Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=CC=C.[Cl-].[Li+].CO.COC1(OC)CCCCC1.[C:19]([O:29][CH3:30])(=[O:28])[CH2:20]/[CH:21]=[CH:22]/[CH2:23][C:24]([O:26][CH3:27])=[O:25].C(OC)(=O)C=CC=CC(OC)=O.[C]=O.O=O>[Pd](Cl)Cl.[Cu](Cl)Cl.[Mo].[Ni]>[C:24]([O:26][CH3:27])(=[O:25])[CH2:23][CH:22]=[CH:21][CH2:20][C:19]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)C/C=C/CC(=O)OC
Agent: Cl[Cu]Cl
Agent: Cl[Pd]Cl
Agent: [Mo]
Solvent: CO
Product: COC(=O)CC=CCC(=O)OC
Temperature: 25 °C

Procedure:
1,3-butadiene (1000 mmoles) along with 0.444 g. (2.5 mmole) palladium (II) chloride, 3.36 g. (25 mmole) copper (II) chloride and 0.21 g. (5 mmole) lithium chloride, 32 mmole of methyl alcohol and 1000 mmole of 1,1-dimethoxycyclohexane was reacted in a 500 ml nickel-molybdenum (Hastelloy alloy) stirred autoclave to prepare a mixture of 41.80 g. (243 mmoles) of cis and trans dimethyl hex-3-endioate, at a trans to cis ratio of 3:1, and 2.04 g. (12 mmoles) of dimethyl hex-2,4-diendioate. The liquid feed and solid catalyst components were charged into the autoclave as homogeneous solutions. The 1,3-butadiene was charged into a sight glass and allowed to come to thermal equilibrium and then charged into the autoclave as a liquid under pressure. The reaction temperature was 100° C. and the total initial carbon monoxide pressure was 1600 psig. The reaction was initiated by a 100 psig charge of oxygen and 1000 psig line purging charge of carbon monoxide giving a total system pressure of 1800 psig. A strong exotherm and pressure drop of 150-200 psig over a course of 20 minutes was observed. The oxygen cycle was repeated five more times in increments of 50 psig oxygen and 100 psig carbon monoxide at intervals of 20 minutes during an autoclave residence period of 120 minutes. A total pressure drop of about 1000 psig was observed. The reaction was terminated before completion and cooled to ambient temperature and vented to ambient pressure. Solids were separated from liquids by vacuum filtration. The 1,3-butadiene conversion and selectivities to the dimethyl hex-3-endioate based on the butadiene was 55 percent and 74 mole percent respectively. The dimethyl hex-3-endioate was isolated from the oxidative carbonylation reaction mixture by fractional vacuum distillation and analyzed by gas liquid chromatography (Fraction b.p. 123° C. @ 9 mm Hg.) for use in a subsequent hydrogenation step to prepare dimethyl adipate. The prefraction (b.p. 67° C. @ 54 mm Hg) containing cyclohexanone, 1-methoxycyclohexene and minor amounts of unreacted 1,1-dimethoxycyclohexane was cycled to a regeneration step for subsequent use in further oxidative carbonylation reactions. The pot residue from the oxidative carbonylation reaction containing a very small amount of dimethyl hex-3-endioate product heal and a slurry containing approximately 99.9 percent of the original charged palladium (II) chloride/copper (II) chloride and lithium chloride carbonylation catalyst mixture was recycled for use in a subsequent second pass 1,3-butadiene oxidative carbonylation reaction.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH2:25][CH2:26][CH:27]([OH:29])[CH3:28]>>[OH:29][CH:27]([CH3:28])[CH2:26][CH2:25][NH:24][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(O)CCN
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCCC(C)O)cn1
Yield: 90 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using 4-amino-2-butanol instead of 2-aminoethyl isopropylether, to the title compound (221 mg, 90%) which was obtained as a white solid. MS: m/e=380.3 [M−H]−.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[C:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21].[Al+3].[Cl-].[Cl-].[Cl-]>CCCCCC.C1C=CC=CC=1.O1CCCC1>[OH:4][C:3]1[CH2:5][C:16]([CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:23][C:1](=[O:6])[CH:2]=1.[C:16]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)(=[O:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: COC(=O)CC(C)=O
Agent: CC(C)CCCC(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)CCCC1(c2ccccc2)CC(O)=CC(=O)O1

Procedure:
The title compound was prepared as described in General Method 1 using 14.2 mmol of methyl acetoacetate, 15.6 mmol of NaH 60% dispersion in oil, 14.9 mmol of 1.6 M n-butyl lithium in hexane, 14.2 mmol of isoheptanophenone and 50 mL of tetrahydrofuran. Isoheptanophenone was prepared by reacting the appropriate acid chloride with AlCl3 in benzene as described by Vogel in Practical Organic Chemistry 1978, 770-775. Upon concentrating the reaction, a solid precipitated out which was recrystallized from ethyl acetate (m.p. 124-125° C.). 1H NMR (CDCl3) δ 0.80 (d,d, 6 H), 1.1-1.2 (m, 2 H), 1.15-1.40 (m, 2 H), 1.4-1.5 (m, 1 H), 1.9-2.0 (m, 2 H), 2.88 (d, 1 H), 2.9 (d, 1 H), 3.2 (d, 1 H), 3.3 (d, 1 H), 7.2-7.5 (m, 5 H).
