Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[H-].[Na+].Cl[C:8]1[N:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11]>CN(C=O)C>[Cl:17][C:15]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[C:8]([O:4][CH:2]([CH3:3])[CH3:1])[N:16]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1nc(Cl)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
To a solution of propan-2-ol (2.94 mL, 39.26 mmol) in DMF (15 mL) at 0° C. was added sodium hydride (95% in mineral oil, 0.94 g, 39.26 mmol) in portions and stirred for 1 h at room temperature. This mixture was slowly added to a solution of 2,6-dichloro-nicotinamide (5.0 g, 26.17 mmol) in DMF (25 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. DMF was removed under reduced pressure, and the resulting mixture was diluted with EtOAc (50 mL), washed with water (2×20 mL) and brine (2×10 mL) solution, dried over anhydrous Na2SO4, filtered, and concentrated to give yellow oil. Purification was accomplished by flash chromatography on silica gel using 5-50% EtOAc/hexanes gradient elution to yield the title compound (2.94 g, 64%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.45 (d, J=8.2 Hz, 1H), 7.73 (br. s., 1H), 7.03 (d, J=7.8 Hz, 1H), 5.84 (br. s., 1H), 5.64-5.47 (m, 1H), 1.45 (d, J=6.3 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].C(N(CC)CC)C.[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:24][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:6]
Reactant: NC1CCCCC1
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)c1cccc(Br)c1
Reaction time: 2 h

Procedure:
A solution of 3-bromobenzoyl chloride (2.0 g, 9.1 mmol) in CH2Cl2 was added to a solution triethylamine (1.9 ml, 13.7 mmol) and cyclohexylamine (1.15 ml, 10.0 mmol) in CH2Cl2 at room temperature with stirring. After 2 h, the mixture was washed with HCl (4N), brine, dried over Na2SO4 and concentrated under reduced pressure to give 3-bromo-N-cyclohexylbenzamide as a white solid. Yield (2.43 g, 95%): 1H NMR (400 MHz, CD3OD) δ 8.29 (br s, 1H), 7.95 (t, J=2.0 Hz, 1H), 7.42-7.77 (m, 1H), 7.64-7.67 (m, 1H), 7.36 (t, J=8.0 Hz, 1H), 3.78-3.84 (m, 1H), 1.92-1.94 (m, 2H), 1.78-1.81 (m, 2H), 1.65-1.69 (m, 1H), 1.16-1.46 (m, 5H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26]O)=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][CH:4]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:26][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:25][CH:24]=2)=[CH:15][CH:16]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Reactant: OCc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(OCC)c1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) and [4-(trifluoromethyl)phenyl]methanol (111 mg, 0.630 mmol) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a colorless oily substance (125 mg, yield: 75%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][O:25][C:26](=[O:33])[C@H:27]([C@H:29]([CH2:31][CH3:32])[CH3:30])[NH2:28].C(N(CC)CC)C.CS(ON1C2C=CC=CC=2N=N1)(=O)=O>ClCCl>[CH3:24][O:25][C:26](=[O:33])[C@H:27]([C@H:29]([CH2:31][CH3:32])[CH3:30])[NH:28][C:20](=[O:22])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CS(=O)(=O)On1nnc2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)OC
Yield: 81 %

Procedure:
N-Benzyloxycarbonyl-L-phenylalanine (3.0 g) and L-isoleucine methyl ester hydrochloride (1.82 g) are dissolved in anhydrous dichloromethane (30 ml), and thereto are added triethylamine (2.80 ml) and further 1-methanesulfonyloxy-1,2,3-benzotriazole (2.15 g) with stirring under ice-cooling, and the mixture is stirred at room temperature for 40 hours. After reaction, the solvent is distilled off and the resulting residue is extracted with ethyl acetate. The extract is washed with water, a saturated aqueous sodium hydrogen carbonate (5 times), water, 2 N hydrochloric acid and water in order and then dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off to give crystalline powder of N-(N-benzyloxycarbonyl-L-phenylalanyl)-L-isoleucine methyl ester (3.46 g), melting point: 94.5°-95.5° C.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[S:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:27](O)(=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:3][C:2]1[CH2:4][S:5][C:6](=[O:7])[C:1]=1[C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCCCC/C=C\CCCCC(=O)O
Reactant: O=C1CSC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC/C=C\CCCCC(=O)C1=C(O)CSC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.4 %

