Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18](=[O:41])[CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1>CN(C)C=O>[CH3:1][N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18](=[O:41])[CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1CCN(CCCCC(=O)c1ccc2c(c1)CCN2)C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccccc1CCN(CCCCC(=O)c1ccc2c(c1)CCN2C)C(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 5 h
Yield: 33.5 %

Procedure:
Potassium carbonate (166 mg) and methyl iodide (170 mg) were added to a solution of tert-butyl 5-(2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate (362 mg) obtained in Reference Example 50 in dimethylformamide (2 ml), and the mixture was stirred at 60 to 70° C. for 5 hours. The solvent was evaporated under reduced pressure, water was added to the resulting residue, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluting solvent; hexane:ethyl acetate=1:1) to give the title compound as a pale yellow oil (125 mg).
Reaction SMILES: [C:1]1([OH:9])[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[C:2]=1[OH:8].[C:10](=O)(O)[O-].[K+].CI>CC(C)=O>[CH3:10][O:8][C:2]1[C:3]([OH:7])=[CH:4][CH:5]=[CH:6][C:1]=1[OH:9]
Reactant: O=C([O-])O
Reactant: Oc1cccc(O)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(O)cccc1O
Temperature: 25 °C
Yield: 27 %

Procedure:
To a stirring solution of benzene-1,2,3-triol (2 g, 15.87 mmol) in acetone was added potassium bicarbonate (1.90 g, 19.04 mmol) and methyl iodide (3.38 g, 23.80 mmol) and the resultant reaction mixture was heated to reflux for 16 h. The reaction mixture was cooled to RT and filtered through celite bed. The filtrate was concentrated under reduced pressure, triturated with diethyl ether and the obtained solid was separated and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography (silica gel, 0-15% ethyl acetate in pet ether) afforded 2-Methoxybenzene-1,3-diol as a solid (600 mg, 27.2%). 4-Bromo-2-methoxybenzene-1,3-diol: To a stirring solution of 2-methoxybenzene-1,3-diol (3.0 g, 21.42 mmol) in tetrahydrofuran (30 mL) at −78° C. was added N-bromosuccinimide (4.57 g, 25.71 mmol) and the reaction mixture was stirred at −78° C. for 2 h. The reaction mixture was diluted with ice-cold water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The obtained residue has mixture of products (mono and dibromo) which was used as such for further reactions (4.2 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[N:8][CH:7]=[CH:6][N:5]2[CH:16]=1.[NH:17]1[CH2:20][CH:19]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)[CH2:18]1>>[N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][C:21]=1[CH:19]1[CH2:18][N:17]([C:2]2[N:3]=[C:4]3[C:9]([N:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)=[N:8][CH:7]=[CH:6][N:5]3[CH:16]=2)[CH2:20]1
Reactant: c1ccc2nc(C3CNC3)ccc2c1
Reactant: Clc1cn2ccnc(N3CCOCC3)c2n1
Product: c1ccc2nc(C3CN(c4cn5ccnc(N6CCOCC6)c5n4)C3)ccc2c1

Procedure:
Compound 25a was prepared from compound 24a and compound 24d using the procedure described in Example 24, Step E. Mass Spectrum (LCMS, ESI pos.) Calcd. For C22H22N6O: 387.2 (M+H). Found 387.2.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][C:16](=[O:20])[N:17]([CH3:19])[CH3:18])[CH:6]=1)C.[OH-].[Na+].Cl>>[CH3:19][N:17]([CH3:18])[C:16]([CH2:15][CH2:14][CH2:13][C:12]#[C:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([OH:21])=[O:3])=[O:20]
Reactant: CCOC(=O)c1cccc(C#CCCCC(=O)N(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(C)C(=O)CCCC#Cc1cccc(C(=O)O)c1
Yield: 73.7 %

