Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(OC[C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])(=O)=O.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>CN(C)C=O>[CH3:45][N:46]1[CH2:51][CH2:50][N:49]([C@@H:7]2[CH2:11][C@H:10]([S:12][C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:9][N:8]2[C:32]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=2)=[O:33])[CH2:48][CH2:47]1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)OC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: CN1CCN([C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of (2S,4S)-2-(methanesulfonyloxy)methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (10.37 g) in dimethylformamide (100 ml) was added N-methylpiperazine (5.45 ml) and the mixture was stirred at 80°-90° C. for 5 hours. The reaction mixture was poured into ice-water (300 ml) and extracted twice with ethyl acetate (200 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of chloroform and methanol (9:1 V/V). The fraction containing the desired compound were collected and evaporated in vacuo to give (2S ,4S) 2-(4-methylpiperazin-1-yl)-1-(4-nitrobenzyloxy carbonyl)-4-(triphenylmethylthio)pyrrolidine (6.87 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.[C:33](O)(=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[N+:36]([O-:40])[CH:35]=1.C(N=C=NC(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C=O)C.CO.C(OCC)C>[C:33]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)(=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[N+:36]([O-:40])[CH:35]=1
Reactant: O=C(O)c1ccc[n+]([O-])c1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1)c1ccc[n+]([O-])c1
Reaction time: 24 h
Yield: 53.6 %

Procedure:
(5R)-3-(3-fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1: 130 mg, 0.30 mMol), nicotinic acid 1-oxide (100 mg, 0.72 mMol), 1,3-diisopropylcarbodiimide (290 mg, 2.3 mMol), and 4-dimethylaminopyridine (5 mg, 0.04 mMol) were suspended in 2 ml of DMF at room temperature. The mixture was stirred one day, diluted with methanol (2 ml), stirred 5 minutes and then further diluted with diethyl ether (20 ml) to give a suspension. The solids were collected and rinsed with diethyl ether, then suspended in acetonitrile:methanol (1:1, 150 ml), the mixture was warmed and stirred a few minutes, then allowed to cool. The suspension was filtered and the filtrate was concentrated to a volume of 10 ml to give a suspension. The solids were collected, rinsed with acetonitrile, then diethyl ether and dried under vacuum to yield the title compound as an off-white solid (90 mg), melting point: 255° C.
Reaction SMILES: I[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[F:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=1[CH:76]1[C:80]([CH3:82])([CH3:81])[O:79][C:78](=[O:83])[NH:77]1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=1[CH:76]1[C:80]([CH3:81])([CH3:82])[O:79][C:78](=[O:83])[N:77]1[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc2cccnc12)c1ccc(I)cc1
Reactant: CC1(C)OC(=O)NC1c1ccccc1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N(c2ccc(C(=O)Nc3cccc4cccnc34)cc2)C1c1ccccc1F
Temperature: 100 °C
Reaction time: 3 h
Yield: 20 %

Procedure:
To a nitrogen purged solution of 4-iodo-N-(quinolin-8-yl)benzamide (250 mg, 0.66 mmol) in 1,4-dioxane (5 mL) were added cesium carbonate (435.37 mg, 1.33 mmol), xantphos (77.31 mg, 0.13 mmol), Pd2(dba)3 (61.18 mg, 0.06 mmol) and 4-(2-fluorophenyl)-5,5-dimethyloxazolidin-2-one (167.73 mg, 0.80 mmol). The mixture was purged with nitrogen for 5-10 minutes. The reaction mixture was then stirred for 3 hours at 100° C. After completion of the reaction (monitored by TLC, TLC system: 30% EtOAc in hexane), the reaction mixture was cooled to ambient temperature and filtered through Celite® brand filter aid. The filtrate was concentrated and purified by column chromatography using silica gel and eluting with 30% EtOAc in hexane to afford (R+S) 4-(4-(2-fluorophenyl)-5,5-dimethyl-2-oxooxazolidin-3-yl)-N-(quinolin-8-yl)benzamide (60 mg, 19.71%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.57 (s, 1H), 8.95 (dd, J=1.2 Hz, 1H), 8.68 (d, J=7.6 Hz, 1H), 8.46 (d, J=8.3 Hz, 1H), 8.00-7.95 (m, 2H), 7.82-7.62 (m, 5H), 7.41-7.35 (m, 2H), 7.19-7.08 (m, 2H), 5.84 (s, 1H), 1.69 (s, 3H), 1.03 (s, 3H). m/z (ESI) 456.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:9])=[CH:3][CH2:4][CH2:5][S:6](Cl)=[O:7].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.O.Cl>C(OCC)C.C(OCC)(=O)C.CCCCCC>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][S:6]([CH2:5][CH2:4][CH:3]=[C:2]([F:9])[F:1])=[O:7])=[CH:13][CH:12]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=S(Cl)CCC=C(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: O=S(CCC=C(F)F)NCc1ccc(Cl)cc1
Reaction time: 48 h