Procedure:
To a stirring solution of 1.71 g (14.7 mmol) of thiotetronic acid in 20 mL of dimethylformamide is added 2.22 mL (15.9 mmol) of triethylamine and 592 mg (4.85 mmol) of 4-dimethylaminopyridine at 0° C. Next, 3.38 g (17.6 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 5.0 g (17.7 mmol) of petroselinic acid are added and the reaction mixture is stirred overnight at room temperature. The reaction is acidified with 1.0N HCl and extracted three times with diethyl ether. The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue is subjected to HPLC chromatography (2 inch Dynamax silica gel column, 25 mL/min) eluting with 100% ethyl acetate to give 1.2 g (21%) of 4-hydroxy-3-[(Z)-1-oxo-6-octadecenyl]-2(5H)-thiophenone as an oil.
Reaction SMILES: [C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[N:13]=[C:12](Cl)[N:11]=[C:10](Cl)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]1([NH:28][C:29]#[N:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na]>CC(C)=O.O>[C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[N:13]=[C:12]([N:28]([C:29]#[N:30])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:11]=[C:10]([N:7]([C:8]#[N:9])[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1nc(Cl)nc(N(c2ccccc2)c2ccccc2)n1
Reactant: N#CNc1ccccc1
Agent: [Na]
Solvent: O
Solvent: CC(C)=O
Product: N#CN(c1ccccc1)c1nc(N(C#N)c2ccccc2)nc(N(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.1 %