Procedure:
3-(5-Dimethylcarbamoyl-pent-ynyl)benzoic acid ethyl ester (0.800 g, 2.78 mmol) was treated with sodium hydroxide 1M solution (6 mL) overnight. To the reaction mixture 7 mL of HCl 1M solution was added and the solvent was removed under vacuum. The residue was triturated with ethyl acetate, to give 3-(5-dimethylcarbamoyl-pent-1-ynyl)-benzoic acid (24) (0.590 g, 2.05 mmol; yield 74%) as white off powder.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.Br[CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1>CN(C=O)C>[F:3][C:4]1[CH:9]=[C:8]([O:10][CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: BrCCOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(OCCOC3CCCCO3)cc2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of NaH (21.3 mmol) in DMF (50 ml), 4-(2-fluoro-4-hydroxy-phenyl)-piperazine-1-carboxylic acid, tert.-butyl ester (17.8 mmol) is successively added at 0° C. To the mixture, 2-(2-bromoethoxy)-tetrahydro-2H-pyrane (24.9 mmol) is added at 0° C. and the mixture is stirred for 2 h at ambient temperature. The reaction mixture is quenched with ice-water and extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over magnesium sulfate. Chromatography on silica gel using n-hexane, n-hexane:AcOEt=6:1, n-hexane:AcOEt=4:1 gives the desired 4-{2-fluoro-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-piperazine-1-carboxylic acid, tert-butyl ester.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([N:11]([CH2:19][CH3:20])[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[CH3:10].[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[C:21]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([N:11]([CH2:9][CH3:10])[CH2:19][CH3:20])=[CH:13][CH:14]=1)(=[O:23])[CH3:22]
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(NC(C)=O)cc1
Temperature: 0 °C
Yield: 80 %

Procedure:
Triethylamine (22.3 g, 30.6 mL, 0.22 mol) was added to a suspension of N,N-diethyl-p-phenylenediamine hydrochloride (20 g, 0.1 mol) in dichloromethane (150 mL) at room temperature. The mixture was cooled to 0° C. and acetyl chloride (7.85 g, 0.1 mol) was added dropwise, with stirring. The mixture was allowed to warm to room temperature, and the precipitate which had formed was removed by filtration. The solid residue was washed with dichloromethane, and the combined dichloromethane solutions were concentrated. The dark oil produced was triturated with hexanes (100 mL) to afford a light brown crystalline solid, which was purified by recrystallization from 50% aqueous ethanol to afford the N-acetyl-4-diethylaminoaniline (16.5 g, 80% yield) as a gray solid. The structure of this compound was confirmed by mass spectroscopy and by 1H NMR spectroscopy.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].C1C(=O)N([Br:18])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:10][Br:18])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(C)c(Br)c(C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(C)c(Br)c(CBr)n1
Temperature: 25 °C
Yield: 16.1 %

Procedure:
A mixture of 3-bromo-2,4,6-trimethylpyridine (15.6 g), NBS (13.9 g) and benzoyl peroxide (567 mg) was heated under reflux in a carbon tetrachloride solvent (300 mL) for two hours. The reaction mixture was cooled to room temperature and then filtered, and the filtration residue was washed with carbon tetrachloride. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 10%) to give the title compound (3.51 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:12]([O:14][C:15](=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:13]>>[CH2:12]([O:14][C:15](=[O:20])[CH:16]([C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1])[CH:17]([CH3:19])[CH3:18])[CH3:13]
Reactant: CCOC(=O)CC(C)C
Reactant: O=C(Cl)c1ccc(F)cc1F
Product: CCOC(=O)C(C(=O)c1ccc(F)cc1F)C(C)C
Yield: 68 %

Procedure:
2,4-Difluorobenzoyl chloride (4.9 ml) and isovaleric acid ethyl ester (3.0 ml) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 8(a) to obtain the title compound (3.65 g, 68%) as a colorless liquid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:11])=[O:10])[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.C(O)(=O)C[C:29](CC(O)=O)([C:31](O)=[O:32])[OH:30]>C(O)CO.O>[OH:30][CH2:29][CH2:31][O:32][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:11])=[O:10])[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)CCc2ccccc2)cc1
Solvent: OCCO
Solvent: O
Product: Cc1ccc(-c2c(NS(=O)(=O)CCc3ccccc3)ncnc2OCCO)cc1
Temperature: 120 °C
Reaction time: 27 h