Reaction SMILES: C/C=C(\C1C=CC(O)=CC=1)/C(/C1C=CC(O)=CC=1)=C/C.[CH3:21]/[C:22](/[CH:28]=[CH:29]/[C:30]1[C:35]([CH3:37])([CH3:36])[CH2:34][CH2:33][CH2:32][C:31]=1[CH3:38])=[CH:23]/[C:24](OC)=[O:25].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>O1CCCC1>[CH3:21]/[C:22](/[CH:28]=[CH:29]/[C:30]1[C:35]([CH3:37])([CH3:36])[CH2:34][CH2:33][CH2:32][C:31]=1[CH3:38])=[CH:23]/[CH2:24][OH:25]
Reactant: COC(=O)/C=C(C)\C=C\C1=C(C)CCCC1(C)C
Agent: C/C=C(C(=C/C)/c1ccc(O)cc1)\c1ccc(O)cc1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC1=C(/C=C/C(C)=C\CO)C(C)(C)CCC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
(II, where R1, R2, R3 and R4 are methyl) To 40 mg (0.16 mmol) of methyl (2Z,4E)-3-methyl-5-(2,6,6-trimethylcyclohex-1-enyl)penta-2,4-dienoate I in 2 mL of anhydrous tetrahydrofuran (THF) at -78° C. was added (0.25 mmol) of LiAlH4. The reaction was stirred at -78° C. for 15 min and warmed to room temperature (RT). When the reaction was complete, as monitored by thin-layer chromatography (TLC), 2 mL of H2O was added and the organics extracted with ether and washed 3 X with 5 mL of water. The organic layer was dried with MgSO4, filtered, concentrated in vacuo and the dienol II was used directly in the next step. TLC (20% EtOAc-hexane) Rf 0.26 (cis isomer), 1H-NMR δ1.01 (s, (CH3)2), 1.46 (t, J=6 Hz, CH2 ), 1.62 (dr, J= 6 Hz, J=4 Hz, CH2), 1.70 (s, CH3, 1.91 (s, CH3), 2.01 (t, J=6 Hz, CH2), 4.30 (d, J=6 Hz, CH2 ), 5.54(t,J=6 Hz, CH), 6.19 (d, J=16 Hz, CH), 6.39 (d, J=16 Hz, CH).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.[NH2:11][C:12]1[N:17]([CH3:18])[C:16](=[O:19])[N:15]([CH3:20])[C:14](=[O:21])[CH:13]=1>>[NH2:11][C:12]1[C:13]([CH2:14][NH2:15])=[C:1]([C:3]2[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=2)[C:13]2[C:14](=[O:21])[N:15]([CH3:20])[C:16](=[O:19])[N:17]([CH3:18])[C:12]=2[N:11]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: Cn1c(N)cc(=O)n(C)c1=O
Product: Cn1c(=O)c2c(-c3ccc(CN)cc3)c(CN)c(N)nc2n(C)c1=O

Procedure:
The synthesis of title compounds started from 4-formylbenzonitrile and 6-amino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione, according to the procedures described in the synthesis of Compound 56. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.06 (s, 3H) 3.53 (s, 3H) 3.56 (d, J=5.56 Hz, 2H) 4.12 (d, J=5.56 Hz, 2H) 7.22 (d, J=7.83 Hz, 2H) 7.49 (m, 4H) 7.92 (br. s., 2H) 8.37 (br. s., 2H) MS [m+H] MS [m+H] calc'd C17H20N6O2 341.38; found 341.4.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH3:13])[C:6]3[CH2:20][CH2:21][N:22]([CH3:24])[CH2:23][C:5]=3[C:4]=2[CH:3]=1.CC(C)([O-])C.[Na+].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:24][N:22]1[CH2:21][CH2:20][C:6]2[N:7](/[CH:11]=[C:12](/[C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)\[CH3:13])[C:8]3[CH:9]=[CH:10][C:2]([N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:3][C:4]=3[C:5]=2[CH2:23]1
Reactant: CC(=Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncc1
Reactant: C1CCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: C/C(=C\n1c2c(c3cc(N4CCCC4)ccc31)CN(C)CC2)c1ccncc1
Temperature: 100 °C
Yield: 27.4 %

Procedure:
8-Chloro-2-methyl-5-(2-pyridin-4-yl-propenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.100 g, 0.245 mmol), sodium tertbutoxide (0.283 g, 2.948 mmol), palladium acetate (0.010 g, 0.049 mmol) and 2-di-tertbutylphosphino-2′-4′-6′-triisopropylbiphenyl (0.031 g, 0.0735 mmol) were charged in a reaction bottle which was evacuated and back filled with nitrogen for 5 min. Dry toluene (2 mL) was added under nitrogen atmosphere. Finally, pyrrolidine (0.033 mL, 0.343 mmol) was added to the reaction mixture and the contents heated to 100° C. overnight. The reaction mixture was filtered and precipitate washed with EtOAc (2×25 mL). The filtrate was concentrated under vacuum and purified by reverse phase chromatography to yield 25 mg of desired compound as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.78 (d, 2H), 8.18 (d, 2H), 7.68 (s, 1H), 7.50 (s, 1H), 7.39 (d, 1H), 7.24 (d, 1H), 4.78 (m, 1H), 4.45 (m, 1H), 3.90 (m, 1H), 3.74-3.60 (m, 5H), 3.24 (m, 2H), 3.18 (s, 3H), 2.24 (m, 4H), 2.10 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([NH2:26])=[CH:23]2)=[CH:18][CH:17]=1.[F:27][C:28]1[CH:29]=[C:30]([N:34]=[C:35]=[O:36])[CH:31]=[CH:32][CH:33]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([NH:26][C:35]([NH:34][C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([F:27])[CH:29]=3)=[O:36])=[CH:23]2)=[CH:18][CH:17]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: COc1cc2nccc(Oc3ccc4ccc(N)cc4c3)c2cc1OC
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc4ccc(NC(=O)Nc5cccc(F)c5)cc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 7-(6,7-dimethoxyquinolin-4-yloxy)naphthalen-2-amine (0.158 g, 0.45 mmol) in 20 mL of THF was added 3-fluorophenyl isocyanate (0.057 mL, 0.50 mmol). The solution was stirred for 16 h at RT under an atmosphere of nitrogen. The reaction was concentrated and the crude solid was treated with CH2Cl2. The resulting solid was collected by vacuum filtration and dried in vacuo to afford the desired compound. MS (ESI, pos. ion) m/z: 484.0 (M+1). Mass Calc'd for C28H22FN3O4: 483.497.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[S:17][C:18]4[C:28]5[C:23](=[CH:24][C:25]([CH:29]=[O:30])=[CH:26][CH:27]=5)[CH2:22][CH2:21][C:19]=4[N:20]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([C:35]#[N:36])(C)C.Cl>ClCCl.[I-].[Zn+2].[I-]>[OH:30][CH:29]([C:25]1[CH:24]=[C:23]2[C:28](=[CH:27][CH:26]=1)[C:18]1[S:17][C:16]([C:10]3[O:9][N:8]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:11]=3[C:12]([F:15])([F:14])[F:13])=[N:20][C:19]=1[CH2:21][CH2:22]2)[C:35]#[N:36]
Reactant: C[Si](C)(C)C#N
Reactant: O=Cc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: N#CC(O)c1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To 2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]thiazole-7-carbaldehyde (Preparation 84A, 0.175 g, 0.410 mmol) in dichloromethane (5 mL) was added zinc iodide (0.039 g, 0.123 mmol) followed by trimethylsilyl cyanide (0.083 mL, 0.616 mmol) over a period of 1 min. at room temperature. The reddish-brown reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0° C. and conc. HCl (0.068 mL, 0.821 mmol) was added over a period of 1 min. and the contents stirred at room temperature for 5 min. The reaction mixture was partitioned between dichloromethane (2×20 mL) and 10% aq. Na2S2O3 (10 mL). The dichloromethane layer was dried over sodium sulfate and concentrated to yield 2-hydroxy-2-(2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]thiazol-7-yl)acetonitrile (0.185 g, 0.408 mmol, 99% yield) as a yellow solid. LC/MS M+1=454.