Procedure:
To a solution of 31.7g (0.10 mole) of a 2-diphenylamino-4,6-dichloro-s-triazine in 325 ml of acetone at room temperature was added dropwise to a solution of 0.20 mole of sodium phenylcyanamide in 100 ml of water over a 30 minute period. After stirring for 1 hour at room temperature, the reaction mixture was heated at reflux overnight. After cooling the reaction mixture was filtered. The residue was washed with water, acetone and dried to give 25.5g of crude product. Recrystallization from 1500 ml of acetonitrile gave 20.9g of pure DPNCT, m.p. 280°-284°.
Reaction SMILES: CC([NH:5][S:6]([C:9]1[CH:13]=[CH:12][NH:11][C:10]=1[CH:14]=[N:15][O:16][CH3:17])(=[O:8])=[O:7])(C)C.[C:18](O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:17][O:16][N:15]=[CH:14][C:10]1[N:11]([CH3:18])[CH:12]=[CH:13][C:9]=1[S:6]([NH2:5])(=[O:7])=[O:8]
Reactant: O=C(O)C(F)(F)F
Reactant: CON=Cc1[nH]ccc1S(=O)(=O)NC(C)(C)C
Solvent: ClCCl
Product: CON=Cc1c(S(N)(=O)=O)ccn1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5.74 g (21.9 mmol) of N-(1,1-dimethylethyl)-2-[(methoxyimino)-methyl]-1H-pyrrole-3-sulfonamide in 75 mL methylene chloride under a nitrogen atmosphere was add 75 mL of TFA. The clear orange reaction mixture was allowed to stir at room temperature overnight ca. 16 hours. The orange reaction mixture was concentrated in vacuo. Three portions of diethyl ether were added to the residue and removed by evaporation to remove residual TFA, affording 3.49 g of the title compound as a gray solid, m.p. 120°-122° C. 1H NMR (CDCl3, 200 MHz.) δ: 8.43(s,1H), 6.66(d,1H), 6.54(d,1H), 6.1-6.7(bs,2H), 3.96(s,3H), 3.79(s,3H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O.C(OCC)C>[CH3:3][O:4][C:5](=[O:6])[CH:7]=[C:24]1[CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
60% sodium hydride in mineral oil (7.92 g, 198.02 mmoles) was washed with hexanes then suspended in N,N-dimethylformamide (220.00 mL). The mixture was cooled to 0° C. Trimethyl phosphonoacetate (29.0 mL,189.82 mmoles) was added drop-wise to the reaction. The mixture was held at 0° C. with stirring on and held for 20 min. A solution of N-tert-butoxycarbonyl-4-piperidone (30.41 g, 152.62 mmoles) in 80 mL N,N-dimethylformamide was added to the mixture drop-wise. Reaction was stirred at room temperature for 3 hours. Mixture was diluted with diethyl ether (650 mL). Mixture was washed once with water. Aqueous layer was back extracted once with diethyl ether. Organic layers were combined. The mixture was washed 4 times with water and the aqueous phase was discarded. The mixture was washed with brine and the aqueous phase was discarded. The material was dried over MgSO4, filtered, and concentrated to dryness. Title compound was obtained as white solid in 92% yield. 1H NMR (300 MHz, CDCl3): δ=5.68 (s, 1H), 3.66 (s, 3H), 3.40-3.51 (m, 4H), 2.90 (t, J=5.49, 2H), 2.25 (t, J=5.49, 2H), 1.44 (s, 9H).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][C:8]1([CH3:27])[NH:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C:9]1=[O:26]>O.O1CCCC1>[CH3:21][S:20]([C:17]1[CH:18]=[CH:19][C:14]([N:10]2[C:9](=[O:26])[C:8]([CH3:27])([CH3:7])[NH:12][C:11]2=[O:13])=[CH:15][C:16]=1[C:22]([F:25])([F:24])[F:23])=[O:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc(N2C(=O)NC(C)(C)C2=O)cc1C(F)(F)F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)c1ccc(N2C(=O)NC(C)(C)C2=O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
470 mg of sodium periodate were dissolved in 5 ml of water and admixed slowly with 640 mg of 114.1, dissolved in 10 ml of tetrahydrofuran, with ice bath cooling. The mixture was stirred at room temperature overnight. Another 210 mg of sodium periodate were added and the mixture was stirred for a further 8 h. Thereafter, the reaction mixture was admixed with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The chromatographic purification (silica gel; 96/4 dichloromethane/methanol) afforded 3-(4-methanesulfinyl-3-trifluoromethylphenyl)-5,5-dimethylimidazolidine-2,4-dione (114.1a). Molecular weight 334.05 (C13H13F3N2O3S); retention time Rt=1.69 min. [B]; MS (ES−): 335.19 (M−H+).
Reaction SMILES: [NH2:1][CH2:2][CH: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].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[O:32][CH:33]=[CH:34][CH:35]=1.[C:36]([OH:44])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C.CO>[C:36]([OH:44])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[O:32]1[CH:33]=[CH:34][CH:35]=[C:31]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:1][CH2:2][CH: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]
Reactant: BrCCCCCCOCCCCCCc1ccco1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Agent: O=C(O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CO
Product: CS(=O)(=O)Nc1cc(C(O)CNCCCCCCOCCCCCCc2ccco2)ccc1O
Yield: 70.5 %

