Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC([C:4]([O:10][C:11]([C:14]([C:17]([C:20](F)=[O:21])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([C:6]([F:9])([F:8])[F:7])[F:5])=O.FC(F)(C(F)(F)C(F)=O)C(F)=[O:26].C(=O)([O-])[O-].[Na+].[Na+].C(=O)=O.S(=O)(=O)(O)O.[OH-].[Na+]>COCCOCCOC.O>[C:6]([CH:4]([O:10][C:11]([C:14]([C:17]([C:20]([OH:26])=[O:21])([F:19])[F:18])([F:15])[F:16])([F:13])[F:12])[F:5])([F:9])([F:7])[F:8]
Reactant: O=C(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(C(=O)F)C(F)(F)F
Reactant: O=C(F)C(F)(F)C(F)(F)C(=O)F
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: COCCOCCOC
Product: O=C(O)C(F)(F)C(F)(F)C(F)(F)OC(F)C(F)(F)F
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A sample of diacid fluoride, FCOCF(CF3)—O—(CF2)3COF (503 g, 1.4 mol) prepared from the HFPO coupling of perfluorosuccinyl fluoride as described in U.S. Pub. No. 2004/0116742 and was added over 2 hours to a stirred slurry of sodium carbonate (387 g, 3.7 mol) in 650 g of diglyme at 78° C. to make the disalt. The reaction liberated CO2 gas. Distilled water (35 g, 1.9 mol) was added at 85° C. The mixture was heated up to 165° C. with CO2 off-gassing and held for 30 minutes. Reaction was cooled down and sulphuric acid (250 g, 2.6 mol) in 1250 g of water was added to make the reaction mixture acidic. To the bottom phase was added 60 g NaOH in 60 g of water. Dried the salt in vacuum oven at 112° C./15 mm and recovered 450 g. To the salt was added 300 g of 50% sulphuric acid and the lower fluorochemical phase was washed once with 200 g of 50% sulphuric acid. Vacuum distillation gave CF3—CFH—O—(CF2)3COOH (400 g, 1.3 mol) for a 95% yield having a boiling point of 111° C./15 mm Hg. The acid was treated with caustic followed by sulphuric acid and vacuum distilled. This was repeated a second time to yield a colorless acid. The surfactant CF3—CFH—O—(CF2)3COONH4 having a melting point of 64-68° C. was made quantitatively from the reaction of 208 g of acid reacted with excess ammonium hydroxide and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([CH2:8]O)[CH:7]=1.P(Br)(Br)[Br:19]>ClCCl>[C:12]1([CH2:11][O:10][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=2[CH2:8][Br:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1cc(Cl)ccc1OCc1ccccc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Clc1ccc(OCc2ccccc2)c(CBr)c1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
{5-chloro-2-[(phenylmethyl)oxy]phenyl}methanol (8.2 g, 33 mmol) was dissolved in dry dichloromethane under nitrogen and cooled to −10° C. Phosphorus tribromide (3.12 ml, 33 mmol) in dry dichloromethane (15 ml) was added slowly. The mixture was left at −10° C. for 15 mins, then stirred at room temperature overnight. TLC showed no more starting material. The mixture was then quenched with a saturated sodium hydrogen carbonate solution added very slowly. The mixture was diluted with dichloromethane and brine was added to aid separation. The organic phase was washed with water (×2), then dried (MgSO4) and evaporated. The residue was purified (50 g SPE column). Product comes off using 5% ethyl acetate in isohexane. White-ish solid obtained (8.1 g).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1.Cl>O>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]([N:1]=[O:3])[CH2:14][C:15]([OH:17])=[O:16])=[CH:11][CH:12]=1
Reactant: COc1ccc(NCC(=O)O)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(N(CC(=O)O)N=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
Sodium nitrite (3.97 g, 57.5 mmol) in 10 mL of water was added to a suspension of N-(4-methoxyphenyl)glycine (9.92 g, 54.7 mmol) in 50 mL of water under N2. This was allowed to stir at room temperature until solution clarified, about 6 hours. The solution was acidified with concentrated hydrochloric acid to pH 3 and a precipitate formed. The solid was collected and washed with 50 mL water, then dried in vacuo to give 11.50 g (100%) of the desired compound as a white solid. 1H NMR (CDCl3): δ7.17 (d, J=8.8, 2H); 6.70 (d, J=8.8, 2H); 4.30 (s, 2H), 3.56 (s, 3H), 2.29 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].[CH3:20][C:21]1([CH3:24])[CH2:23][O:22]1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:20][C:21]([CH3:24])([OH:22])[CH3:23])=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19]
Reactant: CC1(C)CO1
Reactant: Fc1ccc(Oc2cc3cn[nH]c3cc2Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(O)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Temperature: 80 °C
Yield: 36.4 %

