Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][C:18](O)=[CH:19][C:14]=2[C:13](=[O:21])[N:12]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:11][C:10]1=[O:29])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][C:18]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)=[CH:19][C:14]=2[C:13](=[O:21])[N:12]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:11][C:10]1=[O:29])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CCOC(=O)CCN1CC(=O)N(CC(=O)OC(C)(C)C)c2ccc(O)cc2C1=O
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCN1CC(=O)N(CC(=O)OC(C)(C)C)c2ccc(Cc3ccc(C#N)cc3)cc2C1=O
Temperature: 40 °C
Reaction time: 96 h
Yield: 85.3 %

Procedure:
1-(Carbo-t-butoxymethyl)-4-(2-carboethoxyethyl)-7-hydroxy-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (19.5 g, 48 mmol), α-bromo-p-tolunitrile (11.3 g, 58 mmol), and potassium carbonate (9.0 g, 65 mmol) were combined in a round bottom flask. Anhydrous DMF (300 mL) was added and the reaction mixture was stirred at 40° C. for 4 days. The reaction mixture was filtered and the filtrate was concentrated in vacuo on a rotary evaporator. The residue was partitioned between ethyl acetate (500 mL) and water (100 mL). The organics were washed with saturated NaCl (50 mL) and dried over Na2SO4. The volatiles were removed in vacuo on a rotary evaporator and the residue was chromatographed on silica gel, eluting the column with 5:6 ethyl acetate/hexanes. Fractions containing pure product (Rf=0.17, 5:6 ethyl acetate/hexanes) were combined and the solvents removed in vacuo on a rotary evaporator to yield 1-(carbo-t-butoxymethyl)-4-(2-carboethoxyethyl)-7-[(4-cyanophenyl)methyl]-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (20.7 g, 83% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[C:9]=2[O:18][CH3:19])[CH:5]=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[NH2:24].[H-].[Na+].O1CCCC1>C(OCC)C>[CH3:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[C:9]=3[O:18][CH3:19])[CH:5]=[CH:4][N:3]=2)[CH:25]=[C:26]([CH3:28])[CH:27]=1
Reactant: COc1ccc(-c2ccnc(Cl)n2)c(OC)c1OC
Reactant: Cc1cc(C)cc(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(-c2ccnc(Nc3cc(C)cc(C)c3)n2)c(OC)c1OC

Procedure:
In a vial was placed 28 mg (100 μmol) of chloropyrimidine 5, 3,5 dimethylaniline (24 mg, 200 μmol), 60% NaH (6 mg, excess), and tetrakis(triphenylphospine)palladium (6 mg, catalytic). Tetrahydrofuran (2 mL) was added and the vial was sealed and heated to reflux for two hours. The reaction was diluted with diethyl ether and washed with 1N hydrochloric acid. The organic layer was separated, washed with 1N NaOH solution, water, and brine. The organic extract was dried (MgSO4), filtered, and evaporated in vacuo to afford the crude product. The compound was purified on silica gel using an eluent of 20% acetone/hexane to afford the pure product II-14 as a white solid. 1H-NMR (CDCl3, 500 MHz) δ 8.41 (d, 1H), 7.78 (d, 1H), 7.35 (d, 1H), 7.31 (s, 1H), 7.08 (s, 1H), 6.82 (d, 1H), 6.68 (s, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 3.83 (s, 3H), 2.34 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH2:7]Br)=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[CH3:13][O-:14].[Na+].O.Cl>CO>[Br:1][C:2]1[O:6][C:5]([CH2:7][O:14][CH3:13])=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1
Reactant: C[O-]
Reactant: COC(=O)c1cc(Br)oc1CBr
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCc1oc(Br)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
To a solution of methyl 5-bromo-2-(bromomethyl)furan-3-carboxylate (3.0 g) in methanol (30 mL) was added sodium methoxide (0.8 g) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane) to give the title compound (1.9 g, 77%) as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[S:3])[NH2:2].[C:15]([C:19]1[CH:28]=[CH:27][C:22]([C:23](=O)[CH2:24]Br)=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([C:19]1[CH:20]=[CH:21][C:22]([C:23]2[N:2]=[C:1]([C:4]3[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=3)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:3][CH:24]=2)=[CH:27][CH:28]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1ccc(C(=O)CBr)cc1
Reactant: CCOC(=O)c1cccc(C(N)=S)c1
Product: CCOC(=O)c1cccc(-c2nc(-c3ccc(C(C)(C)C)cc3)cs2)c1
Yield: 37 %

