Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[CH2:18]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1)[CH2:19][CH3:20]>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(CCC)nc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9.7 %

Procedure:
To a solution of 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g. 0.00045 mol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.20 g, 0.0036 mol) and allowed to stir for 10 min at RT. 2-propyl-5-vinyl-pyridine (0.2 g, 0.00136 mol) was added and stirred for further 24 h. at 100° C. After completion (TLC), reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was semi-purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.016 g, 9.6% yield). 8-Chloro-5-[2-(6-isopropyl-pyridin-3-yl)-ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.016 g, 0.0000435 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.005 g, 0.00007 mol) in THF (0.5 mL) was added and stirred for 30 min at RT. Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.010 g, 52% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:12][CH2:13][O:14][C:15]2[N:16]([CH3:27])[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[CH:19]=2)[CH3:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].Cl>ClCCl.C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:12][CH2:13][O:14][C:15]2[N:16]([CH3:27])[N:17]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([O:26][C:34](=[O:36])[CH3:35])=[CH:24][CH:25]=3)[CH:19]=2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(CCOc1cc(-c2ccc(O)cc2)nn1C)CCc1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(=O)Oc1ccc(-c2cc(OCCN(C)CCc3ccc(Cl)cc3)n(C)n2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
100 mg of 3-{2-[N-(2-(4-chlorophenyl)-ethyl)-N-methylamino]-ethyloxy}-5-(4-hydroxyphenyl)-2-methylpyrazole (preparation see Example 9) were dissolved in 2 ml of dichloromethane. 0.15 ml of pyridine and 1 ml of acetic anhydride were added to the solution and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was subsequently evaporated under reduced pressure, and the residue was taken up in aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase was separated, dried and concentrated. The crude title compound which remained as a residue was taken up in tert-butyl methyl ether. To form a salt, a 2N solution of hydrochloric acid in isopropanol was added. The precipitated salt was separated. 80 mg of the hydrochloride of the title compound were obtained having a melting point of from 160° to 175° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][NH:14][C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)=S)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrCC1C=CC2C(=CC=CC=2)C=1.Cl.[O:42]([NH2:44])[CH3:43].[OH-].[Na+]>C(#N)C.O.FC(F)(F)C(O)=O.CN1CCCC1=O.C(#N)C>[CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][NH:14][C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)=[N:44][O:42][CH3:43])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON
Reactant: S=C(NCc1ccc(OCc2ccccc2)cc1)c1ccc2ncccc2c1
Agent: BrCc1ccc2ccccc2c1
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Solvent: O
Product: CON=C(NCc1ccc(OCc2ccccc2)cc1)c1ccc2ncccc2c1
Yield: 6.4 %

Procedure:
To a mixture of quinoline-6-carbothioic acid 4-benzyloxy-benzylamide described in Preparation Example E+-10 (57 mg, 0.15 mmol) and acetonitrile (3 mL) was added 2-(bromomethyl)naphthalene (200 mg, 0.94 mmol), which was then refluxed for 2 hours. After cooling, the solvent was evaporated in vacuo, and the residue was washed with diethyl ether three times. A mixture of a portion (29 mg) of the resulting crude product (57 mg), methoxylamine hydrochloride (2.9 mg, 0.035 mmol), an aqueous solution of 1N sodium hydroxide (0.035 mL, 0.035 mmol) and N-methylpyrrolidinone (1 mL) was stirred at room temperature for 25 minutes. The reaction solution was directly purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and ditrifluoroacetic acid salt of the title compound (1.9 mg, 0.0030 mmol, 6.4%) was obtained.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:9][NH:8]C(=O)[C@H:6]1[C:11]([OH:13])=[O:12])[CH:2]([CH3:4])[CH3:3].Cl.O>CC(O)=O>[CH3:4][CH:2]([CH2:1][C@H:5]([CH2:9][NH2:8])[CH2:6][C:11]([OH:13])=[O:12])[CH3:3]
Reactant: CC(C)CC1CNC(=O)[C@H]1C(=O)O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C[C@H](CN)CC(=O)O
Temperature: 110 °C
Yield: 80 %