Procedure:
To a solution of 6-bromo-5-(2,4-difluorophenoxy)-1H-indazole (1.35 g, 4.15 mmol) and 2,2-dimethyloxirane (0.755 mL, 8.30 mmol) in DMA (20 mL) in a sealed tube was added potassium carbonate (1.72 g, 12.5 mmol), and the reaction was heated to 80° C. for 16 hours. The reaction mixture was allowed to cool to ambient temperature, diluted with ethyl acetate, and washed twice with water and once with brine. It was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel loaded and eluted with 35% ethyl acetate/hexanes to yield pure 1-(6-bromo-5-(2,4-difluorophenoxy)-1H-indazol-1-yl)-2-methylpropan-2-ol (0.60 g, 36.4% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14]C2C=CC=C(Br)C=2)[CH2:9]1)=O)(C)(C)C.Br[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([F:31])[CH:24]=1.C([C@@H]1OC1)Cl>>[F:31][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[O:29][CH3:30])[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(Br)c2)C1
Reactant: COc1ccc(Br)cc1F
Agent: ClC[C@H]1CO1
Product: COc1ccc(C[C@@H]2CNCCO2)cc1F

Procedure:
(R)-1-chloro-3-(3-fluoro-4-methoxy)-2-propanol was prepared, using the same procedure as described for example 2, intermediate (d), but from 4-bromo-2-fluoroanisole and (R)-epichlorohydrin. Example 47 was prepared as described for example 1, intermediate (d), but using (R)-1-chloro-3-(3-fluoro-4-methoxy)-2-propanol, to obtain the desired morpholine, example 47 as a pale yellow oil (0.12 g, 19%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:10]Br>C(O)(=O)C>[CH2:2]([Br:10])[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(CBr)c1ccccc1

Procedure:
Synthesis of 2-amino-4-arylimidazolamine of the formula (48) (wherein R4, R5, R6, R7, R8 and R9 are as defined above) is described in Scheme 9. Thus, reaction of acetophenone derivative of formula (45) with bromine in acetic acid gives phenacyl bromide, which on reaction with acetyl guanidine in acetonitrile at reflux temperature gives N-acetyl imidazole of the formula (47). The N-deacetylation of (47) under acidic conditions affords 2-amino-4-arylimidazoles of the formula (48). This is similar to the procedure reported by Thomas, L. et al in J. Org. Chem., 1994, 59, 7299-7305.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCCCC1.S(Br)([Br:27])=O.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][Br:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Br)Br
Reactant: OCCN(Cc1ccccc1)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Product: BrCCN(Cc1ccccc1)Cc1ccccc1
Reaction time: 15 h
Yield: 70.9 %

Procedure:
To N,N-dibenzyl-2-aminoethanol (80.68 g) were added cyclohexane (500 ml) and DMF (12.9 ml), and thereto was added dropwise thionyl bromide (83.4 g). The mixture was stirred for 15 hours, and to the reaction solution was added an saturated aqueous sodium hydrogen carbonate solution in an ice-bath, and the mixture was extracted with ethyl acetate. The organic layer was washed with water (three times) and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (72.1 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:17]=[N:18][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:20][CH:21]=1.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:29].[Na+].C(=O)C.C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[CH2:28]([N:25]1[CH2:24][CH2:23][N:22]([C:19]2[N:18]=[CH:17][C:16]([NH:15]/[CH:14]=[C:5]3\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]4[C:4]\3=[CH:3][C:2]([I:1])=[CH:11][CH:10]=4)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)[CH3:29]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)nc1
Agent: CC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
(4Z)-6-Iodo-4-{[(6-piperazin-1-ylpyridin-3-yl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (150 mg, 0.315 mmol) is dissolved in N-methylpyrrolidinone (3 mL) and methylene chloride (0.9 mL), followed by addition of sodium triacetoxyborohydride (0.77 mg, 3.63 mmol), acetaldehyde (0.46 mL, 8.14 mmol) and acetic acid (0.47 mL, 8.2 mmol). After stirring at room temperature for 1 h, methylene chloride and saturated sodium bicarbonate solution were added. The organic layer is separated and dried to give 110 mg (69%) of the title compound as a brown solid. MS (ESI) m/z 504.2 (M+H)+1
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([S:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:29])=[CH:23][CH:22]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: Nn1nc(Sc2ccccc2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(Sc2ccccc2)c2ccccc2c1=O