Procedure:
In the same manner as in Example 74, ethyl 3-thiocarbamoylbenzoate was reacted with 4-t-butylphenacyl bromide to obtain ethyl 3-[4-(4-t-butylphenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 37%. Pale yellow prisms. Melting point: 96 to 97° C.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[Br:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11]>C1C=CC=CC=1>[Br:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH:11][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1]
Reactant: Nc1cccc(Br)c1
Reactant: C=C1CC(=O)O1
Solvent: c1ccccc1
Product: CC(=O)CC(=O)Nc1cccc(Br)c1
Temperature: 20 °C
Reaction time: 5 h
Yield: 73.9 %

Procedure:
84 g of diketene were added over 20 minutes to a mixture of 172 g of m-bromo-aniline and 600 ml of benzene and the mixture was stirred for 5 hours at 20° C. The mixture was filtered and the precipitate was washed with benzene and isopropyl ether. The filtrate was vacuum filtered and evaporated to dryness to obtain 189 g of m-bromo-acetylacetanilide melting at 110° C.
Reaction SMILES: [C:1]([O:18][CH2:19][CH:20]([CH2:22][O:23][C:24](=[O:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[OH:21])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl[C:42]([O:44][CH:45]([Cl:47])[CH3:46])=[O:43].N1C=CC=CC=1>C(Cl)(Cl)Cl.ClCCl>[Cl:47][CH:45]([O:44][C:42]([O:21][CH:20]([CH2:22][O:23][C:24](=[O:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:19][O:18][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:43])[CH3:46]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCC)OC(=O)OC(C)Cl
Temperature: 25 °C
Reaction time: 120 h

Procedure:
1,3-Dipalmitoylglycerol (2.5 g, 4.39 mmol) and 1-chloroethyl chloroformate (1.26 g, 8.79 mmol) were dissolved in chloroform (50 ml). To this was added anhydrous pyridine dropwise. The reaction mixture was stirred at ambient temperature for 5 days, diluted with dichloromethane and extracted with 0.5N HCl solution. The organic layer was washed with a saturated sodium bicarbonate solution, washed again with water, dried over sodium sulphate and concentrated to dryness. The waxy residue was dried under reduced pressure and used without further purification.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]1[CH:16]=[CH:15][C:14]([N:17]([OH:32])[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[O:19])=[CH:13][CH:12]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:18]([N:17]([OH:32])[C:14]2[CH:15]=[CH:16][C:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:12][CH:13]=2)=[O:19])=[CH:22][C:23]=1[C:28]([F:30])([F:31])[F:29]
Reactant: C1COCCN1
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N(O)c1ccc(-n2cnc3c(Cl)ncnc32)cc1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N(O)c1ccc(-n2cnc3c(N4CCOCC4)ncnc32)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-chloropurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)-phenyl)-1-hydroxyurea and morpholine by using the same techniques as in Example 53.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH:11]([C:19](O)=[O:20])[NH:10]1.[ClH:22]>CCOCC>[ClH:22].[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH:11]([C:19]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:20])[NH:10]1
Reactant: OCc1ccccc1
Reactant: O=C(O)C1Cc2ccccc2CN1
Agent: Cl
Solvent: CCOCC
Product: O=C(OCc1ccccc1)C1Cc2ccccc2CN1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
Benzyl alcohol, 750 ml, was treated with 150 g of commercial polyphosphoric acid and warmed and stirred at 90° C. to obtain a homogeneous mixture. Solid 1,2,3,4 -tetrahydro-3-isoquinolinecarboxylic acid (S-form) 65.2 g was added. The mixture was stirred 4 hours at 95°-105° C. and then allowed to stand at room temperature for 18 hours. A solution of 18.5 g gaseous hydrochloric acid in 2.5 of anhydrous ether was added, and the product separated slowly on cooling overnight. Filtration gave the crude benzyl 1,2,3,4-tetrahydro-3-isoquinoline carboxylate hydrochloride. This was purified by recrystallization from ethanol twice to give material with mp 190.5°-191° C.; [α]D 23=-83.3° (1% 1:1 methanol/1N hydrochloric acid).
Reaction SMILES: N1C=CC=CC=1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].O>CCOCC>[C:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([Br:7])=[CH:9][CH:10]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(Br)cc1
Solvent: CCOCC
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A one-necked, 25-mL, round-bottomed flask equipped with an argon inlet adapter was charged with 5 mL pyridine, 4-bromophenol (1.00 g, 5.78 mmol), and acetic anhydride (2.80 g, 27.4 mmol). The resulting mixture was stirred for 12 h at room temperature. A mixture of water (20 mL) and ether (50 mL) was added and the resulting organic phase was washed with a second 20-mL portion of water. The organic phase was dried over MgSO4, filtered, and concentrated to provide a colorless oil:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8](=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:4]1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:34](O)=[O:35].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:12][CH2:11][CH2:10][CH2:9][C:8]([N:5]2[CH2:6][CH2:7][CH:3]([CH2:2][NH:1][C:34](=[O:35])[C:33]3[CH:32]=[C:31]([O:30][CH3:29])[C:39]([O:40][CH3:41])=[C:38]([O:42][CH3:43])[CH:37]=3)[CH2:4]2)=[O:28])=[CH:15][CH:16]=1
Reactant: NCC1CCN(C(=O)CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)C1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cc(C(=O)NCC2CCN(C(=O)CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(3-aminomethyl-pyrrolidin-1-yl)-6,6-bis-(4-fluoro-phenyl)-hexan-1-one (0.69 g, 1.78 mmol) in dry CH2Cl2 (40 ml) was added 3,4,5-trimethoxy benzoic acid (0.38 g, 1.78 mmol) under nitrogen. To the reaction was added EDC (0.68 g, 3.56 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (30 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (15:1) to give a desired product in good yield
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:19]=1.[Cl:31][C:32]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[C:34]([F:47])[C:33]=1[OH:48]>>[Cl:31][C:32]1[CH:37]=[C:36]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)[CH:19]=2)[CH:35]=[C:34]([F:47])[C:33]=1[OH:48]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: O=C(c1cnc2ccc(Br)cc2c1Nc1cccc(CCN2CCCC2)c1)C1CC1
Product: O=C(c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1cccc(CCN2CCCC2)c1)C1CC1
Yield: 31.4 %