Procedure:
A reactor vessel (60 L) was charged with (S)-4-isobutyl-2-oxo-pyrrolidine-3-carboxylic acid (Formula 10), HCl (36-38%, 30 L), and water (29 L). HOAc (1 L) was added to the solution and the resulting slurry was heated for 36-38 h at 80° C. and for an additional 6 h at 110° C. The extent of reaction was monitored by HPLC(C18 column, 4.6 mm×150 mm, detection at 200 nm). Water and excess HCl were evaporated to afford an oil, which was washed with MTBE (2×15 L). Water was added to the oil and the mixture was stirred until the solution cleared. The pH of the solution was adjusted to 5.2-5.5 using KOH (about 6 kg), which resulted in the precipitation of pregabalin. The mixture was heated to 80° C. and subsequently cooled to 4° C. After 10 h, crystalline pregabalin was filtered and washed with IPA (12 L). The filtrate was concentrated under vacuum to afford a residual oil. Water (7.5 L) and EtOH (5.0 L) were added to the residual oil and the resulting mixture was heated to 80° C. and then cooled to 4° C. After 10 h, a second crop of pregabalin crystals were filtered and washed with IPA (1 L). The combined pregabalin crystals were dried in a vacuum oven at 45° C. for 24 h. MS m/z [M+H]+160.1340. 1H NMR (300 MHz, D2O): δ 2.97 (dd, J=5.4, 12.9 Hz, 1H), 2.89 (dd, J=6.6, 12.9 Hz, 1H), 2.05-2.34 (m, 2H), 1.50-1.70 (sept, J=6.9 Hz, 1H), 1.17 (t, J=7.0 Hz, 2H), 0.85 (dd, J=2.2, 6.6 Hz, 6H). 13C NMR (75 ppm, D2O) δ 181.54, 44.32, 41.28, 32.20, 24.94, 22.55, 22.09. Yield 80-85%; ee>99.5%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20]#[N:21])[CH:14]=1.C[O-].[Na+].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(O)C>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[CH:11][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)[C:20]#[N:21])[CH:14]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: N#CCc1cccnc1
Agent: C[O-]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCO
Product: N#CC(=Cc1ccnc2ccccc12)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.1 %

Procedure:
Quinolin-4-carboxaldehyde (4.71 g; 0.03 mol) and 3-pyridylacetonitrile (3.54 g; 0.03 mol) were dissolved in ethanol (100 mL). Sodium methoxide (2 mL of 25% methanol solution) was added. The reaction mixture was heated at reflux for a period of 2.5 hours. The mixture was cooled to ambient temperature. After 18 hours, the precipitated solid was collected, suspended in ethanol and saturated with hydrogen chloride gas. The mixture was cooled and the solid was collected by filtration. The solid was crystallized from methanol to give the title compound (5.8 g; 57% yield) as a dihydrochloride, three quarter hydrate, yellow solid, m.p. 250° C. (dec.). Anal. Calcd for C17H11N3 ·HCl·3/4 H2O; C, 59.40; H, 4.25; N, 12.23. Found: C, 59.75; H, 4.10; N, 11.93. Mass spectrum (EI; M+) m/z 257. 1 H-NMR (DMSO-d6 ; 400 MHz) δ 9.40 (s, 1H), 9.38 (d, 1H), 9.15 (s, 1H), 8.93 (d, 1H), 8.74 (d, 1H), 8.56 (d, 1H), 8.46 (d, 1H), 8.32 (d, 1H), 8.13 (t, 1H), 8.00 (q, 1H), 7.95 (t, 1H), and 7.70 ppm (br s, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:10]=[C:11]([CH2:19][CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(O)C>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([CH2:19][CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: C=C(CCCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)CCCC(CSc1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Temperature: 170 °C
Reaction time: 17 h

