Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])[CH2:2][CH3:3].[NH2:14][C:15]1[N:19]([CH2:20][CH2:21][CH3:22])[N:18]=[C:17]([CH3:23])[C:16]=1[C:24]([NH2:26])=[O:25]>N1C=CC=CC=1>[CH3:23][C:17]1[C:16]([C:24]([NH2:26])=[O:25])=[C:15]([NH:14][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH2:1][CH2:2][CH3:3])[N:19]([CH2:20][CH2:21][CH3:22])[N:18]=1
Reactant: CCCOc1ccccc1C(=O)Cl
Reactant: CCCn1nc(C)c(C(N)=O)c1N
Solvent: c1ccncc1
Product: CCCOc1ccccc1C(=O)Nc1c(C(N)=O)c(C)nn1CCC

Procedure:
The title compound was prepared from 2-n-propoxy-benzoyl chloride (5.33 g, 0.027 mol) and 5-amino-3-methyl-1-n-propylpyrazole-4-carboxamide (Preparation 6; 4.07 g, 0.022 mol) in pyridine (100 ml), following the procedure of Preparation 2, and was obtained as a white solid (5.84 g, 76%). A sample was crystallised from ethyl acetate-hexane, m.p. 111-113° C. Found: C, 62.83; H, 7.09; N, 16.26. C18H24N4O3 requires C, 62.77; H, 7.02; N, 16.27%.
Reaction SMILES: CS([CH2:5][CH2:6][CH:7]1[CH:13]=[CH:12][N:11]([C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]=2[S:8]1)(=O)=O.[CH3:29][NH:30][CH3:31]>O1CCCC1>[CH3:29][N:30]([CH3:31])[CH2:5][CH2:6][CH:7]1[CH:13]=[CH:12][N:11]([C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]=2[S:8]1
Reactant: CS(=O)(=O)CCC1C=CN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2S1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CCC1C=CN(C(=O)c2ccc(N)cc2)c2ccccc2S1
Temperature: 80 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
A mixture of 2-(2-methanesulfonylethyl)-5-(4-nitrobenzoyl)-1,5-benzothiazepine as prepared in Example 6 (0.9 g, 2.1 mM) and dimethylamine (40% solution in water, 3.0 ml) in tetrahydrofuran (10 ml) was heated in a sealed tube with stirring in an 80° C. oil bath for 16 hours. The mixture was cooled to room temperature, evaporated to dryness, diluted with water (30 ml) and extracted with ethyl acetate (2×35 ml). The combined ethyl acetate extracts were dried (MgSO4) and evaporated in vacuo to give the desired product (0.78 g, 97%). This product (0.78 g, 2.0 mM) was dissolved in ethanol, and a catalytic amount of 10% Pd/C was added. The mixture was hydrogenated in a PARR apparatus under 30 psi of H2 pressure for 16 hr, filtered through Celite and evaporated in vacuo to give the desired product (0.64 g, 90%). m/z (M+) 356.
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][CH2:6]1>O1CCCC1>[N:4]([CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][CH2:6]1)=[C:1]=[S:3]
Reactant: CCOC(=O)N1CCCC(N)CC1
Reactant: S=C=S
Solvent: C1CCOC1
Product: CCOC(=O)N1CCCC(N=C=S)CC1
Yield: 100 %

Procedure:
To a stirred and cooled (-10° C.) mixture of 63 parts of carbon disulfide, 52.1 parts of N,N'-methanetetraylbis[cyclohexanamine] and 360 parts of tetrahydrofuran were added dropwise 46.9 parts of ethyl 4-aminohexahydro-1H-azepine-1-carboxylate. Upon complete addition, the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was evaporated and the residue was stirred in 2,2'-oxybispropane. The precipitate was filtered off and the filtrate was evaporated, yielding 70.75 parts (100%) of ethyl hexahydro-4-isothiocyanato-1H-azepine-1-carboxylate as a residue (interm. 29).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:4]([C:12]2[NH:11][CH:15]=[CH:14][CH:13]=2)=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: c1cc[nH]c1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1ccc[nH]1)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-chloronicotinoyl chloride (1 eq.) in dichloromethane (10 mL) was added slowly to a mixture of pyrrole (1.5 eq.) (Aldrich, Milwaukee, Wis.) and aluminum chloride (3.5 g, 1 eq.) in dichloromethane (8 mL) at 0° C. The mixture was stirred at 0° C. for 10 mins and at room temperature for 30 mins. The reaction was diluted with ethyl acetate, washed with brine, dried and concentrated. The residue was purified on a silica gel column to give 2.27 g of (2-chloro-pyridin-3-yl)-(1H-pyrrol-2-yl)-methanone.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[Cl:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[ClH:15].[Cl:15][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:8]=1[S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH:14][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc(Sc2ccccc2)c(Cl)c1
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(Sc4ccccc4)c(Cl)c3)c2cc1OC
Yield: 71 %