Procedure:
4,4-Difluorobut-3-enyl sulfinylchloride (0.5 g) in dry diethyl ether (1.5 ml) was stirred at ambient temperature and 4-chlorobenzylamine (1.0 g) in diethyl ether (1.5 ml) was added dropwise. The mixture was stored at ambient temperature for 2 days then water (100 ml) added. The mixture was made acidic with aqueous hydrochloric acid (2M) and extracted with dichloromethane (100 ml). The organic fraction was separated, washed with water then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give an oil which was fractionated by chromatography (silica; ethyl acetate/hexane 2:1 by volume) to give N-4-chlorobenzyl 4,4-difluorobut-3-enyl-sulfinamide, 0.094 g, as an off-white solid, mp37-8° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[CH:12][C:11]=1[CH2:18][N:19]1[C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[CH2:21][O:20]1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(Cl)Cl.C(OCC)(=O)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH:17][C:27]([CH3:28])=[O:29])=[CH:12][C:11]=1[CH2:18][N:19]1[C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[CH2:21][O:20]1
Reactant: CC1(C)CON(Cc2cc(NN)ccc2Cl)C1=O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)NNc1ccc(Cl)c(CN2OCC(C)(C)C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
Triethylamine (0.6 g, 0.0055 mole) was added to a stirred solution of 2-[(2-chloro-5-hydrazinophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone hydrochloride (1.5 g, 0.005 mole) in methylene chloride (50 ml), followed by the dropwise addition of acetic anhydride (0.6 g, 0.0055 mole). Upon completion of addition, the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with ethyl acetate (200 ml) and washed with water (3×50 ml). The dried (magnesium sulfate) organic layer was concentrated under reduced pressure. The residue was recrystallized from ethanol-water to yield 0.95 g of 2-[[2-chloro-5-(methylcarbonylhydrazo)phenyl]methyl]-4,4-dimethyl-3-isoxazolidinone as a yellow solid; m.p. 178°-180° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11]CC)=[O:10])=[C:7]([OH:14])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.[OH-].[Na+].CO>C(OCC)(=O)C.Cl>[OH:14][C:7]1[CH:6]=[C:5]([C:15]([F:16])([F:17])[F:18])[N:4]=[C:3]([C:2]([F:20])([F:1])[F:19])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 95.5 %

Procedure:
A solution of ethyl 2,6-bis(trifluoromethyl)-4-hydroxy-3-pyridinecarboxylate (product of Example 3, 15 g, 0.0495 mol) in 5% aqueous sodium hydroxide (60 ml, 0.148 mol) was refluxed for 3 hours. The reaction was complete as judged by TLC (10% methanol in ethyl acetate). The mixture was then poured into a mixture of ice in concentrated aqueous hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate, and concentrated to give a light brown solid (13 g). It was treated with petroleum ether to give 11.9 g of a white solid (83%); mp 168°-172° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([F:31])=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:76][CH:77]1[CH2:82][CH2:81][O:80][CH2:79][CH2:78]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([F:31])=[CH:29][C:25]([C:26]([NH:76][CH:77]5[CH2:82][CH2:81][O:80][CH2:79][CH2:78]5)=[O:27])=[C:24]([F:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCOCC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)O)cc3F)ncc21
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)NC4CCOCC4)cc3F)ncc21
Reaction time: 0.17 h
Yield: 71.1 %

Procedure:
To a mixture of 0.0606 g (0.134 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-benzoic acid (I-232) and 4 mL of dimethylformamide was added 0.0292 g (0.216 mmole) of 1-hydroxybenzotriazole, 0.0784 g (0.207 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1083 g (0.804 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0203 g (0.201 mmole) of 4-aminotetrahydropyran was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-90:10) gave 0.0511 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-N-(tetrahydro-pyran-4-yl)-benzamide (I-235).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11](=[O:17])[C:12](=[N+:15]=[N-:16])[CH:13]=O)[CH3:9].CC(O)=O>CCO>[CH2:8]([O:10][C:11]([C:12]1[N:15]=[N:16][N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=1)=[O:17])[CH3:9]
Reactant: CCOC(=O)C(C=O)=[N+]=[N-]
Reactant: Nc1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(-c2ccccc2)nn1
Reaction time: 8 h
Yield: 86.8 %