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[NH:13][CH:12]=2)=[CH:7][CH:6]=1.[H-].[Na+].[Br:22][CH2:23][CH2:24][CH2:25]Br>O>[Br:22][CH2:23][CH2:24][CH2:25][N:13]1[C:14]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[C:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][CH:9]=2)=[CH:12]1
Reactant: COCOc1ccc(-c2c[nH]c3cccnc23)cc1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCOc1ccc(-c2cn(CCCBr)c3cccnc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[4-(methoxymethoxy)phenyl]-1H-pyrrolo[3,2-b]pyridine (650 mg) was added NaH (60% in oil, 153 mg) at 0° C. After stirring at room temperature for 1 h, the mixture was added dropwise to 1,3-dibromopropane (0.778 mL). The mixture was stirred at room temperature for 2 h. The mixture was added to water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (486 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=O)[CH3:2].S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([Cl:16])=[O:13])[CH3:2]
Reactant: CCc1ccccc1CCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1ccccc1CCC(=O)Cl

Procedure:
A mixture of 3-(2-ethylphenyl)propanoic acid (prepared in 3 steps from 1-ethyl-2-iodobenzene, 4.24 g, 23.8 mmole), thionyl chloride (9.50 ml, 130 mmole) and toluene (100 ml) was refluxed for 2 hours. Concentration in vacuo gave 3-(2-ethylphenyl)propanoyl chloride which was taken up in methylene chloride and used in the next step as a crude. Step 2:
Reaction SMILES: C1([C@H]2[N:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][CH:9]([CH2:16][O:17][C:18]3[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][N:19]=3)[O:8]2)C=CC=CC=1.[ClH:26]>C(OCC)C>[ClH:26].[C:12]([NH:11][CH2:10][C@H:9]([OH:8])[CH2:16][O:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][N:19]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)N1CC(COc2ncccc2C#N)O[C@H]1c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CC(C)(C)NC[C@H](O)COc1ncccc1C#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To (S)-2-phenyl-3-tert. butyl-5-hydroxymethyloxazolidine (7 grams, 0.03 moles) in 35 ml. of N,N-dimethylformamide (DMF) is added 1.3 grams (0.03 moles of sodium hydride (57% dispersion in mineral oil). This mixture is heated 5 minutes over steam and then is allowed to stir 15 minutes at room temperature. 4.1 grams (0.03 moles) of 2-chloro-3-cyanopyridine in 20 ml of DMF is then added and the resultant reaction mixture is stirred four hours at room temperature. Water is then added and an oil separates. This oil is extracted three times with 25 ml of chloroform each time. This chloroform extract is dried over sodium sulfate and concentrated under reduced pressure (20 mm) over steam to yield the product, (S)-2-phenyl-3-tert. butyl-5-(3-cyano-2-pyridyloxymethyl)oxazolidine, as an oil. This oil is then suspended in 1N HCl (50 ml), heated 5 minutes over steam and then is stirred for 15 minutes