Procedure:
Using an analogous procedure to that described in Example 1 except that the reaction mixture was heated to reflux for 16 hours, 4-amino-2-chlorophenyl phenyl sulphide was reacted with 4-chloro-6,7-dimethoxyquinazoline hydrochloride to give 4-(3-chloro-4-phenylthioanilino)-6,7-dimethoxyquinazoline hydrochloride salt in 71% yield, m.p. 245°-247° C.;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:13])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1.[CH3:14][CH:15](O)[CH:16]=[CH2:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)(C)C.C1(C)C=CC=CC=1>[CH2:14]([CH:9]1[CH2:8][C:7](=[O:13])[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:10]1)[CH:15]=[CH:16][CH3:17]
Reactant: C=CC(C)O
Reactant: COc1ccc2c(c1)OCCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)OC
Product: CC=CCC1CC(=O)c2ccc(OC)cc2O1
Yield: 41 %

Procedure:
A solution 11.9 g of 7-methoxy-4-chromanone, 13.8 ml of 3-buten-2-ol and 120 mg of p-toluenesulfonic acid in 14 ml of 2,2-dimethoxypropane and 120 ml of anhydrous toluene was boiled under reflux for 24 hours. The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 4:1). 6.3 g (41%) of (RS)-2-(2-buten-1-yl)-7-methoxy-4-chromanone were obtained as a yellow oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]([O:14][C:15]([NH:17][C@H:18]([CH2:22][CH3:23])[C:19]([OH:21])=O)=[O:16])([CH3:13])[CH3:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:46]([CH:48]1[C:52]2[C:53]([O:57][C:58]3[N:63]=[CH:62][C:61]([NH2:64])=[CH:60][CH:59]=3)=[CH:54][CH:55]=[CH:56][C:51]=2[CH2:50][O:49]1)[CH3:47]>CN(C)C=O>[CH2:46]([CH:48]1[C:52]2[C:53]([O:57][C:58]3[N:63]=[CH:62][C:61]([NH:64][C:19]([C@H:18]([NH:17][C:15](=[O:16])[O:14][C:11]([CH3:10])([CH3:12])[CH3:13])[CH2:22][CH3:23])=[O:21])=[CH:60][CH:59]=3)=[CH:54][CH:55]=[CH:56][C:51]=2[CH2:50][O:49]1)[CH3:47]
Reactant: CCC1OCc2cccc(Oc3ccc(N)cn3)c21
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC1OCc2cccc(Oc3ccc(NC(=O)[C@@H](CC)NC(=O)OC(C)(C)C)cn3)c21
Temperature: 60 °C
Yield: 73.7 %

Procedure:
In a 8 ml vial 6-[(3-ethyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinamine (Intermediate 108, 10 mg) was dissolved in N,N-dimethylformamide (1 ml) to give a colourless solution. DIPEA (10.22 μl, 0.059 mmol), (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (9.52 mg, 0.047 mmol) and, finally, TBTU (15.03 mg, 0.047 mmol) were added. The reaction mixture was shaken at 60° C. After overnight shaking, the reaction was completed. The reaction mixture was evaporated under vacuum to give the crude product as a yellow oil which was purified via Biotage SP1 (with Cyclohexane/EtOAc as eluents from 2:1 to 1:1 in 10 CV; then 2:1 for 5 CV; 10 g SNAP Silica column). The collected fractions afforded the title compound as a colourless oil (12.7 mg).
Reaction SMILES: Br[C:2]([CH3:4])=[CH2:3].C([Li])(C)(C)C.[CH2:10]([S:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=[O:17])[C:11]#[CH:12]>C1COCC1.CCCCC>[CH3:4][C:2](=[CH2:3])[CH:16]([C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[S:13][CH2:10][C:11]#[CH:12])[OH:17]
Reactant: C#CCSc1ccccc1C=O
Reactant: C=C(C)Br
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: C#CCSc1ccccc1C(O)C(=C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-bromopropene (4.53 g, 37.4 mmol) in 85 ml of dry THF at -78° C. was added t-butyllithium (44 ml of a 1.7M solution in pentane) dropwise. After 2 hours, 2-(2-propynylthio) benzaldehyde (3.0 g, 17.0 mmol) prepared according to the procedures described in Example 1, Steps A, B, and C in 30 ml of dry THF was added dropwise. The reaction mixture was allowed to warm up to room temperature (RT). The reaction mixture was quenched with 100 ml of a saturated NH4Cl solution, extracted twice with diethyl ether, washed with water and brine, and then dried over K2CO3 to afford the subtitle compound.
Reaction SMILES: C(OC([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11](Cl)=[CH:10][CH:9]=2)=O)C.[H-].[Na+].C1(S(Cl)(=O)=O)C=CC=CC=1.O>CN(C=O)C>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:6]1
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2[nH]ccc2c1
Yield: 90 %