Procedure:
Oxalyl chloride (4.7 g, 30.1 mL, 37.0 mmol) was added to a cold (0-4° C.) solution of DMF (2.25 g, 2.4 mL, 30.8 mmol) in CHCl3 (20 mL) and stirring was continued for 10 minutes. The reaction mixture was heated at 40° C. for 10 minutes and cooled to −10° C. Diazoacetic acid ethyl ester (3.5 g, 3.5 mL, 30.6 mmol) was then added and stirred at room temperature for 1 hr. The reaction mixture was concentrated ether was then added, the precipite was collected and dissolved in 10% aq Hac (10 mL) and stirring was continued for 1 hr. The reaction mixture was extracted with ether, washed with saturated sodium bicarbonate solution and brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 590 mg (21% Yield) of 2-diazo-3-oxo-propionic acid ethyl ester. 1H NMR (300 MHz, CDCl3): δ 9.7 (s, 1H), 4.4 (q, 2H), 1.4 (t, 3H). Aniline (143 mg, 1.5 mmol) was added to a solution of 2-diazo-3-oxo-propionic acid ethyl ester (200 mg, 1.4 mmol) and HOAc (0.2 mL) in EtOH (0.5 mL) and stirring was at room temperature overnight. The reaction mixture was concentrated and cold water was then added, the solid was collected to afford 264 mg (87.41% Yield) of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester. 1H NMR (300 MHz, CDCl3): δ 8.5 (s, 1H), 7.8 (d, 2H), 7.6-7.48 (m, 3H), 4.5 (q, 2H), 1.4 (t, 3H). LiOH.H2O (80 mg, 1.9 mmol) was added to a stirred solution of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (130 mg, 0.6 mmol) in THF:H2O (1:1, 4 mL), and the resulting mixture was stirred at room temperature for 45 min. The reaction mixture was concentrated under reduced pressure. Cold water was then added and it was acidified with 10% aqueous HCl, the solid was collected to afford 40 mg (35.4% yield) of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid. 1H NMR (300 MHz, DMSO-d6): δ 13.4 (bs, 1H), 9.4 (s, 1H), 8.0 (d, 2H), 7.7 (t, 2H), 7.6 (t, 1H).
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)=O.[NH2:18][C:19]1[C:24]([O:25][CH2:26][CH3:27])=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH2:26]([O:25][C:24]1[C:19]2[N:20]([C:2]([CH3:17])=[C:3]([C:5]3[CH:6]=[CH:7][C:8]4[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=4[CH:16]=3)[N:18]=2)[CH:21]=[CH:22][CH:23]=1)[CH3:27]
Reactant: CC(Br)C(=O)c1ccc2c(c1)NC(=O)C(C)O2
Reactant: CCOc1cccnc1N
Product: CCOc1cccn2c(C)c(-c3ccc4c(c3)NC(=O)C(C)O4)nc12
Yield: 46 %

Procedure:
6-(8-Ethoxy-3-methylimidazo[1,2-a]pyridin-2-yl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.25 g) was prepared in substantially the same manner as that of Example 16 from 6-(2-bromopropionyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.4 g) and 2-amino-3-ethoxypyridine (2.8 g). mp. 180°-181° C. (dec.).
Reaction SMILES: CC(C)C(BC(C(C)C)C)C.[CH3:12][Si:13]([CH3:24])([CH3:23])[O:14][CH:15]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:16][C:17]#[CH:18].C[N+]([O-])(C)C.[OH-].[Na+].[I:32]I>O1CCCC1>[I:32]/[CH:18]=[CH:17]/[CH2:16][CH:15]([O:14][Si:13]([CH3:23])([CH3:24])[CH3:12])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: C#CCC(CCCC)O[Si](C)(C)C
Reactant: II
Agent: CC(C)C(C)BC(C)C(C)C
Agent: C[N+](C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(C/C=C/I)O[Si](C)(C)C
Temperature: 25 °C