Procedure:
The product from Example 57B and 2-(4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.34 (dd, J=7.9, 1.1, 1H), 8.08 (d, J=7.4, 1H), 8.00 (td, J=7.7, 1.5, 1H), 7.94 (td, J=7.6, 1.3, 1H), 7.40 (d, J=8.8, 9H), 3.66 (s, 2H); MS (APCI+) M/Z 422 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]([NH:21][CH2:22][CH:23]([OH:26])[CH2:24][CH3:25])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:18][C:19]([NH:21][CH2:22][C:23](=[O:26])[CH2:24][CH3:25])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCC(O)CNC(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCC(=O)CNC(=O)OCc1ccccc1
Temperature: 78 °C
Reaction time: 0.33 h
Yield: 81.9 %

Procedure:
To methylene chloride (60 mL) at -78° C. under argon was added oxalyl chloride (37 mL of 2 M solution in methylene chloride, 74 mmol), followed by DMSO (7.8 g, 100 mmol). The mixture was stirred at 78° C. for 20 min. and to this mixture was added a solution of 1-benzyloxycarbonylamino-2-butanol (13.9 g, 61.8 mmol) in methylene chloride (40 mL). The mixture was stirred at -78° C. for 1 h and triethylamine (21 mL) was added to the mixture. It was warmed to room temperature (rt) and washed successively with 1 N hydrochloric acid and aqueous sodium bicarbonate solution. The methylene chloride solution was dried over MgSO4 and concentrated to afford 1-benzyloxycarbonylamino-2-butanone (11.2 g, 82%) as a solid, which was enough pure for the next reaction. 1H NMR (CDCl3) δ7.32 (m, 5 H), 5.50 (s, 1 H), 5.06 (s, 2 H), 4.07 (s, 2 H), 2.43 (q, J=7.6 Hz, 2 H), 1.06 (t, J=7.6 Hz, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=2)[N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[N:3]=1
Reactant: COc1cccc(CSc2nc(N)cc(Cl)n2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1cc(Cl)nc(SCc2cccc(O)c2)n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
4-amino-6-chloro-2-(3-methoxyphenylmethylthio)-pyrimidine (36 mg, 0.128 mmol; Cpd #39) is dissolved in methylene chloride (0.25 ml), cooled to 0° C. and treated with a solution of BBr3 (0.32 ml, 0.32 mmol, 1M in methylene chloride). The reaction is stirred at 0° C. for 20 min, then refluxed for 2 hrs. After cooling, the reaction is quenched with water, and refluxed for an additional 30 min. Upon cooling the solid is collected and purified by recrystallization from ethanol/water, mp 147.5-148.5° C.
Reaction SMILES: [CH2:1](I)[CH3:2].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[OH:14])[CH:9]=[O:10].BrCCC.OC1C=CC(C=O)=CC=1>>[CH2:1]([O:14][C:13]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:5][CH3:4])[CH3:2]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCI
Agent: O=Cc1ccc(O)cc1
Solvent: CCCBr
Product: CCOc1ccc(C=O)cc1OC
Yield: 90 %

Procedure:
When the EtI and 3-methoxy-4-hydroxybenzaldehyde was substituted for 1-bromopropane and 4-hydroxybenzaldehyde respectively in Example 49, Step A, the identical process afforded the title compound in 90% yield, as light yellow oil. 1H-NMR (CDCl3) 1.49 (tr, 3H, J=6.98 Hz); 3.91 (s, 3H); 4.17 (q, 2H, J=14, 7 Hz); 6.94 (d, 1H, J=8.09 Hz); 7.38-7.43 (m, 2H); 9.02 (s, 1H).
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)[C:10]([OH:12])=O)=[O:7])(C)(C)C.CN1CCOCC1.C(OC(Cl)=O)(C)C.[F:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[CH:44]([NH:50][C@H:51](C(O)=O)[CH2:52][CH:53]([CH3:55])[CH3:54])[C:45]([N:47]([CH3:49])[CH3:48])=[O:46]>O1CCCC1.C1(C)C=CC=CC=1>[F:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[C@@H:44]([N:50]1[C@H:51]([CH2:52][CH:53]([CH3:55])[CH3:54])[C:6](=[O:7])[NH:8][C@H:9]([CH:13]2[CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:21]2)[C:10]1=[O:12])[C:45]([N:47]([CH3:48])[CH3:49])=[O:46]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1Cc2ccccc2C1
Reactant: CC(C)C[C@H](NC(C(=O)N(C)C)c1ccc(F)cc1F)C(=O)O
Agent: CC(C)OC(=O)Cl
Solvent: CN1CCOCC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)N(C)C)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.3 %