Procedure:
Following general procedure A-1, {6-bromo-4-[3-(2-(pyrrolidin-1-yl)ethyl)phenylamino]quinolin-3-yl}(cyclopropyl)methanone (56 mg, 0.120 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (49 mg, 0.180 mmol) to afford the desired product (20 mg, 32%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.45 (s, 1H), 8.22 (dd, J=8.8, 1.9 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.91 (s, 1H), 7.65-7.58 (m, 1H), 7.54 (d, J=7.8, 1H), 7.46 (s, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.12 (dd, 11.5, 2.3 Hz, 1H), 6.95 (s, 1H), 3.72-3.64 (m, 2H), 3.45-3.36 (m, 2H), 3.17-3.05 (m, 4H), 2.92-2.83 (m, 1H), 2.20-2.09 (m, 2H), 2.08-1.99 (m, 2H), 1.31-1.16 (m, 4H); ESI MS m/z 530 [C31H29ClFN3O2+H]+; HPLC>99% (AUC), tR=10.82 min.
Reaction SMILES: [CH:1]12[CH:6]([CH2:7][N:8]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([F:28])[CH:17]=3)[C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[O:10])[CH:5]1[CH2:4][NH:3][CH2:2]2.CCN(C(C)C)C(C)C.[C:38]([C:42]1[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=1)([CH3:41])([CH3:40])[CH3:39]>ClCCCl.CN(C1C=CN=CC=1)C>[C:38]([C:42]1[CH:47]=[CH:46][C:45]([S:48]([N:3]2[CH2:4][CH:5]3[CH:1]([CH:6]3[CH2:7][N:8]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([F:28])[CH:17]=3)[C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[O:10])[CH2:2]2)(=[O:50])=[O:49])=[CH:44][CH:43]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: O=C(c1cccs1)N(CC1C2CNCC21)c1ccc(N2CCOCC2)c(F)c1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(S(=O)(=O)N2CC3C(CN(C(=O)c4cccs4)c4ccc(N5CCOCC5)c(F)c4)C3C2)cc1
Temperature: 80 °C
Yield: 78.1 %