Procedure:
To a stirred solution of 0.20 moles of freshly prepared bis-(3-methyl-2-butyl)borane in 300 ml of tetrahydrofuran at 0°-5° C. is added dropwise a solution of 19.8 g of 4-trimethylsiloxy-1-octyne in 30 ml of tetrahydrofuran. The resulting mixture is stirred at ambient temperature for several hours, cooled in an ice bath, and treated with 53 g of trimethylamine oxide. The mixture is stirred several hours at 25°-40° C. and then poured into 2 liters of 15% sodium hydroxide. The resulting mixture is treated immediately with a solution of 140 g of iodine in 300 ml of tetrahydrofuran. After 0.5 hour the organic phase is separated and the aqueous phase is extracted with ether. The combined organic layers are washed with water, sodium thiosulfate solution, and brine; dried over magnesium sulfate; and concentrated to give an oil, pmr spectrum (CDCl3): 6.2 (d, ICH=) and 6.7 (quintuplet, =H--).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH:9]2[CH2:11][CH2:10]2)[NH:6][C:5](=[O:12])[CH:4]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]2([CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[O:34][C:33](=[O:35])[CH2:32][C:31](=[O:36])[CH2:30]2)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]2([CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[O:34][C:33](=[O:35])[C:32]([CH2:2][C:3]3[N:8]=[C:7]([CH:9]4[CH2:11][CH2:10]4)[NH:6][C:5](=[O:12])[CH:4]=3)=[C:31]([OH:36])[CH2:30]2)=[CH:23][CH:22]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CC(=O)OC(CCc2ccc(OCc3ccccc3)cc2)(C2CCCC2)C1
Reactant: O=c1cc(CCl)nc(C2CC2)[nH]1
Product: O=C1OC(CCc2ccc(OCc3ccccc3)cc2)(C2CCCC2)CC(O)=C1Cc1cc(=O)[nH]c(C2CC2)n1
Yield: 12 %

Procedure:
The title compound was prepared as described in Example B(53), using 6-(chloromethyl)-2-cyclopropylpyrimidin-4(3H)-one in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-{2-[4-(benzyloxy)phenyl]ethyl}-6-cyclopentyldihydro-2H-pyran-2,4-(3H)-dione (Step 6, below) in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 12%. 1H NMR (300 MHz, DMSO-d6) δ 0.91 (m, 4H), 1.15-1.65 (m, 8H), 1.82-1.92 (m, 3H), 2.34 (m, 1H), 2.38-2.58 (m, 3H, overlap with DMSO-d5), 2.75 (d, J=18 Hz, 1H), 3.29 (ABQ pattern, J=16.7 Hz, 2H), 5.05 (s, 2H), 5.72 (s, 1H), 6.90 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 7.43-7.28 (m, 5H). LC-MS (APCI) calcd for C33H36N2O5: 540.26; found (M+H+) 541.1 m/z.
Reaction SMILES: [CH3:1][C:2]12[CH2:15][CH:5]([CH:6]([C:11]([O:13][CH3:14])=[O:12])[CH:7]1[C:8]([OH:10])=[O:9])[CH:4]=[CH:3]2.[C:16]([O:21][CH2:22][CH:23]1[O:25][CH2:24]1)(=[O:20])[C:17]([CH3:19])=[CH2:18].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C>[Cl-].C[N+](C)(C)C>[CH3:1][C:2]12[CH2:15][CH:5]([CH:6]([C:11]([O:13][CH3:14])=[O:12])[CH:7]1[C:8]([O:10][CH2:24][CH:23]([OH:25])[CH2:22][O:21][C:16](=[O:20])[C:17]([CH3:19])=[CH2:18])=[O:9])[CH:4]=[CH:3]2
Reactant: COC(=O)C1C2C=CC(C)(C2)C1C(=O)O
Reactant: C=C(C)C(=O)OCC1CO1
Agent: C[N+](C)(C)C
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Product: C=C(C)C(=O)OCC(O)COC(=O)C1C(C(=O)OC)C2C=CC1(C)C2

Procedure:
This acid ester (50 g) was heated with glycidyl methacrylate (40 g) at 100° C. in the presence of 0.27 g of tetramethylammonium chloride and 0.13 g of 2,6-di-tert.butyl-p-cresol until the epoxide content had fallen to a negligible level; the desired ester so formed was a viscous liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.C(N(CC)CC)C.[C:23]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])#[CH:24]>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:28][C:27]1[CH:26]=[C:25]([C:23]#[C:24][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: C#Cc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(C#Cc2cccc(N)c2)ccn1
Temperature: 70 °C
Yield: 15.5 %

