Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[NH:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[CH2:27][CH2:28]Br>CN(C=O)C>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:28][CH2:27][N:17]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:16]2=[O:25])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: BrCCBr
Reactant: CCCCCCCCc1ccc(NC(=O)NCCC(=O)OCC)cc1
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(N2CCN(CCC(=O)OCC)C2=O)cc1
Temperature: -50 °C
Reaction time: 1 h
Yield: 37.3 %

Procedure:
To a solution of the product of Example 11, Step A (0.05 g; 0.143 mmol) in anhydrous DMF (2 ml) 60% NaH in mineral oil (0.014 g; 0.344 mmol) was added at room temperature. After stirring for 1 h, to it 1,2-dibromoethane (0.172 ml; 0.2 mmol) was added. This was stirred at −50° C. for 1 h under N2, cooled to room and solvents were removed in vacuo. The residue was diluted to 15 ml with Et2O, washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, hexane/EtOAc 9.5:0.5) to give the title compound (0.02 g; 37%) as a colourless solid. 1H-NMR (CDCl3) 7.4 (d, 2H, J=8.5 Hz); 7.1 (d, 2H, J=8.5 Hz); 4.13 (q, 2H, J=7.1 Hz); 3.76 (m, 2H); 3.57 (t, 2H, J=6.7 Hz); 3.5 (m, 2H); 2.6 (t, 2H, J=6.7 Hz); 2.53 (t, 2H, J=7.9 Hz); 1.55 (m, 2H); 1.24 (m, 13H); 0.85 (t, 3H, J=6.9 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:12]([O:11][C:9](=[O:10])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH2:19][C:20]([OH:22])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)CC(C(=O)OCc1ccccc1)c1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: O=C(O)CC(C(=O)OCc1ccccc1)c1ccc(Br)cc1
Yield: 88.3 %

Procedure:
A suspension of 1-benzyl 4-tert-butyl 2-(4-bromophenyl)succinate (2.00 g, 4.77 mmol) and silica gel (23.8 g) in toluene (100 mL) was heated at reflux for 3 h. The crude mixture was cooled to room temperature and filtered. The filter cake was washed with dichloromethane/methanol (8:2; 2×100 mL) then the organic filtrates were combined and evaporated to dryness to give the title compound as a white solid (1.53 g, 88%). LC/MS: 3.43 min; z/e 361 and 363, calcd (M−1) 361 and 363. 1H NMR (400 MHz: DMSO-d6): 7.55 (2H), 7.30 (7H), 5.10 (2H), 4.05 (1H), 3.05 (1H), 2.65 (1H).
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH:40][C:7]3[N:8]=[CH:9][C:4]4[CH:3]=[C:2]([Br:1])[C:14](=[O:15])[N:13]([CH:16]5[CH2:20][CH2:19][CH2:18][CH2:17]5)[C:5]=4[N:6]=3)=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CS(=O)c1ncc2cc(Br)c(=O)n(C3CCCC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4cc(Br)c(=O)n(C5CCCC5)c4n3)nc2)CC1
Temperature: 120 °C
Yield: 21 %

Procedure:
Under a dry argon atmosphere were combined 6-bromo-8-cyclopentyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.78 g, 2.19 mmol, prepared as in Example 107 of WO 98/33798 (incorporated herein by reference)) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.67 g, 2.4 mmol) without solvent. The flask was evacuated and heated to 120° C. for 1 hour. The mixture was purified by chromatography on silica gel, eluting with chloroform, to give a yellow foam, 0.288 g. Recrystalization from acetonitrile gave 4-[6-(6-bromo-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.266 g, 21%). MS (APCI); M++1: Calc'd, 570.17, Found, 570.0.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:16]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br)#[N:17]>CN(C)C=O>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([O:13][CH2:21][C:20]2[CH:19]=[C:18]([CH:25]=[CH:24][CH:23]=2)[C:16]#[N:17])=[CH:11][CH:12]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(COc2ccc(-c3ccccc3)cc2)c1
Temperature: 0 °C
Yield: 103.3 %

