Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=O)=[CH:11][CH:10]=1.S(Cl)(Cl)=O>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]2[O:4][CH2:3][C:2]([CH3:6])([CH3:5])[N:1]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(N)CO
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc(C2=NC(C)(C)CO2)cc1
Reaction time: 3 h
Yield: 87.9 %

Procedure:
A solution of 2-amino-2-methyl-propan-1-ol (104.5 g, 1.17 moles) in CH2Cl2 (400 ml) under N2 was dropwise added in 30 minutes with a solution of 4-methoxybenzoyl chloride (100 g, 0.59 moles) in CH2Cl2 (500 ml), keeping the temperature at about 8° C. with water/ice. After 3 hours under stirring the precipitate was filtered over celite and washed with CH2C2. The organic phase was stirred under N2 at 2° C. and dropwise added with thionyl chloride (123 ml, 1.77 moles), keeping the temperature below 10° C. At the end of the dropping the reaction mixture was stirred overnight, then concentrated under vacuum. The residue was taken up in 5% HCl and twice extracted with ethyl ether. The extracts were in turn extracted with 5% HCl. The aqueous phase was alkalinised with concentrated NaOH and extracted three times with ethyl ether, then anhydrified and concentrated under vacuum. The crude was distilled at 95-98° C. (30 Pascal) to give 106.43 g of the title compound (yield: 87.6%).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23](C)([O-:25])[CH3:24].[K+].CN(C)C=O.O1CC[CH2:35][CH2:34]1>>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:22][C@H:23]2[CH2:24][CH2:35][CH2:34][O:25]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(Cl)cc1C(=O)Nc1nnc(C(C)(C)C)s1
Reactant: C1CCOC1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)nn1C[C@H]1CCCO1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of Example 4A (200 mg, 0.62 mmol) in N,N-dimethylformamide/tetrahydrofuran (1:4, 10 mL) were added a solution of potassium tert-butoxide (Aldrich, 103 mg, 0.92 mmol) and Example IB (189 mg, 0.74 mmol). The reaction mixture was stirred at 80° C. for 16 h, cooled to room temperature, quenched with saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-1% methanol in dichloromethane) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (s, 9H), 1.69-2.04 (m, 4H), 3.60-3.70 (m, 1H), 3.73-3.79 (m, 1H), 3.80 (s, 3H), 4.24 (dd, J=4.7, 15.0 Hz, 1H), 4.31-4.42 (m, 1H), 4.49 (dd, J=15.0, 7.5 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 7.50 (dd, J=8.8, 2.7 Hz, 1H), 7.73 (d, J=3.1 Hz, 1H); MS (ESI+) m/z 410 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[N:5](=[C:7]([C:11](=[O:13])[CH3:12])[C:8](=O)[CH3:9])O>C(#N)C>[C:11]([C:7]1[NH:5][C:1]([CH:2]=[CH2:3])=[N:4][C:8]=1[CH3:9])(=[O:13])[CH3:12]
Reactant: CC(=O)C(=NO)C(C)=O
Reactant: C=CCN
Solvent: CC#N
Product: C=Cc1nc(C)c(C(C)=O)[nH]1
Yield: 76.8 %

Procedure:
An acetonitrile solution of allylamine (0.4 g, 7.8 mmol) and 3-oximino-2,4-pentanedione (1 g, 7.8 mmol) was refluxed for 6 hours. The acetonitrile was evaporated to give 0.9 g of 5-acetyl-4-methyl-2-vinylimidazole.
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(OCC)=O)N=1)CC2)=O.OCC1C=CC(B(O)O)=CC=1.Br[C:61]1[N:66]=[CH:65][CH:64]=[CH:63][N:62]=1.CC1(C)C(C)(C)OB([C:75]2[CH:80]=[CH:79][C:78]([OH:81])=[CH:77][CH:76]=2)O1>>[N:62]1[CH:63]=[CH:64][CH:65]=[N:66][C:61]=1[C:75]1[CH:80]=[CH:79][C:78]([OH:81])=[CH:77][CH:76]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: Brc1ncccn1
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Agent: OCc1ccc(B(O)O)cc1
Product: Oc1ccc(-c2ncccn2)cc1