Procedure:
To a stirring solution of thiophene-2-carboxylic acid (3-aza-bicyclo[3.1.0]hex-6-ylmethyl)-(3-fluoro-4-morpholin-4-yl-phenyl)-amide (60 mg, 0.15 mmol) in 3 mL of DCE was added DIEA (0.026 mL, 0.45 mmol), DMAP (cat.) and 4-tert-butylbenzene sulfonyl chloride (0.10 mL, 0.45 mmol). The resulting mixture was heated to 80° C. for 1.5 hours, cooled to room temperature and quenched with saturated NaHCO3. The layers were separated, the aqueous layer was extracted with CH2Cl2, and the combined organic layers were dried and concentrated. The resulting crude material was purified via flash chromatography with 40% EtOAc/hexanes. The product containing fractions were collected and concentrated to yield 70 mg of a white foam. 400 MHz 1H NMR (CDCl3) δ 7.62-7.66 (m, 2H), 7.47-7.50 (m, 2H), 7.29-7.31 (m, 1H), 6.79-6.95 (m, 5H), 3.87-3.89 (m, 4H), 3.68 (d, J=7.47 Hz, 2H), 3.46 (d, J=9.13 Hz, 2H), 3.13-3.15 (m, 4H), 2.94-2.96 (m, 2H), 1.64 (s, 2H), 1.31 (s, 9H), 1.12-1.14 (m, 1H); MS (M+1) 598.2.
Reaction SMILES: B(Br)(Br)[Br:2].C[O:6][C:7]1[CH:8]=[C:9]([C:13]2[O:14][C:15]3[C:21]([CH2:22]O)=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:10]=[CH:11][CH:12]=1>C(Cl)Cl>[Br:2][CH2:22][C:21]1[C:15]2[O:14][C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([OH:6])[CH:8]=3)=[N:17][C:16]=2[CH:18]=[CH:19][CH:20]=1
Reactant: BrB(Br)Br
Reactant: COc1cccc(-c2nc3cccc(CO)c3o2)c1
Solvent: ClCCl
Product: Oc1cccc(-c2nc3cccc(CBr)c3o2)c1
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of boron tribromide in methylene chloride (1.0 M; 7 ml, 7 mmol) was added dropwise to a suspension of [2-(3-methoxyphenyl)-benzoxazol-7-yl]methanol (457 mg, 1.79 mmol) in methylene chloride (10 ml) at −78° C., and the mixture was stirred at the same temperature for 1 hr. After the removal of the cooling bath, the mixture was stirred at room temperature for 2.5 hrs. The reaction mixture was poured into ice-water (50 ml), and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried, and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (n-hexane/ethyl acetate=3−1) to give 7-bromomethyl-2-(3-hydroxyphenyl)-benzoxazole (535 mg, 98%) as a brown solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:21][CH3:22])[C:10]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:23])[CH:3]=1.[CH3:24][NH:25][CH3:26]>CCO>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([C:10]2[C:9]([S:21][CH3:22])=[N:8][N:7]3[C:2]([N:25]([CH3:26])[CH3:24])=[CH:3][C:4]([CH3:23])=[N:5][C:6]=23)(=[O:12])=[O:13])=[CH:15][CH:16]=1
Reactant: CNC
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc(Cl)cc1
Solvent: CCO
Product: CSc1nn2c(N(C)C)cc(C)nc2c1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
In an analogous manner to that described in Example 5, from 7-chloro-3-(4-chloro-benzenesulphonyl)-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine and dimethyl-amine in EtOH there was obtained [3-(4-chloro-benzenesulphonyl)-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-yl]-dimethyl-amine as colorless crystals, m.p. 221-223°.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH3:29])[CH2:23][C:22]([CH3:25])([CH3:24])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:26](=O)[CH3:27])[CH:20]=2)[O:15]1.C(OP(Cl)(OCC)=O)C.C([N-]C(C)C)(C)C.[Li+]>CCCCCC.C1COCC1>[CH3:13][C:14]1([CH3:29])[CH2:23][C:22]([CH3:24])([CH3:25])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:26]#[CH:27])[CH:20]=2)[O:15]1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Agent: CC(C)[N-]C(C)C
Agent: CCOP(=O)(Cl)OCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: C#Cc1ccc2c(c1)C(C)(C)CC(C)(C)O2
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a cooled (-78 degrees C.) solution of 522 mg (5.17 mmol) of diisopropylamine in S ml of dry THF was added slowly, under nitrogen, 3.23 ml of 1.6M (5.17 mmol) n-butyl lithium in hexane. The mixture was stirred at -78 degrees C. for 40 minutes and then treated with a solution of 1.24 g (5.17 mmol) of 2,2,4,4-tetramethyl-6-acetylchroman (Compound 41) in 2 ml of dry THF. The mixture was stirred at -78 degrees C. for a further 1 h and then treated with 895 mg (5.19 mmol) of diethylchlorophosphate. The reaction mixture was allowed to warm to room temperature and transferred by double-ended needle into a solution of lithium diisopropylamide in THF at -78 degrees C. [prepared as described above from 1.04 g (10.34 mmol) of diisopropylamine and 6.46 ml of 1.6M (10.34 mmol) n-butyl lithium in hexane]. The cooling bath was removed and the mixture was stirred at room temperature for 16 h. The mixture was then treated with 10 ml of ice water and acidified to a pH of 2 with 10% HCl. The organic layer was separated and the aqueous layer was extracted with 3×30 ml of pentans. The organic extracts were combined and washed successively with 2×30 ml of dilute HCl, water, 3×30 ml of saturated NaHCO3 solution and saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography (silica; 2% ethyl acetate in hexane) to give the title compound as a pale yellow oil. PMR (CDCl3): & 1.31 (6H, s), 1.32 (6H, s), 1.50 (2H, s), 3.00 (1H, s), 6.72 (1H, d, J-8.4 Hz), 7.20 (1H, dd, J-8.4 Hz, 2.1 Hz), 7.42 (1H, d, J-2.1 Hz). MS exact mass, m/e 214.1251 (calcd. for C15H18O, 214.1357).
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH:7]([C:12]([Br:15])([Br:14])[Br:13])[CH:8]=[C:9]([CH3:11])[CH3:10])=[O:5])=[N-]>C1(C)C=CC=CC=1.CC(CC(C)=O)=O.CC(CC(C)=O)=O.[Cu]>[Br:13][C:12]([Br:15])([Br:14])[CH:7]1[CH:8]2[CH:3]([C:9]2([CH3:11])[CH3:10])[C:4](=[O:5])[O:6]1
Reactant: CC(C)=CC(OC(=O)C=[N+]=[N-])C(Br)(Br)Br
Agent: [Cu]
Solvent: Cc1ccccc1
Solvent: CC(=O)CC(C)=O
Product: CC1(C)C2C(=O)OC(C(Br)(Br)Br)C21
Yield: 28 %