Procedure:
To a solution of 4-phenylphenol (10.0 g, 59 mmol) in dry N,N-dimethyl-formamide (45 mL) kept under an atmosphere of nitrogen, sodium hydride (2.82 g, 71 mmol, 60% dispersion in oil) was added in portions and the reaction mixture was stirred until gas evolution ceased. A solution of m-cyanobenzyl bromide (13 g, 65 mmol) in dry N,N-dimethylformamide (45 mL) was added dropwise and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured on to ice water (150 mL). The precipitate was filtered of and washed with 50% ethanol (3×50 mL), ethanol (2×50 mL), diethyl ether (80 mL), and dried in vacuo at 50° C. for 18 hours affording crude 17.39 g of 3-(biphenyl-4-yloxymethyl)benzonitrile as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[CH3:7][C:8]1([CH2:13][CH2:14][C:15](=O)[CH2:16][C:17](OC)=[O:18])[O:12][CH2:11][CH2:10][O:9]1>>[OH:18][C:17]1[N:3]2[N:4]=[CH:5][CH:6]=[C:2]2[N:1]=[C:15]([CH2:14][CH2:13][C:8]2([CH3:7])[O:9][CH2:10][CH2:11][O:12]2)[CH:16]=1
Reactant: Nc1cc[nH]n1
Reactant: COC(=O)CC(=O)CCC1(C)OCCO1
Product: CC1(CCc2cc(O)n3nccc3n2)OCCO1
Yield: 84.5 %

Procedure:
Using 0.9 g of 3-aminopyrazole and 1.9 g of methyl 2-methyl-β-oxo-1,3-dioxolane-2-valerate, the procedure of Reference Example 1 was followed. As a result, 1.85 g of 7-hydroxy-5-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]pyrazolo[1,5-a]pyrimidine was obtained as colorless crystals.
Reaction SMILES: O.Cl.[NH2:3][C:4]([CH3:9])([CH3:8])[C:5](=[O:7])[CH3:6].C1COCC1.[OH-].[Na+].[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([O:24][C:25]([NH:3][C:4]([CH3:9])([CH3:8])[C:5](=[O:7])[CH3:6])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(=O)C(C)(C)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)C(C)(C)NC(=O)OCc1ccccc1

Procedure:
3-Amino-3-methyl-2-butanone hydrochloride hydrate [J. Org. Chem. 49, 1209 (1984)] (10.6 g., 0.076 mol was dissolved in 700 ml. 1:1 THF:H2O and the pH adjusted to 6.8 with dilute NaOH. Benzylchloroformate (11.93 ml., 0.084 ml.) was added dropwise, maintaining pH 6.8-7.0 by the simultaneous dropwise addition of dilute NaOH. The pH was so maintained until it stabilized. The reaction mixture was extracted 4×100 ml. CHCl3. The organic extracts were combined, filtered and stripped to yield title product as an oil, 9.26.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[C:9]=2[C:8]([NH:21][CH2:22][CH2:23][OH:24])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:32][Si:33]([CH3:36])([CH3:35])Cl>O1CCCC1>[CH3:32][Si:33]([CH3:36])([CH3:35])[O:24][CH2:23][CH2:22][NH:21][C:8]1[C:9]2[C:10](=[O:20])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17](=[O:19])[C:18]=2[C:5]([NH:4][CH2:3][CH2:2][O:1][Si:33]([CH3:36])([CH3:35])[CH3:32])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=C1c2ccccc2C(=O)c2c(NCCO)ccc(NCCO)c21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OCCNc1ccc(NCCO[Si](C)(C)C)c2c1C(=O)c1ccccc1C2=O
Yield: 86 %

