Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:10])[CH:8]=2)[CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](I)[CH:18]=[CH2:19]>CC(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>[CH2:19]([O:10][C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[N:2][NH:1]2)=[CH:5][CH:6]=1)[CH:18]=[CH2:17]
Reactant: Oc1ccc2cn[nH]c2c1
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.3 %

Procedure:
To a solution of 1H-indazol-6-ol (20.0 g, 150 mmol) in acetone (450 mL) was added pulverized potassium carbonate (22.4 g, 162 mmol), cesium carbonate (2.00 g, 5.7 mmol), and allyl iodide (14.63 mL, 160 mmol) and the mixture was stirred for 18 h at ambient temperature. Additional potassium carbonate (5.00 g, 36 mmol) and allyl iodide (1.4 mL, 15 mmol) were added and the mixture was stirred for 2 h followed filtration. Water (200 mL) was added to the filtrate and the volume of the mixture was reduced by about half in vacuo and extracted with dichloromethane (2×100 mL). The combined extracts were dried (MgSO4) and evaporated to a residue which was purified by chromatography (silica, 20% to 50% EtOAc/hexane) to give a yellow solid (14.7 g, 56%): mp 110-112° C.; LC/MS (+APCI) m/z 175 (M+H). Unreacted starting material was recovered (4.71 g).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:11]Br>C(O)(=O)C.O>[Br:11][C:7]1[CH:8]=[C:9]([CH3:10])[C:2]([OH:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: Cc1cccc(C=O)c1O
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(Br)cc(C=O)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
The solution of 2-Hydroxy-3-methylbenzaldehyde (1.0 g, 7.35 mmole) in acetic acid (6 mL) was cooled to 0° C. (ice bath). Bromine (1.36 g, 8.52 mmole) was added dropwise and allowed to stir for 2 hours. The reaction was warmed to room temperature and diluted with water (100 mL) yielding a light orange precipitate. The solid was filtered and washed with water (10 mL). Dried on high vacuum to give a light brown solid (1.4 g, 88.6%). 1H NMR (CDCl3/400 MHz) 11.16 (s, 1H), 9.79 (s, 1H), 7.48 (s, 1H), 7.46 (s, 1H), 2.23 (s, 3H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH:9]=[CH:8][C:7]([C:12]2[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=23)=[N:6]1)#[N:2].[N-:27]=[N+:28]=[N-:29].[Na+].Cl.C(N(CC)CC)C.Cl>CN1CCCC1=O.O>[NH:27]1[C:1]([CH2:3][CH2:4][N:5]2[C:10](=[O:11])[CH:9]=[CH:8][C:7]([C:12]3[C:13]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=34)=[N:6]2)=[N:2][N:29]=[N:28]1
Reactant: N#CCCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1CCc1nnn[nH]1
Temperature: 150 °C
Reaction time: 4 h
Yield: 15.2 %

Procedure:
A mixture of 3-[2-(2-cyanoethyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.35 g), sodium azide (0.20 g) and triethylamine hydrochloride (0.21 g) in N-methylpyrrolidone (10 ml) was stirred at 150° C. for 4 hours under nitrogen atmosphere. The reaction mixture was poured into water (30 ml), acidified with 10% hydrochloric acid (5 ml), and extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of chloroform and methanol (20:1) as an eluent. The fractions containing the object compound were combined and evaporated in vacuo. The residue was recrystallized from ethyl acetate to give 3-[2-{2-(1H-tetrazol-5-yl)ethyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.06 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[CH:16]1([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]3[O:30][N:29]=[C:28]([CH:31]([CH3:33])[CH3:32])[N:27]=3)[CH2:22][CH2:21]2)[CH2:18][CH2:17]1.C(N(C(C)C)C(C)C)C>ClCCl>[CH:16]1([N:19]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]3[O:30][N:29]=[C:28]([CH:31]([CH3:33])[CH3:32])[N:27]=3)[CH2:22][CH2:21]2)[C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:7]([C:6]3[O:5][CH:4]=[N:3][C:2]=3[CH3:1])=[CH:8][CH:9]=2)[CH2:17][CH2:18]1
Reactant: Cc1ncoc1-c1ccc(C(=O)Cl)cc1
Reactant: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ncoc1-c1ccc(C(=O)N(C2CC2)C2CCN(c3nc(C(C)C)no3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(4-Methyl-oxazol-5-yl)-benzoyl chloride (89 mg) is added portionwise to a mixture of cyclopropyl-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine (100 mg) and ethyldiisopropylamine (100 μL) in dichloromethane (5 mL). The mixture is stirred for 1 h at room temperature, washed with water and 1 M HCl, dried over Na2SO4 and concentrated in vacuo. The residue is triturated with diethyl ether to give the title compound. LC (method 6): tR=1.83 min; Mass spectrum (ESI+): m/z=436 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:8]2[CH:9]=[C:10]([CH3:12])[O:11][C:7]=2[CH:6]=1)(=O)C.[C:15](Cl)(=[O:19])C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].[C:25]([O-])([O-])=[O:26].[K+].[K+]>CO>[OH:4][C:5]1[CH:14]=[CH:13][C:8]2[C:9]([C:25]([O:19][CH3:15])=[O:26])=[C:10]([CH3:12])[O:11][C:7]=2[CH:6]=1
Reactant: CC(=O)Oc1ccc2cc(C)oc2c1
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1c(C)oc2cc(O)ccc12
Yield: 69 %