Procedure:
tert-Butyl (4-bromopyridin-2-yl)carbamate (1.935 g, 7.09 mmol), copper(I) iodide (0.67 g, 3.5 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.20 g, 0.28 mmol) were stirred in tetrahydrofuran (22 mL) with triethylamine (1.09 mL, 7.82 mmol) under N2 at rt. 3-Ethynylaniline (0.815 mL, 7.79 mmol) was added and the mixture was heated at 70° C. for 2 hours and only very little product was observed. Thus more 3-ethynylaniline (0.41 mL, 3.9 mmol) was added and the mixture was heated at 70° C. over the weekend. The reaction mixture was filtered and concentrated to give a brown residue, which was purified by silica gel column chromatography to give the desired product (340 mg, 16%). LCMS for C18H20N3O2 (M+H)+: m/z=310.1
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]#[C:7][CH2:8][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])(=[O:3])[CH3:2].[Cl:15][C:16]1[N:21]=[CH:20][C:19]([CH2:22][NH:23]C)=[CH:18][CH:17]=1>O1CCCC1>[C:1]([O:4][CH2:5][C:6]([NH:23][CH2:22][C:19]1[CH:20]=[N:21][C:16]([Cl:15])=[CH:17][CH:18]=1)=[CH:7][CH2:8][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])(=[O:3])[CH3:2]
Reactant: CNCc1ccc(Cl)nc1
Reactant: CC(=O)OCC#CCC(=O)OC(C)C
Solvent: C1CCOC1
Product: CC(=O)OCC(=CCC(=O)OC(C)C)NCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an initial charge of 124 mg (0.672 mmol) of iso-propyl 4-acetoxybut-2-ynecarboxylate in 5 ml of anhydrous tetrahydrofuran (THF) are added dropwise 116 mg (0.739 mmol) of 1-(6-chloropyridin-3-yl)-N-methylmethanamine, dissolved in 1 ml of anhydrous THF, at room temperature. The reaction mixture is stirred at room temperature for 16 h and concentrated under reduced pressure. Subsequently, the residue is taken up with toluene and washed successively with dilute aqueous sulphuric acid and sodium hydrogencarbonate solution. After drying over magnesium sulphate and concentrating the organic phase under reduced pressure, 120 mg (50% of theory) of iso-propyl 4-acetoxy-3-[(4-chlorobenzyl)(methyl)amino]but-2-enecarboxylate are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>C(#N)C>[F:9][C:5]1[C:6]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[N:7][C:2]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[N:3][C:4]=1[C:10]([F:13])([F:12])[F:11]
Reactant: c1c[nH]cn1
Reactant: Fc1c(Cl)nc(Cl)nc1C(F)(F)F
Solvent: CC#N
Product: Fc1c(-n2ccnc2)nc(-n2ccnc2)nc1C(F)(F)F

Procedure:
2,4-Dichloro-5-fluoro-6-trifluoromethylpyrimidine (2.74 g) was dissolved in acetonitrile (30 ml) and imidazole (3.97 g) was added at room temperature with stirring. The mixture was stirred over night and then the solvent was removed under reduced pressure. The residue was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, respectively and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was triturated with carbon tetrachloride to give crude, 5-fluoro-2,4-diimidazol-1-yl-6-trifluoromethylpyrimidine. It was recrystallized from isopropanol as colorless crystalline solid, mp 142-150° C. (decomposed).
Reaction SMILES: C([N:8]([CH2:19][CH:20]([OH:40])[CH2:21][O:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:39])[CH:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30]2)=[CH:25][CH:24]=1)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1)C1C=CC=CC=1.C1CCCCC=1.C(O)(=O)C>O.[Pd]>[CH2:12]([CH2:11][CH2:10][CH2:9][NH:8][CH2:19][CH:20]([OH:40])[CH2:21][O:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:39])[CH:28]=[C:29]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[O:30]2)=[CH:25][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1
Reactant: O=c1cc(-c2ccccc2)oc2cc(OCC(O)CN(CCCCc3cccnc3)Cc3ccccc3)ccc12
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc(-c2ccccc2)oc2cc(OCC(O)CNCCCCc3cccnc3)ccc12
Yield: 54 %

Procedure:
A suspension of 7-[3-[N-benzyl,N-(3-nicotinylpropyl)amino]-2-hydroxypropoxy]flavone (4.50 g, 8.64 mmol), Example 17b, palladium black (0.1 g), cyclohexene (30 ml), and acetic acid (30 ml) was refluxed for 6 hours. The solvent was evaporated to give a residue which was dissolved in water and washed with chloroform (twice) to remove impurities. The aqueous solution was basified with 2.5N NaOH and then extracted with methylene chloride several times. The extracts were washed with water, dried (MgSO4), and evaporated to afford a yellow solid of 2.9 g. Recrystallization from isopropyl alcohol gave light yellow crystals (2.0 g; 54% yield), mp 116°-119° C.