Procedure:
To a refluxing solution of cupric acetylacetonate (0.005 g, 0.019 mmole) in 40 ml of toluene was added dropwise over a period of 2.5 hours under an atmosphere of argon gas a solution of (±)-3-methyl-1-tribromomethyl-2-butenyl diazoacetate (0.203 g, 0.005 ml) in 10 ml of toluene. The mixture was then heated under reflux for one hour. After cooling, the reaction mixture was washed successively with two portions of 1N aqueous hydrochloric acid, once with saturated aqueous sodium bicarbonate, and twice with saturated aqueous sodium chloride. After drying over magnesium sulfate, the solution was evaporated to give a yellow oil as the residue. The residue was purified by column chromatography on a silica gel column using 9/1 n-hexane/ethyl acetate as the eluent, yielding (±)-4-tribromomethyl-6,6-dimethyl-2-oxo-3-oxabicyclo[3.1.0]hexane (0.053 g, yield 28%); mp 101°-103° after recrystallization from n-hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[N:29]1[CH:34]=[C:33]([CH2:35]OS(C)(=O)=O)[CH:32]=[N:31][CH:30]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:35][C:33]2[CH:34]=[N:29][CH:30]=[N:31][CH:32]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: CS(=O)(=O)OCc1cncnc1
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cncnc4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with methanesulfonic acid pyrimidin-5-ylmethyl ester gave the title compound. ES-MS m/e (%): 491.0 (M+H+).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[O:10]1[C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+].C(#N)C>O.C(OCC)C>[O:10]1[C:14]2([CH2:19][CH2:18][N:17]([C:8]3[CH:9]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]#[N:7])[CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccc(F)cc1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: N#Cc1ccccc1N1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.5 %

Procedure:
A mixture of 10 g (0.0825 mol) p-fluorobenzonitrile, 47 g (0.3282 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, 17 g (0.123 mol) of K2CO3, and 100 ml of acetonitrile is stirred at 90°-100° C. for three days. The reaction mixture is allowed to cool to ambient temperature, diluted with water and extracted with methylene chloride. The combined extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo to give a pasty solid. Trituration with ethyl ether furnishes 13.4 g (67%) of title compound: m.p. 134°-135° C.; IR (KBr) 2210 and 1600 cm-1 ; NMR (CDCl3) δ7.48 (d, 2H), 6.88 (d, 2H), 4.0 (s, 4H), 3.58-3.40 (m, 4H), and 1.90-1.70 (m, 4H).