Procedure:
2-Phenyl-ethanesulfonic acid (6-chloro-5-p-tolyl-pyrimidin-4-yl)-amide (850 mg) was added to a solution of K-tert. butylate (1.1 g) in ethylene glycol (15 ml). The mixture was stirred at 120° C. for 27 h before it was diluted with water (100 ml), acidified with 10% aq. citric acid (13 ml). The resulting precipitate was collected, washed with water and diethyl ether and dried to give 2-phenyl-ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (716 mg) as a beige powder. LC-MS: tR=4.44 min, [M+1]+=414.18, [M−1]−=412.13.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6](O)=[O:7].CC[N:18]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([NH2:18])=[O:7]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(Oc1ccc(Cl)cc1Cl)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(Oc1ccc(Cl)cc1Cl)C(N)=O
Reaction time: 18 h
Yield: 62.9 %

Procedure:
The reaction mixture of 3-(3-endo-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)benzonitrile hydrochloride (300 mg, 1.03 mmol), commercially available 2-(2,4-dichlorophenoxy)-2-methylpropanoic acid (310 mg, 1.24 mmol), EDCI (300 mg, 1.54 mmol), HOBT (210 mg, 1.54 mmol) and triethylamine (0.75 mL, 5.38 mmol) in CH2Cl2 (10 mL) was stirred 18 h. The resulting mixture was washed with satd. aq. NaHCO3 (5 mL) and brine (5 mL) successively, then dried over MgSO4, filtered and evaporated to give a residue which was purified by column chromatography (ethyl acetate: CH2Cl2=1:1) to give N-(8-(3-cyanobenzoyl)-8-azabicyclo[3.2.1]octan-3-endo-yl)-2-(2,4-dichlorophenoxy)-2-methylpropanamide (378 mg, 0.78 mmol, 76% yield) as a white foam. 1H NMR (CDCl3, 400 MHz): δ 1.55 (s, 6H), 1.85 (m, 2H), 2.00 (m, 3H), 2.20 (m, 3H), 2.50 (m, 1H), 4.04 (br s, 1H), 4.28 (q, 1H), 4.86 (br s, 1H), 7.05 (d, 1H), 7.22 (dd, 1H), 7.44 (d, 2H), 7.58 (m, 2H), 7.77 (m, 3H).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]#[N:9].[OH:16][CH:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1>C(O)C>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([N:19]1[CH2:20][CH2:21][CH2:22][CH:17]([OH:16])[CH2:18]1)=[NH:9]
Reactant: N#CNc1ccccc1-c1ccccc1
Reactant: OC1CCCNC1
Solvent: CCO
Product: N=C(Nc1ccccc1-c1ccccc1)N1CCCC(O)C1

Procedure:
A mixture of 2-biphenylylcyanamide (4 g), 3-hydroxypiperidine (2.5 g) and ethanol (30 ml) was heated at 90°-95° C. for 8 hours to give a brown solid which was purified by chromatography on an aluminia column eluted successively with hexane, 1:4, 2:3, 3:2 and 4:1 mixtures of dichloromethane and hexane and then a 99:1 mixture of dichloromethane and methanol to yield a solid which was recrystallised from ethyl acetate to give N-(2-biphenylyl)-3-hydroxypiperidine-1-carboxamidine (m.p. 144°-145° C.).
Reaction SMILES: C([N:4]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](Br)=[CH:10][N:9]=1)[C:5](=[O:7])[CH3:6])(=O)C.Cl[C:20]1[N:21]=[C:22]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[C:23]2[S:28][C:27]([CH2:29][N:30]3[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]3)=[CH:26][C:24]=2[N:25]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:5]([NH:4][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:20]2[N:21]=[C:22]([N:42]3[CH2:43][CH2:44][O:45][CH2:46][CH2:47]3)[C:23]3[S:28][C:27]([CH2:29][N:30]4[CH2:31][CH2:32][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:34][CH2:35]4)=[CH:26][C:24]=3[N:25]=2)=[CH:10][N:9]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)N(C(C)=O)c1ncc(Br)c2ccccc12
Reactant: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(C)(C)C(N)=O)CC4)cc3n2)c2ccccc12
Temperature: 60 °C
Yield: 18.3 %