Procedure:
Compound 81A was prepared in a similar manner to the synthesis of compound 34D by substituting compound 34C and 4-(hydroxymethyl)phenylboronic acid with 2-bromopyrimidine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, respectively: 1H NMR (DMSO-d6): δ 9.92 (s, 1H), 8.80 (d, J=4.6 Hz, 2H), 8.22-8.26 (m, 2H), 7.31 (t, J=4.6 Hz, 1H), 6.89-6.89 (m, 2H).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](O)=[O:20])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[NH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([NH:49][C@@H:50]([CH2:54][S:55][C:56]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]([NH2:53])=[O:52])=[O:48].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:40])[C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13](=[O:14])[NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([NH:49][C@@H:50]([CH2:54][S:55][C:56]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:51]([NH2:53])=[O:52])=[O:48])=[O:20])=[CH:30][CH:31]=1)[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:2]=[CH2:3]
Reactant: NCCCCCC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(N)=O
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCCCC(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
457 mg (0.81 mmol) of the compound from example 2A was dissolved in 15 ml dichloromethane. 384 mg (0.81 mmol) of the compound from example 21A, 141 μl (0.81 mmol) N,N-diisopropylethylamine and 307 mg (0.81 mmol) HATU were added. The reaction mixture was heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the reaction mixture the solvent was removed under reduced pressure. The raw product was purified in two portions by preparative RP-HPLC on a C18 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 255 mg (0.22 mmol, 28% of theory) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C(COC)OC.C([O-])(O)=O.[Na+]>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.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1-c1cc(Cl)ncn1

Procedure:
To a solution of 4,6-dichloropyrimidine (6.0 g, 40 mmol) and 2-methoxyphenylboronic acid (4.41 g, 29 mmol) in mixture of dimethoxyethane (120 mL) and water (18 mL) were added NaHCO3 (6.72 g, 80 mmol) and (PPh3)2PdCl2 (0.84 g) and the reaction mixture was refluxed for 8 h, and concentrated under reduced pressure. The resulting residue was taken up in CH2Cl2 (100 mL) and the solution washed with water, dried over anhydrous K2CO3, filtered and the solvent removed under reduced pressure. The obtained crude product was purified by flash chropatography on silica (eluent CH2Cl2) and recrystallized from hexanes. Yield of 4-chloro-6-(2-ethoxyphenyl)-pyrimidine 4.78 g (75%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:19]=[C:18]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:17]=[CH:16][C:4]=1[O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl.Cl>[C:24]([O:23][C:21](=[O:22])[CH2:20][C:18]1[CH:17]=[CH:16][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=2)=[C:3]([CH2:2][NH:1][S:35]([CH3:34])(=[O:37])=[O:36])[CH:19]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2CN)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2CNS(C)(=O)=O)cc1
Reaction time: 12 h
Yield: 67.7 %

Procedure:
The product of step B (1.87 g, 5.03 mmol) was diluted with methylene chloride (2 mL) followed by the addition of pyridine (0.489 mL, 6.04 mmol) and methanesulfonyl chloride (0.779 mL, 10.1 mmol). After stirring for 12 hours, the reaction mixture was diluted with methylene chloride and 2N HCl, the layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a biotage 40M cartridge eluting with hexanes:ethyl acetate (1:1) to yield methyl 4-(4-(2-tert-butoxy-2-oxoethyl)-2-(methylsulfonamidomethyl)phenoxy)benzoate (1.53 g, 67.6% yield) as a clear oil.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([NH:16][C:17]1[C:18]([F:43])=[CH:19][C:20]([F:42])=[C:21]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([F:35])=[C:30](F)[C:31]=3[Cl:33])[C:26](=[O:36])[C:25]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:24]2)[CH:22]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CN1CCCC1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([NH:8][C:30]1[C:31]([Cl:33])=[C:32]2[C:27]([C:26](=[O:36])[C:25]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:24][N:23]2[C:21]2[CH:22]=[C:17]([NH:16][C:14]([O:13][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:15])[C:18]([F:43])=[CH:19][C:20]=2[F:42])=[CH:28][C:29]=1[F:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Agent: CN1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(NCc3ccccc3)c(F)cc2c1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
Benzylamine (750 mg) and ethyl 1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (4,200 mg) were added to a solution of N-methylpyrrolidine (800 mg) and N,N-dimethylformamide (20 ml), and the mixture was stirred overnight at 80° C. After the reaction mixture was cooled to room temperature, ethyl acetate (100 ml) was added to the reaction mixture, and the resultant mixture was washed 3 times with water (100 ml). After an organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent; chloroform) to obtain the title compound (3,200 mg) as an amorphous substance.
Reaction SMILES: ClC1C=CC(C2(C[Br:17])CCC(CCC)O2)=CC=1.[OH:18][CH2:19][CH:20]([CH2:32][CH2:33][CH3:34])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[CH2:23].BrBr.N1C=CC=CC=1>ClCCl>[Cl:31][C:25]1[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]=1[C:22]1([CH2:23][Br:17])[CH2:21][CH:20]([CH2:32][CH2:33][CH3:34])[CH2:19][O:18]1
Reactant: C=C(CC(CO)CCC)c1ccc(Cl)cc1Cl
Reactant: CCCC1CCC(CBr)(c2ccc(Cl)cc2)O1
Agent: BrBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC1COC(CBr)(c2ccc(Cl)cc2Cl)C1
Yield: 98 %