Procedure:
This material was prepared from 6-acetoxy-2-methylbenzofuran 89b (0.81 g, 4.3 mmole) by acylation with oxalyl chloride in the presence of AlCl3, followed by treatment with methanol and K2CO3 in a manner as previously described for example 11a to give a beige solid (607 mg, 69%). 1H NMR (DMSO-d6) δ 9.64 (1H, s), 7.62 (1H, d, J=8.5 Hz, 6.93 (1H, d, J=1.9 Hz), 6.78 (1H, dd, J=8.5, 2.0 Hz), 3.79 (3H, s), 2.66 (3H, s).
Reaction SMILES: [O:1]1[CH2:4][CH:3]([NH2:5])[CH2:2]1.C(N(CC)CC)C.Br[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][N:15]=1>C(O)(C)C>[O:1]1[CH2:4][CH:3]([NH:5][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][N:15]=2)[CH2:2]1
Reactant: NC1COC1
Reactant: N#Cc1ccc(Br)nc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC2COC2)nc1
Yield: 24.7 %

Procedure:
In a microwave vial, oxetan-3-amine (125 mg, 1.736 mmol), triethylamine (526 mg, 5.21 mmol) were added to a solution of 2-bromo-5-cyanopyridine (317 mg, 1.736 mmol) in isopropanol (3 mL). The vial was capped and irradiated in a microwave oven at 120° C. for 5 h. The reaction mixture was partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The resulting crude product was purified by column chromatography over silica gel (chloroform/MeOH, 0-5% EtOAc) to afford 75 mg (25%) of 6-(oxetan-3-ylamino)nicotinonitrile (I-25) as an off-white solid. 1H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 7.58-7.61 (dd, J=1.9, 6.9 Hz, 1H), 6.39 (d, J=8.7 Hz, 2H), 5.37 (br. s, 1H), 4.91-5.06 (m, 3H), 4.54-4.57 (m, 2H); ESI-LC/MS (m/z): [M+H]+ 176.2, RT 1.65 min.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]([O:13][CH:14]3[CH2:19][CH2:18][CH:17]([C:20]4[NH:24][C:23]5[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=5[N:21]=4)[CH2:16][CH2:15]3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1>CO.[Pd]>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8]([O:13][C@H:14]3[CH2:15][CH2:16][C@H:17]([C:20]4[NH:21][C:22]5[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=5[N:24]=4)[CH2:18][CH2:19]3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8]([O:13][C@@H:14]3[CH2:15][CH2:16][C@H:17]([C:20]4[NH:21][C:22]5[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=5[N:24]=4)[CH2:18][CH2:19]3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: C1=C(c2cccnc2OC2CCC(c3nc4ccccc4[nH]3)CC2)CCOC1
Agent: [Pd]
Solvent: CO
Product: c1cnc(O[C@H]2CC[C@@H](c3nc4ccccc4[nH]3)CC2)c(C2CCOCC2)c1
Product: c1cnc(O[C@H]2CC[C@H](c3nc4ccccc4[nH]3)CC2)c(C2CCOCC2)c1
Temperature: 40 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
The mixture of 2-{4-[3-(3,6-dihydro-2H-pyran-4-yl)-pyridin-2-yloxy]-cyclohexyl}-1H-benzoimidazole (0.15 g, 0.45 mmol), Pd/C (0.5 g) in MeOH (50 mL) was stirred under H2 atmosphere at 40° C. for 24 h. Then the reaction mixture was filtrated and the filtrate was concentrated and purified by prep-HPLC to give trans-2-{4-[3-(Tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclohexyl}-1H-benzoimidazole (0.11 g, 0.292 mmol, 65% yield) and cis-2-{4-[3-(Tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclohexyl}-1H-benzoimidazole (0.1 g, 0.265 mmol, 60% yield) as white solid. [M+1] 378 each. IC50 (uM): (trans) 0.023 and (cis) 0.025.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[C:29]4[C:30](=[O:34])[N:31]([CH3:33])[CH2:32][C:28]=4[CH:27]=[CH:26][N+:25]=3[O-])[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[C:12](OC)[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].Cl.O>CCO.[Fe]>[CH2:6]([O:5][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[C:29]4[C:30](=[O:34])[N:31]([CH3:33])[CH2:32][C:28]=4[CH:27]=[CH:26][N:25]=3)[C:20]([C:36]([F:38])([F:39])[F:37])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3c4c(cc[n+]3[O-])CN(C)C4=O)n2)c(OC)c1)OCC
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3nccc4c3C(=O)N(C)C4)n2)cc1)OCC
Yield: 52.6 %