Procedure:
To a solution of (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoic acid (84 mg) in dry tetrahydrofuran (6 ml) at −20° C. under a nitrogen atmosphere was added N-methylmorpholine (32 □l) and a solution of isopropylchloroformate in toluene (1.0M, 290 □l). After 10 minutes, a solution of N-[1-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucine (95 mg) in tetrahydrofuran (10 ml) was added and the reaction was allowed to warm to room temperature. After 20 hours, the solvent was removed in vacuo and the residue was dissolved in 4N hydrochloric acid in dioxan (4 ml). After 4 hours methanol (5 ml) was added and the reaction was left to stand for a further 18 hours. The solvent was then removed in vacuo and the residue was dissolved in dioxan (5 ml) and to this was added triethylamine (0.5 ml). After 1 hour, the solvent was removed and the residue was applied to an SPE (10 g, silica). The product was eluted using methanol. A second SPE was used to further purify the material (2 g, silica) using an ethyl acetate: methanol gradient (20:1 to 1:1) to afford (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide (38 mg).
Reaction SMILES: [OH-].[Li+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[C:14]([C:18]1[CH:44]=[CH:43][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)=[CH:26][C:25]=2[CH:41]=O)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].Cl>O1CCCC1>[C:14]([C:18]1[CH:44]=[CH:43][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[CH:32][C:33]([O:36][C:37]([F:39])([F:40])[F:38])=[CH:34][CH:35]=3)=[CH:26][C:25]=2[CH:41]=[CH:5][C:3]#[N:4])=[CH:20][CH:19]=1)([CH3:16])([CH3:17])[CH3:15]
Reactant: CC(C)(C)c1ccc(COc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2C=O)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(COc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2C=CC#N)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
A mixture of lithium hydroxide (101 mg, 2.40 mmol), diethyl cyanomethylphosphonate (390 mg, 2.20 mmol) and tetrahydrofuran (20 ml) was stirred at 70° C. for 30 minutes under argon atmosphere. After the reaction mixture was cooled to room temperature, 4-[4-(tert-butyl)benzyloxy]-4′-(trifluoromethoxy)biphenyl-3-carbaldehyde (compound of Example 4 (2); 857 mg, 2.00 mmol) was added, and the mixture was stirred at room temperature for 4 hours. 1N Hydrochloric acid was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1) to give the title compound (631 mg, 70.0%) as a colorless oil.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][CH2:15][CH:16]([OH:31])[C:17]2[N:18]=[C:19]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:20][CH:21]=2)=[CH:8][CH:7]=1)([O:3]CC)=[O:2].[OH-].[Na+]>>[C:1]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][NH:14][CH2:15][CH:16]([OH:31])[C:17]2[N:18]=[C:19]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:20][CH:21]=2)=[CH:10][CH:11]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)c1ccc(CCNCC(O)c2csc(NC(=O)c3ccccc3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(CCNCC(O)c2csc(NC(=O)c3ccccc3)n2)cc1

Procedure:
Prepared analogously to Example 2 by reaction of N-[2-(4-carboethoxyphenyl)ethyl]-2-hydroxy-2-(2-benzoylamino-thiazol-4-yl)ethanamine with 1N sodium hydroxide solution, followed by purification of the crude product on a silica gel column using chloroform/methanol=1:1 and trituration with water/ethanol=9:1.
Reaction SMILES: BrBr.[Mg].Br[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[C:20]1(=[O:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[OH:25][C:20]1([C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1CCCC1
Reactant: N#Cc1ccc(Br)cc1
Agent: BrBr
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Product: N#Cc1ccc(C2(O)CCCC2)cc1
Yield: 94.8 %

Procedure:
According to Example 2, the Grignard reagent 1C (freshly prepared via bromine-magnesium exchange[6] from 4-bromo-benzonitrile (400 mg, 2.20 mmol, 1.10 equiv) and i-PrMgCl.LiCl (1.00 M in THF; 2.16 mL, 2.16 mmol, 1.08 equiv) at −20° C.) was reacted with cyclopentanone (168 mg; 2.00 mmol) in the presence of LaCl3.2LiCl (0.33 M; 6.06 mL, 2.00 mmol, 1.00 equiv). The crude product was purified by flash column chromatography (silica; pentane:Et2O, 7:3) to give the desired product as a colorless oil (355 mg, 95%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19](CC3C=CC=CC=3)[CH2:18][CH2:17]2)[CH:3]=1.C(Cl)(Cl)Cl>C(O)C.[Pd]>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)[CH:3]=1
Reactant: COc1cc2nc(N3CCN(Cc4ccccc4)CC3)cc(N)c2cc1OC
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1cc2nc(N3CCNCC3)cc(N)c2cc1OC
Yield: 51.2 %

