Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=1[O:5][CH:6]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7][NH+:8]([CH2:11][CH3:12])[CH2:9][CH3:10].C(N(CC)CC)C>O1CCCC1>[Cl:2][C:3]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=1[O:5][CH:6]([C:13](=[O:18])[C:14]([CH3:16])([CH3:17])[CH3:15])[CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10]
Reactant: CC[NH+](CC)CC(Oc1ccc(Cl)cc1Cl)C(=O)C(C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)CC(Oc1ccc(Cl)cc1Cl)C(=O)C(C)(C)C
Temperature: 25 °C
Yield: 89.2 %

Procedure:
38.1 g (0.1 mole) of [2-(2,4-dichlorophenoxy)-4,4-dimethyl-pentan-3-onyl]-diethylammonium chloride were dissolved in 200 ml of anhydrous tetrahydrofuran and 20.2 g (0.2 mole) of triethylamine were added dropwise at room temperature. After stirring for quarter of an hour at room temperature, the triethylammonium chloride which had precipitated was filtered off and the solvent was distilled off in vacuo. 30.9 g (90% of theory) of [2-(2,4-dichlorophenoxy)-4,4-dimethyl-pentan-3-onyl]-diethylamine were obtained as a yellow oil, which was immediately dissolved in 300 ml of anhydrous acetonitrile (0.09 molar batch). 21.3 g (0.15 mole) of methyl iodide were added dropwise thereto at room temperature, while stirring. The reaction mixture was stirred for 1 hour at room temperature and for 30 minutes under reflux and thereafter the solvent was distilled off under reduced pressure. The oil residue was taken up in 200 ml of a mixture of ethyl acetate and methyl ethyl ketone (1:1) and the whole was heated to the boil. This produced a crystalline residue, which was filtered off and rinsed with ether. 22.8 g (51.6% of theory) of [2-(2,4-dichlorophenoxy)-4,4-dimethyl-pentan-3-onyl]-diethylmethylammonium iodide of melting point 114°-118° C were obtained. ##STR155##
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]#[N:23])[CH:18]=[CH:19][CH:20]=1.Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>O1CCCC1.Cl>[CH3:36][O:35][C:33](=[O:34])[CH2:32][C:21]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:22]#[N:23])[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=1
Reactant: COC(=O)CBr
Reactant: COc1cccc(C(C#N)Cc2ccccc2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)CC(C#N)(Cc1ccccc1)c1cccc(OC)c1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a solution of diisopropylamine (0.7 ml, 5.1 mmol) in 20 ml dry tetrahydrofuran at −78° C. was added n-butyl lithium (1.6 M in hexan, 3.2 ml, 5.1 mmol) and stirred for 1 h. A solution of 2-(3-methoxy-phenyl)-3-phenyl-propionitrile (1.0 g, 4.2 mmol) in 5 ml dry tetrahydrofuran was added to the mixture, stirred for 30 min, followed by addition of methyl 2-bromoacetate (0.6 ml, 6.3 mmol). The mixture was stirred over night at room temperature, diluted with 50 ml 1M HCl and the resulting mixture extracted with dichloromethane. The organic layer was washed with water and brine, dried over sodium bicarbonate, filtered and the solvent evaporated to obtain a yellow oil (1.3 g). Purification on 12 g SiO2 using dichloromethane afforded a clear colourless oil.
Reaction SMILES: [CH3:1][C@@:2]12[C:11]3[CH:12]=[CH:13][C:14]([S:16][C:17]4[S:18][C:19]5[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=5[N:21]=4)=[CH:15][C:10]=3[CH2:9][CH2:8][C@H:7]1[NH:6][C:5](=[O:26])[CH2:4][CH2:3]2.[CH3:27]I>>[CH3:27][N:6]1[C@H:7]2[C@@:2]([CH3:1])([C:11]3[CH:12]=[CH:13][C:14]([S:16][C:17]4[S:18][C:19]5[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=5[N:21]=4)=[CH:15][C:10]=3[CH2:9][CH2:8]2)[CH2:3][CH2:4][C:5]1=[O:26]
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(Sc3nc4ccccc4s3)ccc12
Reactant: CI
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5ccccc5s4)cc3CC[C@@H]12