at room temperature. The solution obtained is then extracted twice with 25 ml of diethylether each time. The extracted aqueous layer is made basic by addition of saturated aqueous sodium carbonate solution. This aqueous solution is then extracted with ethyl acetate (3 × 25 ml) and the ethylacetate solution is dried over sodium sulfate. The dried ethyl acetate solution is then concentrated under reduced pressure (20 mm) over steam to yield an oil. This oil is chromatographed on alumina. The chromatographic fractions are concentrated to yield an oil which is dissolved in diethyl ether. Ethanolic HCl (saturated solution) is added to this ether solution until solid separation is substantially complete. The separated semi-solid is recrystallized from isopropanol/ether (ether added to isopropanol to the point of turbidity) to yield 1 gram of (S)-2-(3-tert-butylamino-2-hydroxypropoxy)-3-cyanopyridine hydrochloride, melting at 161°-163° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:11]([CH3:35])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([C:19](=[N:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[O:33][CH3:34])[CH2:20][CH2:21][CH3:22])=[CH:14][CH:13]=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO[CH:38]=[C:39]([C:44]([O:46]C)=O)[C:40]([O:42][CH3:43])=[O:41]>O(C1C=CC=CC=1)C1C=CC=CC=1>[Si:1]([O:8][CH2:9][C:10]1[N:11]([CH3:35])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([C:19]1[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[O:33][CH3:34])[C:44](=[O:46])[C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][C:20]=1[CH2:21][CH3:22])=[CH:14][CH:13]=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCCC(=NCc1ccc(OC)cc1OC)c1ccc2c(c1)cc(CO[Si](C)(C)C(C)(C)C)n2C
Reactant: COC=C(C(=O)OC)C(=O)OC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc(CO[Si](C)(C)C(C)(C)C)n2C
Temperature: 190 °C

Procedure:
N-(1-(2-((tert-butyldimethylsilyloxy)methyl)-1-methyl-1H-indol-5-yl)butylidene)-1-(2,4-dimethoxyphenyl)methanamine (5.94 g, 12.0 mmol), prepared according to procedure described in Example 164 Step 1, was suspended in Ph2O (20 mL) then dimethyl 2-(methoxymethylene)malonate (3.55 g, 20.4 mmol, 1.7 eq) was added. The reaction mixture was heated to 190° C. for 1 h before mixture was cooled to room temperature then purified by flash column chromatography (0-50% EtOAc in CH2Cl2) to give the title compound. LC-MS 605.5 [M+H]+, RT 1.75 min.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][CH:8]=2)=[N:5][C:4]([S:15][CH3:16])=[N:3]1.N[C@H](C(O)=O)CCSC.CS(O)(=O)=O>C(O)(C)C>[OH:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([S:15][CH3:16])[N:5]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(-c2nc(SC)nn2C)cc1
Agent: CS(=O)(=O)O
Agent: CSCC[C@H](N)C(=O)O
Solvent: CC(C)O
Product: CSc1nc(-c2ccc(O)cc2)n(C)n1

Procedure:
Analogously to Example (15b), a mixture of 49.6 g of 1-methyl-3-methylthio-5-(4-methoxyphenyl)-1H-1,2,4-triazole, 40 g of L-methionine and 380 ml of methanesulphonic acid is heated for 24 hours in a bath at 110°-120° and analogously worked up, yielding 5-(4-hydroxyphenyl)-1-methyl-3-methylthio-1H-1,2,4-triazole having a melting point of 216°-220° (from isopropanol).