Procedure:
To a stirred and cooled (0° C.) solution of ethyl-5-chloroindole-2-carboxylate (1.052 g, 4.70 mmol) in DMF (25 mL) under N2, was added NaH (60% in oil, 230 mg, 5.64 mmol) portionwise. After the end of gas evolution, phenylsulfonyl chloride (0.72 mL, 5.64 mmol) was added. The reaction mixture was stirred for 1H (TLC monitoring, eluant dichloromethane). A little amount of water was added carefully and DMF was evaporated. Crude residue was dissolved in EtOAc and washed with water and brine. After drying and evaporation of solvents the compound was purified by chromatography on silica gel (eluant:cyclohexane/EtOAc 9/1 to 7/3) to afford protected indole (1.547 g, 90% yield. Off-white solid; 1H NMR (d6-DMSO) δ 1.30 (t, J=7.2 Hz, 3H), 4.35 (q, J=7.2 Hz, 2H), 7.37 (s, 1H), 7.53 (dd, J=2.2 and 9.1 Hz), 7.62-7.77 (m, 3H), 7.80 (d, J=2.2 Hz, 1H), 7.99 (m, 2H), 8.06 (d, J=9.1 Hz); MS (ESI, El+) m/z=364 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:21])[NH:5][N:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2].[C:22](#[N:25])[CH:23]=[CH2:24]>N1C=CC=CC=1.O>[C:22]([CH2:23][CH2:24][N:5]1[C:4](=[O:21])[C:3]([C:1]#[N:2])=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6]1)#[N:25]
Reactant: N#Cc1c(-c2ccccc2)c(-c2ccccc2)n[nH]c1=O
Reactant: C=CC#N
Solvent: c1ccncc1
Solvent: O
Product: N#CCCn1nc(-c2ccccc2)c(-c2ccccc2)c(C#N)c1=O

Procedure:
4.0 grams (0.0146 mole) of 4-cyano-5,6-diphenyl-3-(2H)-pyridazinone was dissolved in 40 mls of pyridine along with 10 mls of distilled water. 2 mls of acrylonitrile was added into this solution and the mixture heated to reflux for 2 hours. The solution was cooled and the solvent distilled at reduced pressure. The residual solid was recrystallized from ethyl alcohol to give 2 grams (42%) yield of a white solid which melted at 160°-161° C. The infrared spectrum showed the C-C band at 3.3μ, the nitrile group at 4.5μ, and the carboxy groups for an amide at 6.0μ.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([CH3:19])[N:13]=[C:14]([CH2:17][OH:18])[C:15]=3[N:16]=2)[CH2:4][CH2:3]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>CCOC(C)=O>[CH3:21][S:22]([O:18][CH2:17][C:14]1[C:15]2[N:16]=[C:8]([CH:5]3[CH2:4][CH2:3][C:2]([CH3:20])([CH3:1])[CH2:7][CH2:6]3)[S:9][C:10]=2[N:11]=[C:12]([CH3:19])[N:13]=1)(=[O:24])=[O:23]
Reactant: Cc1nc(CO)c2nc(C3CCC(C)(C)CC3)sc2n1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: Cc1nc(COS(C)(=O)=O)c2nc(C3CCC(C)(C)CC3)sc2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of [2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl]methanol (6.42 g) and EtOAc (65 mL) were added dropwise TEA (4.5 mL) and MsCl (2.1 mL) under ice-cooling, followed by stirring at 0° C. for 1 hour. The reaction mixture was filtered and then to the liquid was added saturated aqueous sodium bicarbonate, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure to obtain [2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl]methyl methanesulfonate (9.3 g).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[NH:14]1[CH2:20][CH2:19][CH2:18][C@H:15]1[CH2:16][OH:17]>C1(C)C=CC=CC=1>[OH:17][CH2:16][C@@H:15]1[CH2:18][CH2:19][CH2:20][N:14]1[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: OC[C@@H]1CCCN1
Reactant: N#Cc1ccc(F)c2ccccc12
Solvent: Cc1ccccc1
Product: N#Cc1ccc(N2CCC[C@H]2CO)c2ccccc12