Procedure:
A 170 mg portion of (4aR)-(10bR)-10b-methyl-8-(2-benzothiazolylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one was alkylated with methyl iodide substantially according to the process of Example 95 to obtain 84 mg of the desired product. mp 188°-189° FDMS: m/e=394.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:4](=O)[CH2:5][C:6](=O)[C:7]([CH3:10])([CH3:9])[CH3:8])[CH3:3].Cl.[N+:15]([C:18]1[CH:22]=[N:21][NH:20][C:19]=1[NH2:23])([O-:17])=[O:16]>C(O)(=O)C>[C:2]([C:4]1[CH:5]=[C:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:20]2[N:21]=[CH:22][C:18]([N+:15]([O-:17])=[O:16])=[C:19]2[N:23]=1)([CH3:13])([CH3:3])[CH3:1]
Reactant: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Reactant: Nc1[nH]ncc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C(C)(C)C)n2ncc([N+](=O)[O-])c2n1
Yield: 46 %

Procedure:
36.85 g of 2,2,6,6-tetramethyl-3,5-heptanedione, 200 cc of acetic acid and 32.91 g of 4-nitro-2H-pyrazol-3-ylamine hydrochloride (prepared in accordance with H. Dorn and H. Dilcher, Liebigs Ann. Chem., 707,141, 1967) were introduced into a 500 ml three-necked flask fitted with a condenser, a thermometer and a magnetic bar. The mixture was refluxed for 8.5 hours. The solution was poured, hot, onto ice. The yellow solid which precipitated was filtered off. It was recrystallized from an acetic acid/water mixture. Drying under vacuum and over phosphoric anhydride yielded 25.4 g of 5,7-di-tert-butyl-3-nitropyrazolo[1,5-a]pyrimidine (yield=46%).
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[C:15]([C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([Cl:28])=[C:23]([O:29][CH3:30])[CH:22]=2)([CH3:18])([CH3:17])[CH3:16].[CH:31]([C:33]1[N:38]=[C:37]([C:39]([O:41][CH3:42])=[O:40])[CH:36]=[CH:35][CH:34]=1)=O.C(=O)([O-])O.[Na+]>ClCCl.O>[C:15]([C:19]1[NH:20][C:21]2[C:26]([C:27]=1[CH2:31][C:33]1[N:38]=[C:37]([C:39]([O:41][CH3:42])=[O:40])[CH:36]=[CH:35][CH:34]=1)=[CH:25][C:24]([Cl:28])=[C:23]([O:29][CH3:30])[CH:22]=2)([CH3:18])([CH3:16])[CH3:17]
Reactant: COc1cc2[nH]c(C(C)(C)C)cc2cc1Cl
Reactant: COC(=O)c1cccc(C=O)n1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cccc(Cc2c(C(C)(C)C)[nH]c3cc(OC)c(Cl)cc23)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
To a solution of triethylsilane (0.202 mL) and trifluoroacetic acid (0.049 mL) in dichloromethane (2 mL) was added a suspension of 2-tert-butyl-5-chloro-6-methoxy-1H-indole (100 mg) and methyl 6-formylpyridine-2-carboxylate (76.2 mg) in dichloromethane (1.5 mL) under ice-cooling, and this mixture was stirred at room temperature overnight. To the reaction mixture was added water, and then the resulting mixture was alkalified by the addition of sodium hydrogen carbonate. The organic layer was separated and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (152 mg). 1H-NMR (CDCl3) δ ppm: 1.39 (9H, s), 3.90 (3H, s), 4.05 (3H, s), 4.52 (2H, s), 6.91 (1H, s), 6.95-7.05 (1H, m), 7.28 (1H, s), 7.60 (1H, t, J=7.8 Hz), 7.80-8.20 (2H, m).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.FC(F)(F)C([O-])=O.[C:32]([C:35]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:40][CH2:39][NH2+:38][CH2:37][CH2:36]1)(=[O:34])[NH2:33].C(N(CC)CC)C>C(O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:5]1[N:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:7]2[C:3]([N:4]=1)=[C:2]([N:38]1[CH2:37][CH2:36][C:35]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)([C:32]([NH2:33])=[O:34])[CH2:40][CH2:39]1)[N:10]=[CH:9][N:8]=2
Reactant: NC(=O)C1(c2ccccc2)CC[NH2+]CC1
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=O)C1(c2ccccc2)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 55 °C
Yield: 62.3 %