Procedure:
In a flame dried 250 ml, three-necked flask equipped with magnetic stirring bar, reflux condenser with nitrogen inlet and rubber septum on one side neck, are placed 1.63 g (5.0 mmol) 1,4-bis(2-hydroxyethylamino)anthraquinone (C.I. Disperse Blue 23, available as Disperse Blue NSP from Inmont Corporation), 4 ml triethylamine and 50 ml tetrahydrofurane (THF) (Aldrich, freshly opened). The mixture is purged with nitrogen and stirred until the dye is at least partially dissolved and 1.55 ml (12 mmol) trimethylchlorosilane is added to the mixture during a two minute period by means of a syringe having its needle through the septum. A mild exothermic reaction occurs and a precipitate forms immediately. The color of the mixture remains deep blue throughout the reaction. After stirring overnight, the reaction mixture is filtered and the whitish solid (triethylamine hydrochloride) washed with fresh THF until it remains white. The filtrate is evaporated on a rotary evaporator and the residue recrystallized from hot hexane. 1,4-Bis(2-trimethylsilyloxyethylamino)anthraquinone is obtained in two crops of blue needles in 86% yield, m.p. 123°-126° C.
Reaction SMILES: [C:1]([C:9]1[CH:21]=[CH:20][C:12]([NH:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O-])(O)=O.[Na+].CI>CN(C=O)C>[CH3:22][N:13]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:12]1[CH:20]=[CH:21][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1
Reactant: O=C([O-])O
Reactant: O=C(O)CCCNc1ccc(C(=O)c2ccccc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(CCCC(=O)O)c1ccc(C(=O)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
1.41 g (0.05 mole) of 4-(4-benzoylanilino)butyric acid are dissolved in 15 ml of DMF, and 0.84 g of NaHCO3 (0.01 mole) and 1.42 g (0.01 mole) of methyl iodide are added, and the mixture is stirred at 80° C. for about 3 h. It is then poured onto ice-water, the mixture is extracted with ethyl acetate, the organic phase is dried with MgSO4, and the solvent is evaporated off in vacuo. The residue is chromatographed on silica gel using n-hexane/ethyl acetate as eluent. The oily product is immediately hydrolyzed with 2 N LiOH. The title compound is obtained and has the melting point 111°-113° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH3:11][NH:12][CH2:13][CH2:14][OH:15]>C1(C)C(C)=CC=CC=1>[OH:15][CH2:14][CH2:13][N:12]([CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)[CH3:11]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CNCCO
Solvent: Cc1ccccc1C
Product: CN(CCO)Cc1ccc(C#N)cc1
Reaction time: 7 h

Procedure:
A mixture of 4-bromomethylbenzonitrile (49.7 g), N-methylethanolamine (19.0 g) and xylene (100 ml) was boiled under reflux with stirring for 7 hours and then worked up as described in the previous example to give an oil which was distilled at 142°-146° C. at 0.5 mbar to give 4-[N-(2-hydroxyethyl)-N-methylaminomethyl]benzonitrile as an oil.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[Cl:32][C:33]1[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=[CH:37][C:38]=1[F:39].N1C=CC=CC=1>ClCCl>[Cl:32][C:33]1[CH:34]=[C:35]([S:40]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]3[C:16]([C:17]4[N:25]=[CH:24][N:23]=[C:22]5[C:18]=4[N:19]=[CH:20][N:21]5[CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)=[CH:15][CH:14]=[CH:13][N:12]=3)[C:2]=2[F:1])(=[O:41])=[O:42])[CH:36]=[CH:37][C:38]=1[F:39]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(F)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 3-chloro-4-fluorobenzene-1-sulfonyl chloride (16 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[N:31][N:30]=[N:29]4)=[CH:24][CH:23]=3)=[C:17]([CH3:19])[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:33]>ClCCl.O1CCOCC1>[CH3:19][C:17]1[N:18]=[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[S:15][C:16]=1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[N:31][N:30]=[N:29]2)=[CH:24][CH:23]=1.[ClH:33]
Reactant: Cc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)sc1COc1ccc(-n2cnnn2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nc(C2CCNCC2)sc1COc1ccc(-n2cnnn2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 4-[4-Methyl-5-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 93) (500 mg, 1.10 mmol) in dichloromethane (5 mL) was treated with 1.5 mL of 4N HCl in dioxane. The resulting solution was stirred at room temperature for 5 hours and all the solvent were removed in vacuo to afford the desired product as an HCl salt.
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34][C:35]([C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)([F:39])[C:36]([OH:38])=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.Cl.[N:49]1([C:55]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[N:58]=[CH:57][N:56]=2)[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:25]([O:29][C:30](=[O:31])[NH:32][CH2:33][CH2:34][C:35]([C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)([F:39])[C:36](=[O:38])[N:52]1[CH2:53][CH2:54][N:49]([C:55]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[N:58]=[CH:57][N:56]=2)[CH2:50][CH2:51]1)([CH3:26])([CH3:27])[CH3:28]
Reactant: c1ccc2c(N3CCNCC3)ncnc2c1
Reactant: CC(C)(C)OC(=O)NCCC(F)(C(=O)O)c1ccc(Cl)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCC(F)(C(=O)N1CCN(c2ncnc3ccccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36 %