Procedure:
A solution of diethyl[3-methoxy-4-({4-[(2-methyl-5-oxido-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate (Example 310, 35.0 mg, 0.0587 mmol) in EtOH (2.0 mL) was charged with iron (6.9 mg, 0.12 mmol) and heated to reflux. The reaction mixture was charged with 1 M of HCl in H2O (0.07 mL, 0.07 mmol) and stirred at reflux for 10 minutes. Additional 1 M of HCl in H2O (0.03 mL, 0.03 mmol) was added to the reaction mixture and stirred at reflux for 10 minutes. The reaction mixture was filtered through a pad of celite. The filtrate was quenched with NaHCO3 (10 mL) and extracted with EtOAc (15 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to a yellow solid. The crude material was purified by silica gel chromatography on an ISCO Combi-flash Rf system using DCM/MeOH (100:0→95:5) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a white solid (17.0 mg, 50%). The material was re-purified by HPLC. The fractions containing product were combined and concentrated to yield a white solid (4.3 mg, 13%). 1H NMR (DMSO-d6, 400 MHz): δ=8.71 (br. s., 1H), 8.60 (d, J=5.05 Hz 1H), 8.54 (s, 1H), 8.47 (br. s., 1H), 8.32 (s, 1H), 7.41 (d, J=5.05 Hz, 1H), 6.95 (s, 1H), 6.85-6.92 (m, 1H), 4.57 (s, 2H), 3.90-4.01 (m, 4H), 3.84 (s, 3H), 3.21 (s, 1H), 3.06 (s, 3H), 1.19 (t, J=6.95 Hz, 6H). MS (ES+): m/z 581.10 [MH+] (TOF, polar).
Reaction SMILES: O1CCCC1.[C:6]1([C:12]([NH:25][CH:26]2[C:44](=[O:45])[N:28]3[CH:29]([C:34]4[N:38](C(OCC)=O)[N:37]=[N:36][N:35]=4)[C:30]([CH3:33])([CH3:32])[S:31][C@H:27]23)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[C:6]1([C:12]([NH:25][CH:26]2[C:44](=[O:45])[N:28]3[CH:29]([C:34]4[NH:35][N:36]=[N:37][N:38]=4)[C:30]([CH3:32])([CH3:33])[S:31][C@H:27]23)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)n1nnnc1C1N2C(=O)C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2SC1(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 2 ml. of tetrahydrofuran and 4 ml. of water is added 150 mg. of 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[ethoxycarbonyl]tetrazol-5-yl)penam. The pH of the mixture is adjusted to 9.5, and stirring is continued at that pH for a further 30 minutes, at ambient temperature. The bulk of the tetrahydrofuran is removed by evaporation in vacuo, and the residue is portioned between water and ethyl acetate at pH 9. The ethyl acetate is removed and discarded. Fresh ethyl acetate is added and the pH is adjusted to 2.0. The ethyl acetate layer is removed, washed with water, dried using anhydrous sodium sulfate, and evaporated in vacuo to give the crude title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]([C:11]2([C:14]3[O:18][N:17]=[C:16]([CH3:19])[CH:15]=3)[CH2:13][CH2:12]2)=O)=[CH:6][CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])[CH2:21]2)[N:3]=1.C[O-].[Na+].CO>C(O)C(C)C>[CH3:19][C:16]1[CH:15]=[C:14]([C:11]2([C:9]3[NH:1][C:2]4=[N:3][C:4]([N:20]5[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([N:28]6[CH2:29][CH2:30][CH2:31][CH2:32]6)=[O:27])[CH2:21]5)=[CH:5][CH:6]=[C:7]4[N:8]=3)[CH2:12][CH2:13]2)[O:18][N:17]=1
Reactant: Cc1cc(C2(C(=O)Nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3N)CC2)on1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)CO
Product: Cc1cc(C2(c3nc4ccc(N5CCC[C@@H](C(=O)N6CCCC6)C5)nc4[nH]3)CC2)on1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
To a solution of (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridine-3-yl)-1-(3-methylisoxazol-5-yl)cyclopropanecarboxamide (94 mg, 0.21 mmol) in isobutanol (2 mL) was added sodium methoxide (25% in methanol, 98 μL, 0.43 mmol) followed by methanol (0.9 mL). The reaction mixture was stirred at 110° C. for 18 h. An additional portion of sodium methoxide (25% in methanol, 98 μL, 0.43 mmol) was added and the reaction mixture was stirred at 110° C. for 3 h. The mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via HPLC to afford (R)-(1-(2-(1-(3-methylisoxazol-5-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone. MS (ESI+) (M+H) 421.2; HPLC retention time 2.02 min (Method A).
Reaction SMILES: [Cl:1][C:2]([Cl:19])=[CH:3][CH2:4][O:5][C:6]1[CH:16]=[C:15]([Cl:17])[C:9]([O:10][CH2:11][CH2:12][CH2:13]O)=[C:8]([Cl:18])[CH:7]=1.C(Br)(Br)(Br)[Br:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]([Cl:19])=[CH:3][CH2:4][O:5][C:6]1[CH:16]=[C:15]([Cl:17])[C:9]([O:10][CH2:11][CH2:12][CH2:13][Br:21])=[C:8]([Cl:18])[CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 42 h
Yield: 188.3 %