Procedure:
By the cyclisation procedure described for the preparation of 2-(4-chlorophenyl)-2-bromomethyl-5-prop-1-yltetrahydrofuran (see Example 1), 4-(hydroxymethyl)-2-(2,4-dichlorophenyl)hept-1-ene (1.5 g), bromine (0.88 g), and pyridine (0.43 g) in dry dichloromethane (30 ml) gave 2-(2,4-dichlorophenyl)-2-bromomethyl-4-prop-1-yltetrahydrofuran (1.9 g, 98%) as a pale yellow oil.
Reaction SMILES: [CH3:1][Mg+].[Br-].CC[O:6][CH2:7][CH3:8].C(OC([C:14]1[N:15]=[C:16]([C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:28]=2[Cl:34])[N:17]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])[CH:18]=1)=O)C>C1COCC1>[Br:33][C:30]1[CH:31]=[CH:32][C:27]([C:16]2[N:17]([C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[CH:18]=[C:14]([C:7]([OH:6])([CH3:8])[CH3:1])[N:15]=2)=[C:28]([Cl:34])[CH:29]=1
Reactant: CCOC(=O)c1cn(-c2c(Cl)cccc2Cl)c(-c2ccc(Br)cc2Cl)n1
Reactant: C[Mg+]
Reactant: CCOCC
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(O)c1cn(-c2c(Cl)cccc2Cl)c(-c2ccc(Br)cc2Cl)n1
Temperature: 25 °C
Yield: 77 %

Procedure:
To a 3.0 M solution of MeMgBr in Et2O (7.0 mL, 21.0 mmol) at 0° C. added slowly a solution of 2-(4-bromo-2-chlorophenyl)-1-(2,6-dichlorophenyl)-1H-imidazole-4-carboxylic acid ethyl ester (2.80 g, 5.90 mmol) in THF (30 mL, anhyd). After addition was completed the flask was removed from the ice-water bath and allowed to warm to ambient temperature. At 50 min the reaction mixture was quenched by addition of satd NH4Cl, extracted with EtOAc, dried (Na2SO4), concentrated and purified by chromatography (silica, EtOAc/Hex, 15:85 to 55:45) to give the title compound (2.1 g, 77%) as a white solid. 1H-NMR (DCM-d2): δ 7.58 (d, 1H), 7.37-7.41 (m, 2H), 7.26-7.32 (m, 2H), 7.11 (d, 1H), 6.93 (s, 1H), 2.73 (br s, 1.61 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]([OH:14])=O)#[N:2].O=S(Cl)[Cl:17]>ClCCl>[Cl:17][C:1]1[C:3]2[C:4](=[CH:5][C:6]([O:9][CH3:10])=[CH:7][CH:8]=2)[CH:11]=[C:12]([OH:14])[N:2]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C#N)c(CC(=O)O)c1
Solvent: ClCCl
Product: COc1ccc2c(Cl)nc(O)cc2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
2-(2-cyano-5-methoxyphenyl)acetic acid (3.8 g, 19.88 mmol), and SOCl2 (20 mL, 274 mmol) were stirred in dichloromethane (25 mL) at RT. The suspension became a solution over 8 h. The reaction was stirred overnight. The volitile organics were removed under vacuum and the residue was taken up in DCM and filtered. The filtrate was concentrated and then dissolved in 4 N HCl dioxane (30 mL) and transferred to a sealed vessel and heated to 60° C. for 3 h. The reaction was cooled and the solid was collected, washed with dioxane, and dried under vacuum to give the product 1-chloro-6-methoxyisoquinolin-3-ol (3.3 g, 70% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (d, J=9.6 Hz, 1H), 7.12 (dd, J=9.3, 2.5 Hz, 1H), 6.95 (s, 2H), 3.98 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=O)[CH2:21][C:22]([O:24][CH3:25])=[O:23])(=[O:13])=[O:12].O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-]>CO>[CH3:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:8][C:3]2[C:2](=[CH:7][CH:6]=[CH:5][N:4]=2)[N:1]=1)(=[O:13])=[O:12]
Reactant: Nc1cccnc1C=O
Reactant: COC(=O)CC(=O)c1ccccc1S(C)(=O)=O
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc2ncccc2nc1-c1ccccc1S(C)(=O)=O
Temperature: 100 °C
Yield: 26 %