Procedure:
To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purine (23.1 mg, 0.062 mmol, 1 eq.) in 2 mL of ethanol was added 4-carbamoyl-4-phenylpiperidin-1-ium trifluoroacetate (25 mg, 0.123 mmol, 2 eq.) and triethylamine (0.03 mL, 0.19 mmol, 3 eq.). The reaction was heated to 55° C. for 3 d. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 21 mg (63%) of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidine-4-carboxamide. 1H NMR (300 MHz, METHANOL-d4) δ ppm 2.02-2.21 (m, 2 H) 2.62 (d, J=13.37 Hz, 2 H) 3.82 (br. s., 2H) 4.98 (d, J=15.54 Hz, 2H) 7.07-7.67 (m, 13 H) 8.02-8.29 (m, 1 H), [M+H]+ 543.6.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[C:6]=1[O:16][CH3:17]>C(O)(=O)C>[Br:1][C:10]1[C:9]([CH3:11])=[C:8]([O:12][CH3:13])[C:7]([O:14][CH3:15])=[C:6]([O:16][CH3:17])[C:5]=1[O:4][CH3:3]
Reactant: COc1cc(C)c(OC)c(OC)c1OC
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1c(C)c(Br)c(OC)c(OC)c1OC
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
Bromine (46.7 g, 0.292 mols) was dropwise added to a solution of 1,2,3,4-tetramethoxy-5-methylbenzene (51.6 g, 0.243 mols) in acetic acid (100 ml) at room temperature, and the reaction mixture was stirred for 15 minutes and then concentrated in vacuo. The residue was diluted with ethyl acetate, and the organic layer was washed with water, a saturated aqueous sodium bicarbonate solution, water and a saturated aqueous sodium chloride solution, then dried, and concentrated in vacuo. The thus-obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain the entitled compound (59.1 g) as an oil.
Reaction SMILES: [Na].[CH2:2]([O:9][C:10]1[CH2:14][CH:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.BrBr.[CH3:25][NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(O)CCCCCC.C1C=CC=CC=1>[CH2:27]([N:26]([CH3:25])[CH:12]1[CH:11]([O:9][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:10]([O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:14][CH:13]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: C1=C(OCc2ccccc2)CC(OCc2ccccc2)C1
Reactant: CCCCCCCNC
Agent: BrBr
Agent: [Na]
Solvent: CCCCCCCO
Solvent: c1ccccc1
Product: CCCCCCCOC1C(OCc2ccccc2)CC(OCc2ccccc2)C1N(C)CCCCCCC

Procedure:
0.23 g of sodium are dissolved in 30 ml of 1-heptanol at 50° under nitrogen. Dropwise, with stirring, there is added 4.88 g of N-heptyl-N-methyl-2-bromo-4,5-bibenzyloxycyclopentane-1-amine (obtainable from 3,5-dibenzyloxy-2-cyclopentene by the addition of bromine and reaction with 1-equivalent of methyl heptylamine), dissolved in 30 ml of benzene. Stirring is carried on for 6 hours at 50°. After cooling, 100 ml of benzene is added thereto. This is washed with water. The organic phase is dried over MgSO4 and the solvent is distilled off. After chromatographic purification of the residue (silica gel/chloroform:acetone=9:1), N-heptyl-N-methyl-5-heptyloxy-2,4-dibenzyloxy-cyclopentane-1-amine is obtained.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:16]3[C:11]([C:12]([NH2:17])=[N:13][CH:14]=[N:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(Cl)Cl.[C:28](OC([O-])=O)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C1COCC1>[NH2:17][C:12]1[C:11]2=[CH:10][CH:9]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH2:2]3)[N:16]2[N:15]=[CH:14][N:13]=1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: Nc1ncnn2c(CN3CCNCC3)ccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cooled (0° C.) solution of 7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.85 g, 3.66 mmol) and triethylamine (0.56 mL, 4.03 mmol) in THF (8.5 mL)/DCM (8.5 mL) was added iii-tert-butyl dicarbonate (0.88 g, 4.03 mmol) and the mixture was allowed to warm to rt and further stirred for 18 h and concentrated. The residue was taken up in ethyl acetate, washed with water and dried over Na2SO4 and concentrated (used in the next step without further purification). LC-MS [M+H]+=332.8, RT=1.17 min
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Br:11])[CH:10]=1)=[N+]=[N-].O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1>[Br:11][C:9]1[CH:10]=[C:5]([CH2:4][NH2:1])[CH:6]=[N:7][CH:8]=1
Reactant: [N-]=[N+]=NCc1cncc(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: NCc1cncc(Br)c1
Reaction time: 8 h