Procedure:
A stirred solution of 3.5 grams (0.010 mole) of 3-[4-(3,3-dichloroprop-2-enyloxy)-2,6-dichlorophenoxy]propan-1-ol and 3.3 grams (0.010 mole) of carbon tetrabromide in 50 mL of methylene chloride was cooled to 0–4° C. and 2.9 grams (0.011 mole) of triphenylphosphine was added portion-wise. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it stirred during a 42 hour period. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:3 methylene chloride:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 7.7 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[C:9]1([P:15]([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)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[Br-:1].[CH:4]1([CH2:3][CH2:2][P+:15]([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)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: BrCCC1CCCC1
Solvent: Cc1ccccc1
Product: [Br-]
Product: c1ccc([P+](CCC2CCCC2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
17.7 g (100 mmole) (2-bromoethyl)-cyclopentane, 32.5 g (124 mmole) triphenylphosphine and 100 ml toluene were boiled for 56 hours under reflux. The mixture was stirred overnight at room temperature. The crystals formed were filtered off by suction, washed with ether and dried under vacuum. The yield of compound (53) was 35.6 g (82% theoretical).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH-].[Na+].CCOCC>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:3]2[CH:2]([CH3:1])[CH2:6][N:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(N)cc1
Reactant: CC1CN(c2ccccc2)N=C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(NC2=NN(c3ccccc3)CC2C)cc1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
A 100 ml round bottom flask was charged with 4-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-3-ol (1.00 g, 5.68 mmol), 4-methoxybenzenamine (2.27 g, 18.44 mmol), and p-toluenesulfonic acid monohydrate (0.59 g, 3.12 mmol). The reaction mixture was stirred at 140° C. under a nitrogen atmosphere for 16 h. The reaction was cooled and dissolved in 1% NaOH solution and ether. The organic layer was separated, washed with 1% HCl solution and water, then dried over Na2SO4, filtered, and concentrated to afford N-(4-methoxyphenyl)-4-methyl-1-phenyl-4,5-dihydro-1-H-pyrazol-3-amine as a brown solid. MS m/z=282.2 [M+H]+. Calc'd for C17H19N3O: 281.35.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C([Sn](CCCC)(CCCC)[C:15]([O:17][CH2:18][CH3:19])=[CH2:16])CCC.CN(C=O)C.[F-].[K+]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH2:18]([O:17][C:15]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1)=[CH2:16])[CH3:19]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CSc1nccc(Cl)n1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(OCC)c1ccnc(SC)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
A mixture comprising 16.4 g of 4-chloro-2-methylsulfanylpyrimidine, 38 g of tributyl(1-ethoxyvinyl) tin, 1.43 g of bis(triphenylphosphine)palladium (II) dichloride and 100 ml of DMF was stirred at 80° C. for 3 hours. After cooling the reaction mixture, 300 ml of ethyl acetate and 17.8 g of potassium fluoride were added to the mixture, and the resulting mixture was stirred at room temperature overnight. After filtration with Celite, the filtrate was washed, dried and concentrated. The residue was purified by silica gel column chromatography (hexane:ethylacetate=20:1) to give 18.9 g of 4-(1-ethoxy-vinyl)-2-methylsulfanylpyrimidine.
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[NH:15])[NH2:14])=[CH:9][CH:8]=1.[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(=O)([O-])[O-].[Na+].[Na+].O.C(Cl)Cl>[Br:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[NH:14])[NH:15][C:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:25])=[CH:9][CH:8]=1
Reactant: N=C(N)c1ccc(OCCCBr)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N=C(NC(=O)OCc1ccccc1)c1ccc(OCCCBr)cc1
Reaction time: 0.5 h