Procedure:
Following General Procedure B of Suzuki coupling, N-acetyl-N-(4-bromoisoquinolin-1-yl)acetamide (57 mg) was reacted with 2-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide (107 mg). After reaction completion, 1 M Na2CO3 (2 mL) and 1,4-dioxane (2 mL) were added to the mixture. The suspension was heated at 60° C. for 3 h. The reaction mixture was concentrated. Water (5 mL) was added. The contents were extracted with DCM (2×10 mL) The combined DCM solutions were dried (Na2SO4). The crude was purified with reverse-phase HPLC to give 144 (20 mg, 22%). LCMS: M+H+=589. 1H NMR (400 MHz, CDCl3) δ 8.86 (2H), 8.07 (, s, br, 2H), 7.75 (t, J=7.7, 1H), 7.64 (t, J=7.6, 1H), 7.36 (s, 1H), 7.09 (s, 1H), 5.18 (s, 1H), 4.12-4.00 (m, 4H), 3.94-3.81 (m, 6H), 2.62 (s, 8H), 2.44 (s, 3H), 1.25 (s, 6H)
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][C@H:15]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@H:17]([CH2:18][CH2:19][C@@H:20]3[C@@H:29]2[CH2:28][CH2:27][C@@:25]2([CH3:26])[C@:21]3([OH:39])[CH2:22][CH2:23][C@@H:24]2[C:34]2[CH:38]=[CH:37][O:36][CH:35]=2)[CH2:16]1)(C1C=CC(C)=CC=1)(=O)=O.[NH2:40][CH2:41][CH2:42][N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1.O>C(O)C>[N:43]1([CH2:42][CH2:41][NH:40][CH2:12][CH2:13][O:14][C@H:15]2[CH2:32][CH2:31][C@@:30]3([CH3:33])[C@H:17]([CH2:18][CH2:19][C@@H:20]4[C@@H:29]3[CH2:28][CH2:27][C@@:25]3([CH3:26])[C@:21]4([OH:39])[CH2:22][CH2:23][C@@H:24]3[C:34]3[CH:38]=[CH:37][O:36][CH:35]=3)[CH2:16]2)[CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: NCCN1CCCC1
Reactant: Cc1ccc(S(=O)(=O)OCCO[C@H]2CC[C@@]3(C)[C@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](c5ccoc5)CC[C@]43O)C2)cc1
Solvent: O
Solvent: CCO
Product: C[C@]12CC[C@H](OCCNCCN3CCCC3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O

Procedure:
To a solution of 0.20 g of 3β-(2-tosyloxyethoxy)-17β-(3-furyl)-5β-androstan-14β-ol in 2 ml of absolute ethanol 0.15 g of 1-(2-aminoethyl)pyrrolidine were added. The solution was kept at reflux under nitrogen for 3 hrs, then 10 ml of water were added. The residue was extracted with methylene chloride, the organic layer was washed with water to neutral pH, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude residue was purified by flash-chromatography (SiO2) using methylene chloride/methanol 95/5 as eluant to give 0.15 g of the title compound (I-ag).
Reaction SMILES: [O:1]=O.[CH3:3][O:4][C:5]([C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2)=[O:6]>>[CH3:3][O:4][C:5]([C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([OH:1])([CH2:10]3)[CH2:8]1)[CH2:14]2)=[O:6]
Reactant: O=O
Reactant: COC(=O)C12CC3CC(CC(C3)C1)C2
Product: COC(=O)C12CC3CC(CC(O)(C3)C1)C2
Yield: 42 %