Procedure:
To a solution of 3-azidomethyl-5-bromo-pyridine 250 (1.49 g, 7.00 mmol, 1.00 equiv) in 1,4-dioxane (12 mL) was added water (1 mL) and triphenylphosphine resin (2.08 g, 3 mol/g, 200-400 mesh, 1.2 equiv). The suspension was stirred overnight. Filtration and concentration afforded C-(5-bromo-pyridin-3-yl)-methylamine 251.
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][O:8][C@H:9]1[CH2:32][O:31][C:12]2=[CH:13][CH:14]=[C:15]3[C:19]([N:18]([CH2:20][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH3:22])[N:17]=[CH:16]3)=[C:11]2[CH2:10]1)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)(O)[O-].[Na+]>C1COCC1>[C:27]([Si:24]([CH3:26])([CH3:25])[O:23][C@H:21]([CH3:22])[CH2:20][N:18]1[C:19]2[C:15](=[CH:14][CH:13]=[C:12]3[O:31][CH2:32][C@H:9]([O:8][CH2:7][CH2:6][OH:5])[CH2:10][C:11]3=2)[CH:16]=[N:17]1)([CH3:29])([CH3:30])[CH3:28]
Reactant: C[C@H](Cn1ncc2ccc3c(c21)C[C@@H](OCC(=O)OC(C)(C)C)CO3)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@H](Cn1ncc2ccc3c(c21)C[C@@H](OCCO)CO3)O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To a cooled (0° C.) solution of the product from Example 13, Step A (1.76 g, 3.70 mmol) in anhydrous THF (30 mL) under nitrogen was added an 1 M solution of lithium aluminum hydride in THF (3.70 mL, 3.70 mmol). The reaction mixture was stirred for 0.5 h, cooled on ice, and a saturated aqueous solution of sodium bicarbonate (100 mL) was added. This mixture was extracted with ethyl acetate and the extract evaporated to an oil which was purified by chromatography (silica, gradient, 10% to 40% ethyl acetate in hexane) to give an oil (1.40 g, 93%): LCMS (+APCI) m/z 407 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[NH:20][C:21](=[O:25])[N:22]=[CH:23][CH:24]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].Br[CH2:31][CH3:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][N:22]([CH2:31][CH3:32])[C:21](=[O:25])[N:20]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:26]([F:27])([F:29])[F:28]
Reactant: N#Cc1cc(COc2ccnc(=O)[nH]2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCBr
Product: CCn1ccc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)c(C#N)c2)nc1=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-{[(2-oxo-2,3-dihydro-4-pyrimidinyl)oxy]methyl}benzonitrile and bromoethane. LC-MS (ESI): m/z 450 [M+H]+; 4.11 min (ret time).
Reaction SMILES: [F:1][CH:2]([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:12](OCC)(OCC)[O:13][CH2:14][CH3:15].C(OC(=O)C)(=O)C>>[CH2:14]([O:13][CH:12]=[C:4]([C:3]([CH:2]([F:11])[F:1])=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:15]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)C(F)F
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)C(F)F
Temperature: 92.5 °C
Yield: 86.4 %

