F)c(F)c1F
Reaction time: 0.17 h
Yield: 64 %

Procedure:
Triethylammonium N-(2,3,4-trifluorophenyl)dithiocarbamate (2.15 g) prepared in the same manner as in Reference Example 1 was added to methylene chloride (30 ml) and thereto 1-acetoxy-3-chloroacetone (1.0 g) was added dropwise at 2° to 7° C. with stirring over a period of 10 minutes. The mixture was stirred for 20 minutes and washed with 3N hydrochloric acid and then with water. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane ethyl acetate to give the title compound (1.43 g) as colorless crystals.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C@@:16]1([C@@H:19]([OH:21])[CH3:20])[CH2:18][O:17]1>CN(C=O)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C@:16]([OH:17])([C@H:19]([OH:21])[CH3:20])[CH2:18][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: C[C@H](O)[C@]1(c2cc(F)ccc2F)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Temperature: 70 °C
Yield: 74.3 %

Procedure:
1,2,4-Triazole (7 mg; 0.1 mmol) is dissolved in DMF (0.5 ml). Sodium hydride (4.4 mg; 60% suspension in paraffin; 0.1 mmol) is added and the reaction mixture is heated to 70° C. for one hour. The reaction mixture is cooled to room temperature and 1(S)-[2(S)-(2,5-Difluoro-phenyl)-oxiranyl]-ethanol (5 mg; 0.025 mmol from example 8) dissolved in DMF (0.5 ml) is added slowly. The reaction mixture is then heated to 70° C. for three hours. The solvent is evaporated. The residue is taken-up in ethyl acetate (5 ml) and water (3 ml). The phases are separated. The aqueous layer is extracted 3 times with ethyl acetate (3 times 5 ml). The combined organic phases are washed twice with water (2 times 5 ml). The organic phase is dried over sodium sulfate. The solids are filtered off and the solvent is removed under reduced pressure. 5 mg of (2R,3R)-2-(2,5-Difluoro-phenyl)-1-[1,2,4]-triazol-1-yl-butane-2,3-diol are obtained as a light yellow oil.