Procedure:
The oxidization in an oxygen atmosphere was conducted in the same manner as in Preparation Example 1 except that 1-methoxycarbonyladamantane was used instead of the adamantane, and, as a result, a 1-methoxycarbonyl-3-hydroxyadamantane (yield: 42%) and a 1-methoxycarbonyl-3,5-hydroxyadamantane (yield : 33%) were obtained with a conversion of 91%.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[CH:4]=[N:5]/O.S(Cl)(Cl)=O.[O:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH2:13]([O:12][CH:16]1[O:1][N:2]=[C:3]([C:4]#[N:5])[CH2:15]1)[CH3:14]
Reactant: C1CCOC1
Reactant: O/N=C(Cl)/C=N/O
Solvent: O=S(Cl)Cl
Product: CCOC1CC(C#N)=NO1
Temperature: 2.5 °C
Reaction time: 6.5 h
Yield: 30.5 %

Procedure:
To a dried 10 L three-necked flask equipped with a thermometer controller, a mechanical stirrer, and a dropping funnel protected under nitrogen was charged 6966.7 g (7.3×) of tetrahydrofuran and 950.0 g (1.0×) of compound (1Z,2E)-N-hydroxy-2-(hydroxyimino)acetimidoyl chloride. The reaction mixture was cooled to 0-5° C. followed by drop wise addition of 1845.2 g (1.9×) thionyl chloride over 60˜90 minutes at 0-5° C. After addition, the reaction mixture was stirred at 10-15° C. for 6-7 hours and deemed complete by HPLC. The reaction mixture was then concentrated under vacuum at 15-20° C. to about 1.0 L (1.0×) followed by addition of a total of 950 g (0.9×) of tetrahydrofuran and distillation to remove residual thionyl chloride. The resulting mixture was added drop wise into a solution of 2755 g (2.9×) of ethoxyethene, 6764 g (7.12×) of tetrahydrofuran and 715.0 g (0.75×) of sodium carbonate in 3200.0 g (3.4×) of water over 30-40 minutes at 0-5° C. After addition, the reaction mixture was stirred at 0-5° C. for 1-2 hours and deemed complete by HPLC. The resulting mixture was separated and the aqueous layer was extracted with 1900 g (2.0×) of methyl t-butyl ether, and then the combined organic layer was dried with 380 g (0.4×) of sodium sulfate, filtered and then concentrated to give 549.7 g yellow oil (Assay 60.3%, purity 97.0%, yield 30.5%). 1H NMR (CDCl3, 400 MHz) δ 5.76 (dd, J=2.0 Hz, 4.8 Hz, 1H), 3.86˜3.90 (m, 1H), 3.60˜3.65 (m, 1H), 3.21 (dd, J=6.8 Hz, 11.2 Hz, 1H), 3.00 (dd, J=2.0 Hz, 16 Hz, 1H), 1.21 (T, J=6.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][C:13](OCC)=[O:14])=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=1.[CH2:24]([Mg]Br)[CH3:25]>C(OCC)C.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][C:13]2([OH:14])[CH2:25][CH2:24]2)=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[N:3]=1
Reactant: CC[Mg]Br
Reactant: CCOC(=O)CCn1cnc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCOCC
Product: OC1(CCn2cnc3c(N4CCOCC4)nc(Cl)nc32)CC1
Reaction time: 2 h
Yield: 46 %