Procedure:
To the concentrated product of crude ethyl difluoroacetoacetate (˜0.93 mole) are added triethyl orthoformate (266.8 g, 1.8 moles) and acetic anhydride (367.6 g, 3.6 moles). The mixture is heated to 90-95° C., and kept gently refluxing for 6 hours. (GC shows ethyl difluoroacetoacetate content <0.1%). The reaction mixture is cooled to 60-70° C. and then concentrated under vacuum to remove excess acetic anhydride, triethyl orthoformate, and generated ethyl acetate. A pale brown liquid (178.6 g) is obtained. The yield of two steps is 80%.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH3:14])=[O:5])#[N:2].CO[C:17](OC)([N:19]([CH3:21])[CH3:20])[CH3:18]>>[C:1](/[C:3](=[C:17](/[N:19]([CH3:21])[CH3:20])\[CH3:18])/[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH3:14])=[O:5])#[N:2]
Reactant: COC(C)(OC)N(C)C
Reactant: CCc1ccccc1NC(=O)CC#N
Product: CCc1ccccc1NC(=O)/C(C#N)=C(/C)N(C)C

Procedure:
As for Example 1, 2-cyano-2'-ethylacetanilide is heated with N,N-dimethylacetamide dimethylacetal to give 2-cyano-3-dimethylamino-2'-ethylcrotonanilide as colorless prisms, m.p. 79°-81.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:35]S(C(C)(C)C)=O)([C:29]2[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=2)[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[CH:5][C:4]=1F)#[N:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl.C(O)(C(F)(F)F)=O>CN(C=O)C.CO.O1CCOCC1>[NH2:35][C:9]1([C:29]2[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=2)[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14]2)[S:19](=[O:20])(=[O:21])[C:22]2=[CH:23][C:24](=[CH:25][CH:26]=[CH:27]2)[O:28][C:8]2=[CH:7][C:6]1=[CH:5][CH:4]=[C:3]2[C:1]#[N:2]
Reactant: Cn1cncc1C(CCCN1CCN(S(=O)(=O)c2cccc(O)c2)CC1)(NS(=O)C(C)(C)C)c1ccc(C#N)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cn1cncc1C1(N)CCCN2CCN(CC2)S(=O)(=O)c2cccc(c2)Oc2cc1ccc2C#N
Reaction time: 24 h

Procedure:
N-[1-(4-cyano-3-fluorophenyl)-4-{4-[(3-hydroxyphenyl)sulfonyl]piperazin-1-yl}-1-(1-methyl-1H-imidazol-5-yl)butyl]-2-methylpropane-2-sulfinamide (0.115 g, 0.186 mmol) was dissolved in DMF (19 mL) and treated with Cs2CO3 (0.304 g, 0.93 mmol). After 24 h at 80° C., the reaction mixture was concentrated in vacuo, partitioned between CH2Cl2 and H2O, the aqueous layer washed with CH2Cl2 (2×), the organic layers combined, washed with brine, and dried (MgSO4). Filtration and concentration in vacuo gave the protected product which was dissolved in MeOH (10 mL) and treated with 4M HCl in dioxane (5 mL) with stirring. After 15 min. the reaction mixture was concentrated in vacuo, dissolved in H2O: 0.1% TFA (3 mL), and purified by RP LC on a Delta PrepPak eluting with 95:5 to 5:95 H2O(0.1% TFA): CH3CN(0.1% TFA) and lyophilized to give the product as the TFA salt of a mixture of enantiomers. This product was chromatographed on a Chiralcel OD column eluting with 0.1% DEA:hexane/EtOH, 60/40 to give the title compound as a single enantiomer. MS (M+1) 493.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([CH3:9])[C:6](OS(C(F)(F)F)(=O)=O)=[C:5]([CH3:18])[CH:4]=1)=[O:2].[C:19]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:24]=CC=C[CH:20]=1.[Li+].[Cl-].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>CN(C=O)C.C([Sn](CCCC)(CCCC)CCCC)C=C.O.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>[CH2:24]([C:6]1[C:7]([CH3:9])=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][C:5]=1[CH3:18])[CH:19]=[CH2:20]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1cc(C=O)cc(C)c1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1c(C)cc(C=O)cc1C
Temperature: 120 °C
Reaction time: 1 h
Yield: 114.8 %