Procedure:
In a mixed solvent of 175 ml of a saturated aqueous sodium carbonate solution, 90 ml of water and 350 ml of methylene chloride was dissolved 17.5 g of 1-bromo-3-(4-amidinophenoxy)propane hydrochloride, and 8.5 ml of benzyloxycarbonyl chloride was added thereto under ice-cooling. The resulting mixture was vigorously stirred at the same temperature for 30 minutes and then at room temperature for 4 hours, after which the organic layer was separated and the aqueous layer was extracted with 150 ml of methylene chloride. The combined organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. Hexane was added to the resulting residue and the crystals were collected by filtration and dried to obtain 19.6 g of 1-bromo-3-(4-benzyloxycarbonylamidinophenoxy)propane as colorless crystals.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:12])/[CH:7]=[CH:8]\[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH2:18]>C(N(CC)CC)C>[CH3:4][CH2:3][CH2:2][CH2:1][O:5][C:6](=[O:12])[C@H:7]([CH2:8][C:9]([OH:11])=[O:10])[NH:18][CH2:17][CH2:16][CH2:15][N:14]([CH3:19])[CH3:13]
Reactant: CCCCOC(=O)/C=C\C(=O)O
Reactant: CN(C)CCCN
Solvent: CCN(CC)CC
Product: CCCCOC(=O)[C@H](CC(=O)O)NCCCN(C)C
Yield: 86.7 %

Procedure:
In the apparatus described in Example 1, 500 ml of triethylamine are added with cooling, within 2 hours and 35 minutes, at 4°-10° C. internal temperature to 430.5 g (2.5 mols) of maleic acid-mono-n-butyl ester. There are subsequently quickly added 306.5 g (2.5 mols+20% excess) of 3-dimethylaminopropylamine, and the mixture is reacted for 30 minutes at 90°-95° C. The reaction product is processed in a manner analogous to that described in Example 1 to obtain a yield of 595 g (86.8% of theory) of a crystalline aspartic acid derivative, which melts at 154°-157.5° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:7][N:8]([C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)[C:1](=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: CCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCC(=O)N(C)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 76 %

Procedure:
To a stirred solution of butyryl chloride (0.770 g, 7.23 mmol) in chloroform ( 15 mL) was added N-methyl-4-nitroaniline and triethylamine (1.2 mL, 8.6 mmol). After overnight stirring, additional butyryl chloride (0.40 mL, 3.9 mmol) was added and the reaction was refluxed for 2-3 hours. The reaction was concentrated and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was combined with a second ethyl acetate extract, dried (sodium sulfate) and concentrated. The resulting dirty yellow oil was purified by flash chromatography over silica (methylene chloride/methanol) to afford 1.11 g (76%) of product as a pale yellow solid: 1H NMR (CDCl3) δ 8.30 (d, J=8.9 Hz, 1H), 7.40 (d, J=8.9 Hz, 1H), 3.34 (s, 3H), 2.18 (t, J=7.5 Hz, 2H), 1.71-1.59 (m, 2H), 0.88 (t, J=7.6Hz,
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:2][CH2:3][OH:4])=[C:8]([C:13]([F:14])([F:15])[F:16])[CH:7]=1
Reactant: OCCBr
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: OCCOc1ccc(Br)cc1C(F)(F)F
Reaction time: 6 h

Procedure:
2-Bromoethanol (23.3 g) was added to a mixture of 4-bromo-2-(trifluoromethyl)-phenol (30 g) and potassium carbonate (34.4 g) in acetonitrile (200 ml). The above mixture was refluxed for 8 hours then another portion of 2-bromoethanol (8 g) was added and the reflux continued for another 6 hours. After diluting with ethyl acetate (500 ml), the mixture was washed with water (300 ml) then 0.1 M sodium hydroxide (200 ml). Organic layer was dried over magnesium sulphate, solvent removed under reduced pressure, the residue was taken into heptane by heat, 2-(4-bromo-2-(trifluoromethyl)-phenoxy)-ethanol crystalised and collected by filtration (17 g).