Procedure:
A solution of N-[5-(2-amino-1-hydroxyethyl)-2-hydroxyphenyl]methanesulphonamide (0.95 g), 2-[6-[(6-bromohexyl)oxy]hexyl]furan (0.84 g) and DEA (0.54 ml) in DMF (20 ml) was heated at 90° for 5 h, then evaporated in vacuo. The residue was purified by FCC with System A (39:10:1) eluant to afford a product which was dissolved in methanol (6 ml) and treated with benzoic acid (21 mg). The solvent was evaporated in vacuo and the residue triturated with dry ether to give the title compound as a beige solid (75 mg), t.l.c. (System A 39:10:1) Rf 0.15.
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[ClH:5].Cl.[C:7]1([CH2:13][O:14][CH2:15][CH:16]([N:20]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27][N:26]([CH:32]([CH2:36][O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]([OH:35])=[O:34])[CH2:25][CH2:24][N:23]([CH:45]([CH2:49][O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:46]([OH:48])=[O:47])[CH2:22][CH2:21]2)[C:17]([OH:19])=[O:18])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[K+].Cl>O>[ClH:5].[ClH:5].[OH:4][CH:2]([CH3:3])[CH2:1][N:29]1[CH2:30][CH2:31][N:20]([CH:16]([CH2:15][O:14][CH2:13][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:17]([OH:19])=[O:18])[CH2:21][CH2:22][N:23]([CH:45]([CH2:49][O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:46]([OH:48])=[O:47])[CH2:24][CH2:25][N:26]([CH:32]([CH2:36][O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]([OH:35])=[O:34])[CH2:27][CH2:28]1
Reactant: O=C(O)C(COCc1ccccc1)N1CCNCCN(C(COCc2ccccc2)C(=O)O)CCN(C(COCc2ccccc2)C(=O)O)CC1
Reactant: CC1CO1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(O)CN1CCN(C(COCc2ccccc2)C(=O)O)CCN(C(COCc2ccccc2)C(=O)O)CCN(C(COCc2ccccc2)C(=O)O)CC1
Reaction time: 0.25 h
Yield: 185 %

Procedure:
4.7 g (0.08 mol) of propylene oxide were added drop by drop, in 15 minutes, to a solution of α,α′,α″-tris[(phenylmethoxy)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid bis hydrochloride (obtained as described in WO 89/05802, Example 2) (31.2 g; 0.04 mol) in 2N KOH (160 mL; 0.32 mol). After 18 hours at room temperature (20° C.), the reaction mixture was diluted with H2O (250 mL). The solution was acidified with 37% HCl (60 mL), to obtain a precipitate which, after 18 hours, was filtered, washed with 2N HCl (50 mL) and dried (P2O5—NaOH; 50° C.; 2 kPa) to obtain the desired compound (31.7 g dry; 0.037 mol). Yield: 92%.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:18])=[N:4][C:5]2[N:6]([N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=2)[C:7]=1O.O=P(Cl)(Cl)[Cl:21]>ClCCl>[Cl:21][C:7]1[N:6]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=[C:5]2[N:4]=[C:3]([CH3:18])[C:2]=1[F:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2cc(-c3ccccc3)nn2c(O)c1F
Solvent: ClCCl
Product: Cc1nc2cc(-c3ccccc3)nn2c(Cl)c1F
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of 6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-ol x133 (25 mmol, 1 eq, 6.2 g) in POCl3 (150 ml) is heated at 125° C. overnight. After cooling to room temperature, the solution is diluted in dichloromethane and quenched on ice (temperature must be kept under 25° C.). After separation of the organic layer, the aqueous phase is extracted twice with dichloromethane. The cumulated organic-layers are dried over MgSO4, filtered, evaporated under reduced pressure and the residue purified by chromatography on silicagel (CH2Cl2) to afford 6.6 g of 7-chloro-6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine x136.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(I)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 61 %

Procedure:
To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 225, 30 g, 0.1 mol), Cs2CO3 (50 g, 0.15 mol) in DMF (150 mL), MeI (28.4 g, 0.2 mol) was added dropwise at 0° C. After addition, the mixture was stirred at room temperature for 10 hours. The reaction mixture was cooled to 0° C. and quenched by the addition of water (500 mL). Then the solid was collected by filtration and washed with Et2O (100 mL) to afford 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine as a brown solid in 61% yield, 20 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([CH2:11][NH2:12])[O:7][C:6]=2[CH:13]=1.Cl[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][C:25](=[O:29])[O:26]2)=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([CH2:11][NH:12][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[CH:23]=[CH:24][C:25](=[O:29])[O:26][C:27]=4[CH:28]=3)[O:7][C:6]=2[CH:13]=1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Reactant: NCC1COc2ccc(Cl)cc2O1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1ccc2ccc(OCCCNCC3COc4ccc(Cl)cc4O3)cc2o1
Yield: 8.5 %