Procedure:
A mixture of 3-aminopicolinaldehyde (1.09 g, 8.97 mmol), methyl 3-(2-(methylsulfonyl)phenyl)-3-oxopropanoate (2.3 g, 8.97 mmol) and cerium chloride heptahydrate (587 mg, 1.79 mmol) was heated to 100° C. for 3 h. The residue was dissolved in MeOH and purified by column chromatography on neutral alumina using 0-50% EtOAc in hexane to give methyl 2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridine-3-carboxylate (800 mg, 26% yield): 1H NMR (400 MHz, DMSO-d6) δ 3.155 (s, 3H), 3.688 (s, 3H), 7.486-7.507 (m, 1H), 7.733-7.816 (m, 2H), 7.951-7.982 (m, 1H), 8.059-8.081 (m, 1H), 8.510 (d, J=8.4 Hz, 1H), 8.965 (s, 1H), 9.165-9.178 (m, 1H); LC-MS (ESI) m/z 342.9 [M+H]+.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH3:10])([CH3:9])[CH3:8])(=O)=O.O1[CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]12.C1CCN2C(=NCCC2)CC1.N>C1C=CC=CC=1>[CH3:8][Si:7]([CH3:10])([CH3:9])[O:6][CH:19]1[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C1CCC2OC2C1
Agent: N
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: C[Si](C)(C)OC1C=CCCC1
Reaction time: 20 h
Yield: 86.9 %

Procedure:
Into a solution of 2.26 g (0.0102 mole) of trimethylsilyl trifluoromethanesulfonate in 20 ml of benzene was added dropwise a mixed solution of 1.06 g (0.0107 mole) of 1,2-epoxycyclohexane and 2 ml of DBU in 5 ml of benzene at room temperature under an atmosphere of argon. After further agitation for 20 hours at room temperature, the reaction mixture was subjected to column chromatography with silica gel treated with ammonia as the adsorbent. Subsequent distillation of a chromatographic fraction gave 1.51 g of 3-trimethylsiloxycyclohexene boiling at 50° to 60° C. under a pressure of 50 mmHg. The yield was about 87% of the calculated value.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][Si](C)(C)N[Si](C)(C)C.[K].IC.[Cl-].[NH4+]>CN(C=O)C>[CH2:18]([C:17]1[O:16][N:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]=1[C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[O:25][CH3:26])=[N:12][N:11]=1)[CH3:27]
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [K]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(F)cc2OC)o1
Reaction time: 1 h
Yield: 1.3 %

Procedure:
To a solution of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (1.00 g, 2.85 mmol) in DMF (10 mL) was added potassium hexamethyldisilazane (0.91 M in tetrahydrofuran, 3.44 mL, 3.13 mmol) at ambient temperature and the resulting mixture was stirred for 1 h. After addition of iodomethane (0.20 mL, 3.13 mmol) the reaction mixture was stirred for 20 h at this temperature. Further potassium hexamethyldisilazane (0.91 M in tetrahydrofuran, 3.44 mL, 3.13 mmol) and iodomethane (0.20 mL, 3.13 mmol) were added and stirring was continued for another 1.5 h. The reaction mixture was poured onto aqueous ammonium chloride (saturated, 50 mL) and was extracted with ethyl acetate. Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 0:80:20) afforded the title compound (14 mg, 1%) as a white solid. MS: m/e=366.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[CH:4][C:5]2[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1.I[CH2:19][CH3:20]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:17][CH2:19][CH3:20])[C:6]([CH3:15])([CH3:16])[CH2:7][CH:8]=[C:9]2[CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)C1=CCC(C)(C)c2cc(O)c(Br)cc21
Reactant: CCI
Product: CCOc1cc2c(cc1Br)C(C(C)C)=CCC2(C)C
Yield: 37 %