Reaction SMILES: Br[C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]>CC1C=CC(C)=CC=1>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1
Reactant: NCCCCCO
Reactant: Cn1c(=O)c2[nH]c(Br)nc2n(C)c1=O
Solvent: Cc1ccc(C)cc1
Product: Cn1c(=O)c2[nH]c(NCCCCCO)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
A solution of 5.16 grams of 8-bromotheophylline and 5.15 grams of 5-amino-1 pentanol in 18 ml of p-xylene was refluxed for 18 hours. The reaction solution was allowed to cool and upon cooling to room temperature formed a solid/liquid mixture. The xylene was decanted and the solid was washed with pentane (3×40 ml). The resulting solid was stirred in 20 ml of water for 30 minutes and filtered to collect the solid material. The collected solid material was washed with water (3×20 ml), and dried to provide 3.73 g of 8-(5-hydroxypentylamino)theophylline. To a solution of 1.12 g of 8-(5-hydroxypentylamino)theophylline in 15 ml of anhydrous N,N-dimethylformamide (DMF) was added 0.516 g of succinic anhydride and 0.2 g of 4-dimethylamino pyridine (DMAP). The mixture was stirred with a magnetic stirrer overnight at room temperature under anhydrous conditions. The colorless solid that precipitated was collected by vacuum filtration, washed with dichloromethane and air dried to provide 1.20 g of theophylline-8-N-(5-hydroxypentylamino)-O-succinic acid ester. This solid was recrystallized from a boiling 1:1 propanol/water mixture and dried over calcium sulfate to provide a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[O:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[C:11]([OH:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CC(C)=O>[CH2:1]([O:8][C:9]1[C:18]2[O:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[C:11]([O:19][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cc2c(c(OCc3ccccc3)c1)OCCC2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc2c(c(OCc3ccccc3)c1)OCCC2
Yield: 99.5 %

Procedure:
0.82 g of 8-benzyloxy-3,4-dihydro-6-hydroxy-2H-1-benzopyran (0.82 g) was dissolved in 300 ml of anhydrous acetone, and 0.88 g of anhydrous potassium carbonate and 1.07 g of ethyl bromoacetate were added. The mixture was stirred under reflux for 7 hours. After the reaction, the insoluble matter was removed by filtration, and the solvent was distilled off. The residue was dissolved in 50 ml of chloroform, washed with water and dried. The solvent was distilled off to give 1.09 g (yield 99.5%) of 8-benzyloxy-3,4-dihydro-6-ethoxycarbonylmethoxy-2H-1-benzopyran.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:19][CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)=[N:4]1)[CH3:2].C(N(C(C)C)CC)(C)C.FC1C([CH:53]([C:57]([O-])=[O:58])[N:54]([CH3:56])[CH3:55])=C(F)C(F)=C(F)C=1F>CN(C)C=O>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:19][CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:57](=[O:58])[CH2:53][N:54]([CH3:56])[CH3:55])=[CH:32][CH:31]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)cc23)c(-c2ccc(N)cc2)n1
Reactant: CN(C)C(C(=O)[O-])c1c(F)c(F)c(F)c(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)cc23)c(-c2ccc(NC(=O)CN(C)C)cc2)n1
Reaction time: 18 h
Yield: 57 %

Procedure:
A solution of [4-(1-ethyl-4-{2-[4-(4-morpholinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)phenyl]amine (0.104 mmol) in N,N-dimethylformamide (1 mL) was treated with diisopropylethylamine (0.4 mmol) and then pentafluorophenyl-N,N-dimethylglycinate (0.104 mmol). The reaction was stirred 18 h and purified directly on the Gilson reverse phase HPLC which provided the title product as a yellow solid (57%). ESMS [M+H]+: 564.2
Reaction SMILES: [Br-].[OH:2][C@@H:3]1[CH:8]2[CH2:9][CH2:10][N+:5]([CH2:11][C:12](=[O:19])[NH:13][C:14]3[CH:18]=[CH:17][O:16][N:15]=3)([CH2:6][CH2:7]2)[CH2:4]1.[Br:20][CH2:21]C(NC1C=C(C)ON=1)=O>>[Br-:20].[OH:2][C@@H:3]1[CH:8]2[CH2:9][CH2:10][N+:5]([CH2:11][C:12](=[O:19])[NH:13][C:14]3[CH:18]=[C:17]([CH3:21])[O:16][N:15]=3)([CH2:6][CH2:7]2)[CH2:4]1
Reactant: Cc1cc(NC(=O)CBr)no1
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1ccon1
Agent: [Br-]
Product: Cc1cc(NC(=O)C[N+]23CCC(CC2)[C@@H](O)C3)no1

Procedure:
This compound is prepared analogously to (R)-3-hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide [Intermediate A] by substituting 2-bromo-N-isoxazol-3-yl-acetamide (in step Aii) with 2-bromo-N-(5-methyl-isoxazol-3-yl)-acetamide.