Procedure:
2,3-Dihydro-7-chloro-1,4-benzodioxin-2-methanamine (1.72 g, 8.62 mmole), 7-(3-chloropropoxy)coumarin (1.88 g, 7.88 mmole), diisopropylethylamine (7.5 ml, 43.1 mmole) and sodium iodide (1.37 g, 9.14 mmole) were combined in 200 ml of DMF and heated at 80°-100° C. for 3 days under a nitrogen atmosphere. The solvent was then removed in vacuum and the residue was column chromatographed on silica gel using first 0.5% methanol/dichloromethane and then 1% methanol/dichloromethane as eluant. The product-containing fractions were combined and concentrated in vacuum, during which procedure the free base began to come out of solution. This material was collected by filtration and recrystallized from isopropanol with addition of 4N HCl/isopropanol to give 0.27 g of white solid, monohydrochloride, m.p. 235°-242° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[NH2:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17]>>[NH2:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8](=[O:12])[CH:9]([CH3:10])[CH3:11])[CH2:4][CH2:3]2)[C:15]=1[C:16]#[N:17]
Reactant: N#Cc1c(N)cccc1F
Reactant: CC(C)C(=O)N1CCC(O)CC1
Product: CC(C)C(=O)N1CCC(Oc2cccc(N)c2C#N)CC1

Procedure:
Prepared as in Example Ca from 1-(4-hydroxypiperidin-1-yl)-2-methylpropan-1-one (Example 10c) and 2-amino-6-fluorobenzonitrile as an off-white solid (87%). MS 288 (MH+).
Reaction SMILES: [CH2:1]=[CH2:2].[C:3]1([CH3:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[CH2:1]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:9])[CH3:2]
Reactant: C=C
Reactant: Cc1ccccc1
Product: CCc1ccccc1C

Procedure:
In a manner similar to the preceding examples, 3.25 grams of HZSM-5 but having a crystallite size of about 2 microns was mixed with 1.75 grams of alumina binder and extruded to produce a 1/16 inch cylindrical particle. The extrudate with a volume of 8.5 ml. was diluted with 4 volumes of low surface area quartz and tested for its ability to alkylate toluene with ethylene to yield ethyltoluene. The conditions of reaction and results are shown in Table III below.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9]([C:24]#[N:25])[N:8]([C@@H:26]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[OH-:38].[Na+]>COCCO.O>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)=[C:9]([C:24](=[O:38])[NH2:25])[N:8]([C@@H:26]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2c(C#N)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: COCCO
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 125 °C
Yield: 100.5 %

Procedure:
A mixture of (R)-tert-butyl 3-(4-amino-6-cyano-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (101) (290 mg, 0.58 mmol) and NaOH (290 mg, 7 mmol) in 2-methoxyethanol/H2O (8 mL/2 mL) was sealed in a microwave tube. The reaction mixture was purged with N2 (3×) and heated at 125° C. in a microwave reactor for 45 min. After cooling down to r.t., the reaction was diluted with water, and the resulting solid was filtered, washed with water, dried under vacuum. (R)-tert-Butyl 3-(4-amino-6-carbamoyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (125) (300 mg, quant.) was obtained as a brown solid. LC-MS (ESI): m/z (M+1) 515.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]Cl>CC1C=CC=CC=1C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:1]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:3]=1
Reactant: Nc1cccnc1
Reactant: ClCCNCCCl
Agent: Cl
Solvent: Cc1ccccc1C
Product: c1cncc(N2CCNCC2)c1
Temperature: 140 °C
Reaction time: 20 h
Yield: 15.9 %

Procedure:
A suspension of 3-aminopyridine (2.0 g) and bis(2-chloroethyl)amine hydrochloride (3.8 g) in o-xylene (40 ml) was stirred at 140° C. for 20 hr. The reaction mixture was extracted with water and the aqueous layer was made alkaline with a 2N aqueous sodium hydroxide solution and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (developing solvent; chloroform:methanol:aqueous amnmonia=9:1:0.5) to give the title compound (0.55 g) as a black brown oil.