Procedure:
A solution of ethyl 3-(2-chloro-6-morpholino-9H-purin-9-yl)propanoate (500 mg, 1.5 mmol) in diethylether (37 mL) was treated with titanium (IV) ethoxide (31 uL, 0.15 mmol) followed by the dropwise addition of 3.0M ethylmagnesium bromide in ether (0.98 mL, 2.9 mmol) at ambient temperature for 90 minutes. Partial conversion prompted the addition of titanium (IV) ethoxide (31 uL, 0.15 mmol) and 3.0M ethylmagnesium bromide in ether (0.98 mL, 2.9 mmol). After 2 hr, the reaction mixture was quenched with an aqueous 1.0M solution of HCl (20 mL) and filtered through a plug of celite, washing with ethyl acetate. The mixture was diluted with water and ethyl acetate and the layers separated. The aqueous phase was extracted into EtOAc (3×), dried over sodium sulfate, filtered, and absorbed onto celite for purification by flash chromatography to afford 1-(2-(2-chloro-6-morpholino-9H-purin-9-yl)ethyl)cyclopropanol as a colorless oil (220 mg, 46%). LC/MS (ESI+): m/z 324 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:14]=2[N:15]=[C:16]([C:18]2[O:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[O:22]1[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:14]=3[N:15]=2)=[CH:19][CH:20]=[N:21]1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCc1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-dichlorobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[NH:7][N:6]=1)([CH3:3])[CH3:2].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][S:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:23])=[O:22])=[CH:11][CH:12]=2)[NH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Nc1n[nH]c2cc(N)ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CC(C)Nc1n[nH]c2cc(NS(=O)(=O)c3ccccc3)ccc12
Temperature: 100 °C
Yield: 9.6 %

Procedure:
N*3*-Isopropyl-1H-indazole-3,6-diamine (0.036 g, 0.19 mmol) was dissolved in 1 mL pyridine and benzenesulfonyl chloride (0.024 mL, 0.19 mmol) was added. The reaction mixture was heated to 100° C. and stirred for an hour, then cooled and concentrated under reduced pressure. The residue was chromatographed through silica gel (EtOAc/hexanes 0-50%) to give 6.0 mg of N-(3-Isopropylamino-1H-indazol-6-yl)-benzenesulfonamide, MS (M+H)=359.
Reaction SMILES: [N:1]1([C@H:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([C:17]#[N:18])[CH:11]=[CH:10][C:9]=3[CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C=O)C>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][N:4]2[CH2:3][CH2:2][N:1]([C@H:7]3[CH2:16][CH2:15][C:14]4[CH:13]=[C:12]([C:17]#[N:18])[CH:11]=[CH:10][C:9]=4[CH2:8]3)[CH2:6][CH2:5]2)=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: N#Cc1ccc2c(c1)CC[C@H](N1CCNCC1)C2
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc2c(c1)CC[C@H](N1CCN(CCc3ccc([N+](=O)[O-])cc3)CC1)C2

Procedure:
A mixture (6S)-6-piperazin-1-yl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (0.31 mg, 0.13 mmol), 1-(2-bromoethyl)-4-nitrobenzene (80 mg, 0.35 mmol), and triethylamine (0.15 mL, 1.1 mmol) in DMF was heated to 60° C. for 30 hours. LC showed formation of the desired product. The reaction was diluted with EtOAc, washed with water and brine, dried over MgSO4, and purified by MPLC to deliver 13 mg of (65)-6-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}-5,6,7,8-tetrahydronaphthalene-2-carbonitrile. LC-MS (IE, m/z): 391 [M+1]+. (0.083 μM)
Reaction SMILES: [NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:18][CH2:19][CH:20]([OH:30])[CH2:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)[CH3:17]>>[NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([O:22][CH2:21][CH:20]([OH:30])[CH2:19][O:18][CH2:16][CH3:17])=[CH:24][CH:25]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncc(Br)c(Nc2ccccc2)n1
Reactant: CCOCC(O)COc1ccc(N)cc1
Product: CCOCC(O)COc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Yield: 21 %

Procedure:
Using an analogous method to that described in Example 136, but starting from 4-anilino-5-bromo-2-chloropyrimidine (Method 13) and 4-[3-ethoxy-2-(hydroxy)propoxy]aniline (obtained as described in J. Med. Chem., 1998, 41, 330-36), the product was obtained in 21% yield. NMR: 1.10 (t, 3H), 3.42 (m, 2H), 3.45 (q, 2H), 3.75-3.9 (m, 3H), 4.99 (d, 1H), 6.74 (d, 2H), 7.12 (t, 1H), 7.33 (dd, 2H), 7.44 (d, 2H), 7.60 (d, 2H), 8.15 (s, 1H), 9.10 (s, 1H); MS (MH+): 459.3, 461.4.