Procedure:
To a solution of trifluoromethanesulfonic acid 4-formyl-2,6-dimethyl-phenyl ester (3.13 g, 11.1 mmol), bis(triphenylphosphine)palladium dichloride (682 mg, 0.972 mmol), triphenylphosphine (1.76 g, 6.7 mmol), LiCl (3.98 g, 93.8 mmol) and a trace of 2,6-di-tert.-butyl-4-methylphenol in DMF (30 mL), allyltributylstannane (2 mL) is added. The mixture is heated to 120° C. and stirred for 2 h before another portion of allyltributylstannane (2 mL) is added. Stirring is continued at 120° C. for 1 h. The mixture is cooled to rt, diluted with water (100 mL) and extracted with EA. The organic extract is washed with 1.5 M aq. HCl (2×100 mL), dried over MgSO4, and the solvent is evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 20:1 to give 4-allyl-3,5-dimethyl-benzaldehyde (1.34 g) as a colourless liquid; 1H NMR (CDCl3: δ 9.92 (s, 1H), 7.53 (s, 2H), 5.96-5.80 (m, 1H), 5.06-5.00 (m, 1H), 4.87-4.78 (m, 1H), 3.48-3.40 (m, 2H), 2.38 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:66][Si](C(C)(C)C)(C)C)[CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]3[CH:35]=[C:36]([S:40]([C:43]4[CH:44]=[C:45]5[C:50](=[C:51]([CH3:53])[CH:52]=4)[N:49]=[CH:48][C:47]([C:54]([NH2:56])=[O:55])=[C:46]5[NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([O:64][CH3:65])[CH:59]=4)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=3)=[O:33])=[CH:27][CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(O)(=O)C>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:66])[CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([NH:31][C:32]([C:34]3[CH:35]=[C:36]([S:40]([C:43]4[CH:44]=[C:45]5[C:50](=[C:51]([CH3:53])[CH:52]=4)[N:49]=[CH:48][C:47]([C:54]([NH2:56])=[O:55])=[C:46]5[NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([O:64][CH3:65])[CH:59]=4)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=3)=[O:33])=[CH:29][CH:30]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(OCc7ccccc7)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCNC[C@H](O)c6ccc(OCc7ccccc7)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Intermediate 140 (135 mg, 0.133 mmol) was combined with TBAF (1M/THF, 0.4 mL) and acetic acid (23 μL) in anhydrous acetonitrile (0.2 mL) and allowed to stir at rt. After 18 h, the reaction was concentrated in vacuo to a brown oil, which was suspended in H2O. The solid was filtered and washed with H2O and hexane, then dried to give the title compound as a yellow solid, 124 mg, which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 10.46 (s, 1H), 9.09 (s, 1H), 8.37 (s, 1H), 8.32 (s, 1H), 8.30 (br s, 1H), 8.16-8.24 (m, 2H), 8.03 (s, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.77 (br s, 1H), 7.76 (dd, J=7.6, 15.6 Hz, 1H), 7.66 (d, J=8.3 Hz, 2H), 7.55 (d, J=7.6 Hz, 2H), 7.32-7.41 (m, 2H), 7.26-7.32 (m, 1H), 7.07-7.23 (m, 5H), 6.61-6.69 (m, 2H), 6.49-6.59 (m, 2H), 5.28 (s, 2H), 5.03 (t, J=6.1 Hz, 1H), 3.60 (s, 3H), 3.15-3.19 (m, 2H), 2.70 (s, 3H), 2.62-2.81 (m, 7H). ES/MS calcd. for C51H47N6O8S+ 903.3. Found m/z=903.3 (M+H+).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([C:11]2[S:15][C:14]([NH2:16])=[N:13][N:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C(OCC)(=O)C>[CH:5]1([C:11]2[S:15][C:14]([N:16]=[C:1]=[O:2])=[N:13][N:12]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: Nc1nnc(C2CCCCC2)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1nnc(C2CCCCC2)s1

Procedure:
A saturated solution of phosgene in ethyl acetate (500 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. 5-Cyclohexyl-2-amino-1,3,4-thiadiazole (6 grams) is added to the reaction vessel, and the resulting mixture is stirred and heated at reflux for a period of about 4 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized from a dimethyl formamide-water mixture to yield the desired product 5-cyclohexyl-1,3,4-thiadiazol-2-yl isocyanate dimer having a melting point of 237° to 239° C.