Procedure:
4-Amino-6,7-dimethoxy-2-(4-benzylpiperazin-1-yl)quinoline (6.2 g) in ethanol (300 ml) with 5% Pd/C catalyst was stirred at 50° under an atmosphere of hydrogen (50 p.s.i.) for 20 hours. The mixture was cooled, chloroform (100 ml) added and the solution filtered through "Solkafloc". The solid was washed with chloroform-methanol (1:1, 4×100 ml) and the combined filtrates evaporated in vacuo. The residue was partitioned between chloroform-sodium carbonate solution (10%), the organic layer removed, the aqueous phase saturated with salt and further extracted with chloroform. The combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo to yield 4-amino-6,7-dimethoxy-2-(piperazin-1-yl)quinoline (2.42 g). Spectroscopy showed this product to be the same as that of Example 32.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([N:18]1[CH2:23][CH2:22][O:21][CH:20]([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=O)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]1[CH2:23][CH2:22][O:21][CH:20]([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: C(=C(c1ccccc1)C1CN(Cc2ccccc2)CCO1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a cooled solution of KHMDS (0.5M in toluene, 40 ml, 20 mmol) at 0° C. under nitrogen is added diethyl benzyl phosphonate (available from Aldrich Chemical Company) (4. 1 ml, 19.7 mmol). The reaction is held at this temperature and stirred for 30 minutes then warmed to room temperature and after 10 minutes a solution of racemic (4-benzyl-morpholin-2-yl)-phenyl-methanone (5.03 g, 17.9 mmol in 25 ml of dry tetrahydrofuran) is added dropwise and the reaction allowed to stir for 30 minutes. At the end of this time the reaction solvent is removed under reduced pressure and replaced with diethyl ether prior to quenching with water. After extraction with diethyl ether and drying (MgSO4) the solvent is again removed under reduced pressure and replaced with methanol at which point a white precipitate forms. The solution is filtered and the cake washed with cold methanol and air-dried. The methanolic solution is further purified using SCX-2 chromatography followed by silica gel chromatography to provide the required material, which is combined with the white precipitate previously obtained.
Reaction SMILES: S(Cl)(Cl)=O.CN(C)C=O.[C:10]([CH:14]([CH2:21][CH:22]=[CH2:23])[CH2:15][CH2:16][CH2:17][C:18]([NH2:20])=O)([O:12][CH3:13])=[O:11].[OH-].[NH4+]>C(OCC)C.O>[C:10]([CH:14]([CH2:21][CH:22]=[CH2:23])[CH2:15][CH2:16][CH2:17][C:18]#[N:20])([O:12][CH3:13])=[O:11]
Reactant: C=CCC(CCCC(N)=O)C(=O)OC
Agent: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCC(CCCC#N)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (1.125 L, 1.835 kg, 15.42 mol) is cooled to 0° C., and dimethylformamide (1.199 L, 1.132 kg, 15.50 mol) is added dropwise over a period of 2 hours keeping the temperature below 10° C. After the addition is complete the reaction is allowed to come to room temperature over 2 hours. To this is then added 5-carbomethoxy-oct-7-enoic acid amide (see example 22c, 2.671 kg, 13.42 mol) neat over a period of 3 hours. The reaction is allowed to stir at room temperature for 18 hours and is combined with material from a similar run and then diluted with ethyl ether (35 L). The solution is cooled to 0° C. and is admixed with 8 kg of ice and 12 L of water. The mixture is stirred for 30 minutes and is then basified with ammonium hydroxide (12 L, 2.5 M). The layers are separated and the organic phase is washed with water (12 L) and brine (12 L) and dried over anhydrous sodium sulfate (7.5 kg). This is then filtered and evaporated to yield a crude oil which is redissolved in ethyl ether (24 L) and this solution is stirred over 7 kg of silica gel for several hours. After filtration and evaporation there is obtained partially purified material which is then distilled to obtain 5-carbomethoxy-oct-7-enenitrile, b.p. 118-120° /0.15 mm Hg.