Procedure:
PyBrop (562 mg, 1.21 mmol) was added in a single portion to a solution of 4-tert-butoxycarbonylamino-2-(4-chlorophenyl)-2-fluoro-butyric acid (400 mg, 1.21 mmol) and 4-piperazin-1-yl-quinazoline dihydrochloride (346 mg, 1.21 mmol) in DCM (12 mL) cooled in an ice bath. DIEA (0.84 mL, 4.82 mmol) was added and the mixture was allowed to warm to ambient temperature and stirred for 12 hours. The mixture was diluted with DCM and washed with 0.1N HCl. The separated DCM layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was chromatographed (SiO2) using 2% MeOH/DCM followed by 5% MeOH/DCM as eluent to give [3-(4-chlorophenyl)-3-fluoro-4-oxo-4-(4-quinazolin-4-yl-piperazin-1-yl)-butyl]-carbamic acid tert-butyl ester (230 mg). LCMS (APCI+) m/z 528, 530 [M+H]+.
Reaction SMILES: C(O[C@:5]1([C:24]#[CH:25])[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C:14](=[CH:15][C:16](=[O:23])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)(=O)C.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[C:24]([C:5]1[C@:6]2([CH2:22][CH2:21][C@H:20]3[C@@H:11]([CH2:12][CH2:13][C:14]4[C@@H:19]3[CH2:18][CH2:17][C:16](=[O:23])[CH:15]=4)[C@@H:8]2[CH2:9][CH:10]=1)[CH3:7])#[CH:25]
Reactant: C#C[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: C#CC1=CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C
Yield: 60.7 %

Procedure:
One gram of 17α-acetoxy-17β-ethynyl-4-estren-3-one is treated analogously to Example 1 in "Dowtherm" for 10 minutes at 250° C. and worked up. Recrystallization from isopropyl ether yields 500 mg of 17-ethynyl-4,16-estradien-3-one, m.p. 148°-152° C. (40% of theory).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]#[N:16])=[O:9])[C@H:4]([CH2:6][CH3:7])[CH3:5].[C:17](=O)([O:25]C1C=CC([N+]([O-])=O)=CC=1)[O:18][CH:19]([O:21][C:22](=[O:24])[CH3:23])[CH3:20].C(N(CC)CC)C>ClCCl>[C:22]([O:21][CH:19]([O:18][C:17]([NH:2][C@H:3]([C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]#[N:16])=[O:9])[C@H:4]([CH2:6][CH3:7])[CH3:5])=[O:25])[CH3:20])(=[O:24])[CH3:23]
Reactant: CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C#N
Reactant: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)OC(C)OC(C)=O)C(=O)N1CCC[C@H]1C#N
Yield: 69.6 %

Procedure:
A solution of (2S)-1-(isoleucyl)pyrrolidine-2-carbonitrile hydrochloride (500 mg, 2.04 mmol; prepared according to Jenkins et al., WO95/15309), α-acetoxyethyl p-nitrophenyl carbonate (610 mg, 2.27 mmol; prepared according to Alexander et al., J. Med. Chem. 31, 318, 1988) and triethylamine (250 mg, 2.50 mmol) in dichloromethane (40 ml) was stirred at room temperature for 18 hours. After this time the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (eluant EtOAc:Pet. Ether 60–80° C.; 3:7) yielding a colourless oil identified as the title compound (480 mg, 1.42 mmol, 70%).
Reaction SMILES: CS(O[C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)(=O)=O.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[N:18]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](N2CCCCC2)C1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (Reference Example 5a, 12.15 g, 45.8 mmol) and piperidine (100 mL, 1.01568 mole) was stirred at 70° C. overnight. The residue was purified by silica gel chromatography (100% ethyl acetate to 97:3 ethyl acetate/methanol). Fractions containing product were combined and concentrated under reduced pressure to give (R)-tert-butyl 3-(piperidin-1-yl)pyrrolidine-1-carboxylate. 1H NMR (300 MHz, CD3OD) δ ppm 1.45 (s, 9H), 1.45-1.53 (m, 2H), 1.56-1.66 (m, 1H), 1.66-1.84 (m, 1H), 2.09-2.20 (m, 1H), 2.35-2.60 (m, 4H), 2.73-2.89 (m, 1H), 3.06 (t, J=10 Hz, 1H), 3.17-3.29 (m, 1H), 3.51 (t, J=10 Hz, 1H), 3.58-3.66 (m, 1H); MS (DCI/NH3) m/z 255 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH:37]2[CH2:39][CH2:38]2)=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)=[N:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH:37]3[CH2:39][CH2:38]3)=[N:22][C:23]([C:26]3[CH:27]=[CH:28][C:29]([O:32][C:33]([F:35])([F:36])[F:34])=[CH:30][CH:31]=3)=[N:24][CH:25]=2)=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: FC(F)(F)Oc1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(OC(F)(F)F)cc3)nc2C2CC2)cc1C