Procedure:
A mixture of 3,4-dichlorobenzenethiol (0.20 ml), di-tert-butyl 2-methyleneadipate (350 mg), ethanol (2 ml), and triton B (40% methanol solution, 2 drops) was stirred at 170° C. in a sealed tube for 17 hours. After the reaction mixture was concentrated in vacuo, the resulting residue was dissolved in chloroform, washed with a 0.5% sodium hydroxide solution, water and a saturated sodium chloride solution respectively, and dried over MgSO4. The solvent was evaporated at reduced pressure, and the residue was purified by flash column chromatography on silica by eluting with diethyl ether/hexane (1:10) to give 430 mg of di-tert-butyl 2-(3,4-dichlorophenylthiomethyl)adipate as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1.FC(F)(F)C(O)=[O:37].[OH-].[Na+].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]([OH:37])[CH2:17][OH:16])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1OCC1CO1
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1OCC(O)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
3-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-5,6,5′-trimethyl-[2,2′]bipyridine (compound 457) (54 mg) was dissolved in methylene chloride (2 ml) to prepare a solution which was then brought to 0° C. Trifluoroacetic acid (1 ml) was added thereto, and the mixture was stirred at 0° C. for 30 min and then at room temperature for 5 hr. The reaction solution was brought to 0° C., was stirred and was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added to the reaction solution, the mixture was extracted with chloroform, and the chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (35 mg, yield 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](=[N:19]O)[CH2:13][C:14]([OH:18])([CH3:17])[CH2:15][CH3:16])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].O.N>COCCOC.[Ti](Cl)(Cl)(Cl)Cl>[NH2:19][CH:12]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:11][CH2:10][CH2:9]1)[CH2:13][C:14]([CH3:17])([OH:18])[CH2:15][CH3:16]
Reactant: CCC(C)(O)CC(=NO)C1(c2ccc(Cl)cc2)CCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: N
Agent: [BH4-]
Solvent: O
Solvent: COCCOC
Product: CCC(C)(O)CC(N)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 1-[1-(4-chlorophenyl)cyclobutyl]-3-hydroxy-3-methylpentan-1-one oxime (4.6 g) in dry 1,2-dimethoxyethane (16 ml) was added at 0° C. over a period of 40 minutes to the mixture prepared by adding titanium (IV) chloride (3.6 ml) dropwise and then sodium borohydride (2.5 g) portionwise to stirred dry 1,2-dimethoxyethane (62 ml) at 0° C. under nitrogen. The reaction mixture was stirred for 14 hours at room temperature under nitrogen and cooled to 0° C. Water (160 ml) was added dropwise and the mixture basified by the addition of aqueous ammonia solution (17 ml - S.G. 0.880) and extracted with ether. The extracts were washed with brine, dried and the solvent removed to yield 1-amino-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylpentan-3-ol which was dissolved in ether (70 ml). A solution of maleic acid (1.8 g) in ether (170 ml) was added and 1-Amino-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylpentan-3-ol maleate (m.p. 106° C.(dec) softens 101° C.) was deposited.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[C:10]([CH3:12])=[CH2:11]>C(O)C>[CH2:15]([O:14][C:9]([CH:10]([CH3:12])[CH2:11][NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13])[CH3:16]
Reactant: NCc1ccccc1
Reactant: C=C(C)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(C)CNCc1ccccc1
Yield: 60.2 %

Procedure:
To a solution of benzylamine (75 g) in ethanol (150 ml) was added ethyl methacrylate (240 g) and refluxed for 23 hours. The reaction mixture was evaporated and the resulting residue was distilled under reduced pressure to give N-(2-ethoxycarbonylpropyl)benzylamine (93.3 g) as colorless liquid, bp 122° C./4 mmHg.
Reaction SMILES: BrC1C=C2C(=CC=1)C(C(NC)=O)=C(O[Si](C(C)(C)C)(C)C)C=C2.CC(C)C(C1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)O.[Si]([O:60][C:61]1[CH:70]=[CH:69][C:68]2[C:63](=[CH:64][CH:65]=[C:66]([C:71]([OH:99])([C:75]3[N:76]=[CH:77][N:78](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:79]=3)[CH:72]([CH3:74])[CH3:73])[CH:67]=2)[C:62]=1[C:100]([NH:102][CH3:103])=[O:101])(C(C)(C)C)(C)C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:60][C:61]1[CH:70]=[CH:69][C:68]2[C:63](=[CH:64][CH:65]=[C:66]([C:71]([OH:99])([C:75]3[N:76]=[CH:77][NH:78][CH:79]=3)[CH:72]([CH3:74])[CH3:73])[CH:67]=2)[C:62]=1[C:100]([NH:102][CH3:103])=[O:101]
Reactant: CNC(=O)c1c(O[Si](C)(C)C(C)(C)C)ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc12
Agent: CC(C)C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CNC(=O)c1c(O[Si](C)(C)C(C)(C)C)ccc2cc(Br)ccc12
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1c(O)ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Bromo-2-(tert-butyldimethylsilyloxy)-N-methyl-1-naphthamide (3.30 g) and 2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (2.66 g) were used as the starting materials. By the same procedure described in Reference example 33-(i), a crude mixture of 2-(tert-butyldimethylsilyloxy)-6-[1-hydroxy-2-methyl-1-(-1-trityl-1H-imidazol-4-yl)propyl]-N-methyl-1-naphthamide was obtained. The crude mixture and tetrabutylammonium fluoride hydrate (3.00 g) was dissolved in THF (30 mL), and the solution was stirred for 1 h at room temperature. After dilution with water, the resulting mixture was extracted with AcOEt. The organic layer was washed with brine and dried over MgSO4 followed by concentrating in vacuo. The residue was purified by flash column chromatography on silica gel (hexane:AcOEt=2:1→1:2) to give a colorless solid. The solid was washed with iPr2O to afford the titled compound (1.48 g) as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].C([Li])CCC.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>O1CCCC1>[CH2:26]([Sn:21]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9])[CH2:27][CH2:28][CH3:29]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: FC(F)(F)c1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccccc1C(F)(F)F
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a solution of 10.0 g of 2-bromotrifluoromethylbenzene under nitrogen in 100 ml of tetrahydrofuran while cooling in a dry ice-acetone bath is added dropwise 30.6 ml of a 1.6M solution of butyl lithium via syringe. Stirring is continued for 1 hour. To the reaction mixture is added dropwise 15.9 g of tributyltin chloride in 30 ml of tetrahydrofuran. Stirred ? additional hours. The reaction mixture is quenched with 20 ml of water and after stirring for 20 minutes, extracted with chloroform (3×100 ml). The organic layer is filtered through diatomaceous earth and the filtrate washed with saturated NaHCO3 and water. The organic layer is dried (Na2SO4) and evaporated in vacuo to give 16.8 g of the desired product. MS 379.1
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1[N:5]2[C:11]([CH3:12])=[N:10][CH:9]=[C:6]2[S:7][CH:8]=1.S(Cl)([Cl:15])=O>C1COCC1>[ClH:15].[Cl:1][CH2:3][C:4]1[N:5]2[C:11]([CH3:12])=[N:10][CH:9]=[C:6]2[S:7][CH:8]=1
Reactant: Cc1ncc2scc(CO)n12
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ncc2scc(CCl)n12
Temperature: 85 °C
Reaction time: 3.5 h