Procedure:
Following General Procedure O, 3-bromo-5-isopropyl-8,8-dimethyl-7,8-dihydronaphthalen-2-ol (Compound 97, 0.40 g, 1.3 mmol) was reacted with iodoethane to afford 0.16 g (37%) of the title compound as a yellow oil.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.Cl.[N:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.[CH2:33]([S:37](Cl)(=[O:39])=[O:38])[CH2:34][CH2:35][CH3:36]>ClCCl>[N:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([CH2:29][NH:30][S:37]([CH2:33][CH2:34][CH2:35][CH3:36])(=[O:39])=[O:38])=[CH:31][CH:32]=3)[CH2:19][CH2:18]2)=[CH:15][CH:16]=1
Reactant: CCCCS(=O)(=O)Cl
Reactant: NCc1ccc(CCN2CCN(c3ccncc3)CC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCS(=O)(=O)NCc1ccc(CCN2CCN(c3ccncc3)CC2)cc1
Reaction time: 0.08 h

Procedure:
Triethylamine (0.41 ml) was added to a stirred suspension of 4-[2-[4-(4-pyridyl)piperazin-1-yl]ethyl]benzylamine, trihydrochloride (300 mg) in dry dichloromethane (20 ml). After 5 minutes, 1-butanesulphonyl chloride (0.10 ml) was added and the mixture stirred overnight. Dichloromethane (80 ml) was added and the solution washed with water (2×25 ml), dried (MgSO4) and the solvent removed in vacuo, Trituration of the residue with a small volume of ethyl acetate gave the title compound, 50 mg, as an off-white solid: m.p. 154°-156° C.; NMR (d6DMSO) δ8.16(2H,d), 7.53(1H,t), 7.22(4H,m), 6.37(2H,d), 4.10(2H,d), 3.35(6H,m+H2O), 2.81(4H,m), 2.54(4H,m+DMSO), 1.56(2H,m), 1.29(2H,m). 0.82(3H,t), m/e 417 (M+H)+ ; calculated for C22H32N4O2S.0.75H2O: C, 61.5; H, 7.8;, 13.0. found: C, 61.5; H, 7.6; N, 12.7%.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(N(CC)CC)C.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[S:24](Cl)(=[O:26])=[O:25]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[S:24]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])(=[O:25])=[O:26]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: OCC(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=S(=O)(OCC(F)(F)F)c1ccc2ccccc2c1
Reaction time: 8 h
Yield: 89 %

Procedure:
To a stirred solution of 25.0 parts of 2,2,2-trifluoroethanol in 175 parts of N,N-diethylethanamine were added portionwise 62.2 parts of 2-naphthalenesulfonyl chloride. Upon completion, a mixture of 1.5 parts of N,N-dimethyl-4-pyridinamine and 25 parts of ethyl acetate was added during a period of 20 minutes. Upon complete addition, stirring was continued overnight at room temperature. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was stirred in water and solidified product was filtered off under reduced pressure. The precipitated product was dissolved in dichloromethane. The organic layer was dried, filtered and evaporated in vacuo. The residue was treated with petroleum ether. After filtration, the precipitated product was crystallized from 2-propanol. The product was filtered off and dried, yielding 65.3 parts (89%) of 2,2,2-trifluoroethyl 2-naphthalenesulfonate; mp. 72.7° C. (int. 36).
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12]([O-:15])(=[O:14])[CH3:13].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([O:9][C:8]1[CH:10]=[CH:11][C:3](/[CH:2]=[CH:13]/[C:12]([OH:15])=[O:14])=[CH:4][C:5]=1[O:6][CH3:7])(=[O:19])[CH3:18]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C=O)ccc1O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1cc(/C=C/C(=O)O)ccc1OC(C)=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 69.4 %

Procedure:
In a round bottomed flask, 30.04 g of vanillin (0.197 mol) and 26.0 g of sodium acetate (0.317 mol) were dissolved in 200 mL of acetic anhydride (2.12 mol). About 1 mL of pyridine was added to the flask and the mixture was heated to reflux. After 24 h, the brown solution was poured over about 500 g of crushed ice and the solution was stirred until the appearance of a yellow-brown solid. The flask was left overnight in the freezer and a dark yellow solid was obtained by filtration. The crude solid was recrystallized from acetic acid/water to give 32.3 g of a yellow beige solid in a 69% yield.