Procedure:
In analogy to the procedure described in example 113A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethoxy-phenyl)-pyrimidine (example 150D]) to give the title compound as light yellow viscous oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[CH2:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:4][CH2:3][CH2:2][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:6]1
Reactant: C1CCNCC1
Reactant: BrCCCC1=CCc2ccccc21
Solvent: Cc1ccccc1
Product: C1=C(CCCN2CCCCC2)c2ccccc2C1
Yield: 89 %

Procedure:
3-(3'-Bromopropyl)indene (94.8 g, 0.4 M) and piperidine (76 g, 0.9 M) are dissolved in 400 ml toluene. The mixture is heated under reflux 2 hours. After cooling, a large amount of solid is removed by filtration and washed with ether. The combined filtrate and washes are concentrated in vacuo. The residue is dissolved in ether and filtered to remove a small amount of insoluble material. The ether is removed in vacuo and the product is distilled collecting a fraction of 87.3 g (89% yield) boiling 132°-153°/0.05 mm.
Reaction SMILES: [F:1][C:2]([F:27])([O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N+:23]([O-])=[CH:22][CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[C-]#N.[CH3:30][N:31](C)C(Cl)=O>C(#N)C>[F:1][C:2]([F:27])([O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([C:30]#[N:31])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4]
Reactant: CN(C)C(=O)Cl
Reactant: [O-][n+]1ccc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)cc1
Agent: [C-]#N
Solvent: CC#N
Product: N#Cc1cc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)ccn1
Reaction time: 14 h

Procedure:
100 mg (0.26 mmol) of N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(N-oxido-4-pyridyl)-2-pyrimidineamine, 90 μl (0.72 mmol) or trimethylsiyl cyanide and 66 μl (0.72 mmol of N,N-dimethyl-carbamoyl chloride are dissolved in 5 ml of acetonitrile and stirred at 60° for 14 h. Concentration under reduced pressure and recrystalisation from tetrahydrofuran/diethyl ether give N-[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]-4-(2-cyano-4-pyridyl)-2-pyrimidineamine; FAB-MS: 390 (M+ +H), Rf =0.7 (hexane:ethyl acetate=1:1).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)=[CH:18]\[CH2:19][O:20][C:21]2[CH:32]=[CH:31][C:24]([O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[C:23]([CH3:33])[CH:22]=2)=[CH:13][CH:12]=1>O1CCCC1.C(N(CC)CC)C.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:33][C:23]1[CH:22]=[C:21]([O:20][CH2:19]/[CH:18]=[C:17](\[C:14]2[CH:15]=[CH:16][C:11]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[CH:12][CH:13]=2)/[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[CH:32]=[CH:31][C:24]=1[O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2cccc(C(F)(F)F)c2)cc1C
Reactant: C#CCN1CCOCC1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2cccc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-Propargylmorpholine (171 mg, 1.37 mmol) was added to a solution of methyl (E)-[4-[3-(4-iodophenyl)-3-(3-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate (400 mg, 0.68 mmol; prepared as described in example 34) in a mixture of tetrahydrofuran (12 mL) and triethylamine (12 mL). The mixture was degassed and copper(I) iodide (20 mg, 0.108 mmol) and tetrakis(triphenylphosphine)-palladium (62 mg, 0.054 mmol) were added. The reaction mixture was degassed once more and then stirred at ambient temperature for 2 days under argon. The mixture was evaporated in vacuo; the residue was dissolved in ethyl acetate (50 mL) and the solution was washed with water (2×15 mL) and brine (10 mL). The organic solution was dried with anhydrous magnesium sulfate and its evaporation gave oil that was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 1:1) yielding methyl (E)-[2-methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(3-trifluoromethylphenyl)allyl-oxy]phenoxy]acetate as oil.