Procedure:
3-Hydroxymethyl-5-methylimidazo[5,1-b]thiazolehydrochloride (1.10 g) is suspended in 20 ml of THF, 0.7 ml of thionyl chloride is added thereto, and the mixture is stirred at 85° C. for 3.5 hr. The solvent is removed by evaporation to give 1.10 g of 3-chloromethyl-5-methylimidazo[5,1-b]thiazolehydrochloride. This compound is dissolved in 7 ml of DMF, 1.36 g of triphenylphosphine is added thereto, and the mixture is stirred at 83° C. for 15 hr and at 90° C. for 4 hr. The resultant precipitate is collected by filtration and washed with diethyl ether to give 1.87 g of (5-methylimidazo[5,1-b]thiazol-3-yl)methyltriphenylphosphonium chloride hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[C:9](Cl)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-:3])=[O:2].[Cl:17][C:18]1[CH:19]=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=1[Cl:24].C(=O)([O-])[O-].[K+].[K+]>>[N+:1]([C:4]1[C:9]([O:25][C:20]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=2)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-:3])=[O:2]
Reactant: CCOC(=O)Cc1cccc(Cl)c1[N+](=O)[O-]
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cc1cccc(Oc2ccc(Cl)c(Cl)c2)c1[N+](=O)[O-]

Procedure:
A mixture of ethyl 2-(2-nitro-3-chlorophenyl)acetate (10 g.), 3,4-dichlorophenol (7.4 g.), anhydrous potassium carbonate (8.5 g.) and cupric oxide (1 g.) was treated in a similar manner to the above to give oil of the captioned compound (6.6 g.)
Reaction SMILES: [CH3:1][N+:2]([O-])([CH3:4])[CH3:3].[C@@H:6]12[C@@H:11]([C:12]3[N:16]([CH:17]([CH3:19])[CH3:18])[N:15]=[C:14]([I:20])[CH:13]=3)[C@@H:10]1[CH2:9][CH:8]=[CH:7]2.C([N-]C(C)C)(C)C.[Li+]>O1CCCC1.O>[I:20][C:14]1[CH:13]=[C:12]([C@H:11]2[C@@H:10]3[CH2:9][CH:8]4[C@H:7]([C@H:6]23)[CH2:3][N:2]([CH3:4])[CH2:1]4)[N:16]([CH:17]([CH3:19])[CH3:18])[N:15]=1
Reactant: CC(C)n1nc(I)cc1[C@@H]1[C@H]2C=CC[C@H]21
Reactant: C[N+](C)(C)[O-]
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1nc(I)cc1[C@H]1[C@@H]2CC3CN(C)C[C@H]3[C@@H]21
Temperature: 0 °C
Reaction time: 1 h
Yield: 4.6 %

Procedure:
To an ice-cooled solution of trimethylamine oxide (717 mg, 9.55 mmol) and 5-((1S,5R,6S)-bicyclo[3.1.0]hex-2-en-6-yl)-3-iodo-1-isopropyl-1H-pyrazole (2.0 g, 6.4 mmol) in tetrahydrofuran (10 mL) under nitrogen was added lithium diisopropylamide (28 mmol). After 1 h at 0° C., the reaction mixture was diluted with water (50 mL), and the resulting solution was extracted with ethyl acetate (2×20 mL). The collected organic was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (17% ethyl acetate in petroleum ether) afforded a brown oil (110 mg, 4.7%). LCMS (ESI): [MH]+=372.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[O:26]1CCC[CH2:27]1>>[CH3:11][CH:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:27](=[O:26])[N:12]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]3)[C:3]=2[CH:4]=1)[CH3:10]
Reactant: C1CCOC1
Reactant: CC(C)Oc1ccc(N)c(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Product: CC(C)Oc1ccc2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 50 °C
Yield: 69 %

Procedure:
A solution of 1,1-dimethylethyl 4-({2-amino-5-[(1-methylethyl)oxy]phenyl}amino)-1-piperidinecarboxylate (D48, 470 mg, 1.34 mmol) in tetrahydrofuran (5 ml) was treated with N,N′-carbonyldiimidazole (322 mg, 2.01 mmol) and heated at 50° C. for 17 hrs. The mixture was concentrated under vacuum and the residue treated with Na2CO3 solution (10 ml) and extracted with ethyl acetate (2×20 ml). The combined extract was dried (MgSO4), concentrated under vacuum and the residue purified by chromatography on silica gel eluting with 5-60% ethyl acetate/60-80 petrol ether to afford the title compound as a dark orange oil (351 mg, 69%). M+−H=374.3.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH3:15][C:16]1[CH:25]=[CH:24][C:19]([C:20](=[O:23])[CH2:21]Cl)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:13]=[CH:14][C:2]=1[O:1][CH2:21][C:20]([C:19]1[CH:24]=[CH:25][C:16]([CH3:15])=[CH:17][CH:18]=1)=[O:23]
Reactant: Cc1ccc(C(=O)CCl)cc1
Reactant: Oc1ccc2oc3ccccc3c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)COc2ccc3oc4ccccc4c3c2)cc1

Procedure:
Following the procedure given in Example 13a 2-hydroxydibenzofuran was interacted with 4-methylphenacylchloride in the presence of anhydrous potassium carbonate in acetone to give ω-(2-dibenzofuranyloxy)-p-methylacetophenone. Following recrystallization from 2-ethoxyethanol, this compound melted at 162°-164° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Na].[Cl:26][C:27]1[N:32]=[C:31]([NH:33][CH:34]([CH2:42][CH3:43])[C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)[CH:30]=[C:29]([CH2:44][CH3:45])[N:28]=1.[CH2:46]([O:48][CH:49]([O:52][CH2:53][CH3:54])[CH2:50]Br)[CH3:47].O.C1(C)C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:26][C:27]1[N:32]=[C:31]([NH:33][CH:34]([CH2:42][CH3:43])[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:50][CH:49]([O:52][CH2:53][CH3:54])[O:48][CH2:46][CH3:47])=[CH:37][CH:36]=2)[CH:30]=[C:29]([CH2:44][CH3:45])[N:28]=1
Reactant: CCc1cc(NC(CC)c2ccc(O)cc2)nc(Cl)n1
Reactant: CCOC(CBr)OCC
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: [Na]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(COc1ccc(C(CC)Nc2cc(CC)nc(Cl)n2)cc1)OCC
Temperature: 80 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
To a solution of 5.0 g of dl-5-chloro-6-ethyl-4-(α-ethyl-4-hydroxybenzyl)aminopyrimidine sodium salt dissolved in 50 ml of N,N-dimethylformamide was added 4.8 g of bromoacetaldehyde diethylacetal, and the mixture was stirred at 80° C. for 8 hours. After completion of the reaction, the reaction mixture was charged into water and the separated oily product was extracted with ethyl acetate. The extract was washed with water, dried with anhydrous sodium sulfate, and then ethyl acetate was distilled off under reduced pressure. The oily product obtained was isolated by column chromatography (Wako Gel C-200, trade name, eluted with toluene:ethyl acetate=7:1) to give 2.3 g of the desired product as pale yellow liquid.