Procedure:
1-Cyano-4-fluoronaphthalene (86 mg, 0.5 mmol) was transferred to a Pyrex tube and L-prolinol (197 μL, 2.0 mmol) was added followed by toluene (0.5 mL). The tube was capped and the reaction tube was exposed to microwave irradiation (180° C., 5 min). The reaction mixture was concentrated and purified by flash chromatography on silica gel (eluent: 0-3% methanol in dichloromethane). Yield: 23 mg (18%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]I)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1-4 (6.45 g, 19.0 mmol), 4-bromophenol (3.29 g, 19 mmol), and Cs2CO3 (3.10 g, 9.5 mmol) in 50 mL of DMF was stirred at room temperature for 18 hr. The solution was then diluted with 200 mL ethyl acetate and washed with H2O (4×100 mL), then dried over Na2SO4, filtered and concentrated. Flash chromatography (silica, 30% EtOAc/hexanes) gave 36-1 as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C@@H:6]([CH3:7])[C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([C:14](=[O:61])[C@@H:15]([CH2:46][CH2:47][C:48]([F:60])([F:59])[C:49]([F:58])([F:57])[C:50]([F:56])([F:55])[C:51]([F:54])([F:53])[F:52])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]/[CH2:24][C@@H:25]2[CH2:42][C:41]3[CH:40]=[C:39]([O:43][CH3:44])[CH:38]=[CH:37][C:36]=3[C@@H:35]3[C@@H:26]2[C@H:27]2[C@@:31]([CH2:33][CH2:34]3)([CH3:32])[C@@H:30]([OH:45])[CH2:29][CH2:28]2)[C:3]1=[O:62].CN1[C@@H](C)[C@@H](C2C=CC=CC=2)N(C(=O)[C@@H](CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CCCCCC/C=C\C[C@@H]2CC3C=C(OC)C=CC=3[C@@H]3[C@@H]2[C@H]2[C@@](CC3)(C)[C@@H](O)CC2)C1=O>C(OCC)(=O)C.[C].[Pd]>[CH3:1][N:2]1[C@@H:6]([CH3:7])[C@@H:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:4]([C:14](=[O:61])[C@@H:15]([CH2:46][CH2:47][C:48]([F:59])([F:60])[C:49]([F:58])([F:57])[C:50]([F:56])([F:55])[C:51]([F:54])([F:53])[F:52])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C@@H:25]2[CH2:42][C:41]3[CH:40]=[C:39]([O:43][CH3:44])[CH:38]=[CH:37][C:36]=3[C@@H:35]3[C@@H:26]2[C@H:27]2[C@@:31]([CH2:33][CH2:34]3)([CH3:32])[C@@H:30]([OH:45])[CH2:29][CH2:28]2)[C:3]1=[O:62]
Reactant: COc1ccc2c(c1)C[C@@H](C/C=C/CCCCCC[C@H](CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)N1C(=O)N(C)[C@@H](C)[C@H]1c1ccccc1)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: [Pd]
Agent: COc1ccc2c(c1)C[C@@H](C/C=C\CCCCCC[C@H](CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)N1C(=O)N(C)[C@@H](C)[C@H]1c1ccccc1)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C[C@@H](CCCCCCCCC[C@H](CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)N1C(=O)N(C)[C@@H](C)[C@H]1c1ccccc1)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 19 h
Yield: 100 %

Procedure:
The mixture of (4S,5R)-3,4-dimethyl-1-[(2R,9E)-11-(17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoyl]-5-phenylimidazolidin-2-one and (4S,5R)-3,4-dimethyl-1-[(2R,9Z)-11-(17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoyl]-5-phenylimidazolidin-2-one (579 mg, 653 μmol) was dissolved in ethyl acetate (14 ml), followed by addition of 10% palladium carbon (58 mg) at room temperature. After purging with hydrogen, the reaction mixture was stirred for 19 hours at room temperature. After the reaction mixture was filtered through cellite, the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Kanto Kagaku, silica gel 60 (spherical, neutral), 40–100 μm, eluent: ethyl acetate/n-hexane=1/1) to give (4S,5R)-3,4-dimethyl-1-[(2R)-11-(17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoyl]-5-phenylimidazolidin-2-one (579 mg, Yield 100%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].C[Si](C)(C)N[Si](C)(C)C.C(N(C(C)C)[CH:20]([CH3:22])[CH3:21])C.C(Br)C#C.C1OC1C>CO.COCCOCCOC>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:22][C:20]#[CH:21])(=[O:7])[OH:6]
Reactant: CCN(C(C)C)C(C)C
Reactant: NCCCP(O)O
Agent: C#CCBr
Agent: CC1CO1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: COCCOCCOC
Solvent: CO
Product: C#CCP(=O)(O)CCCN
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 1,23 g (10 mmol) of 3-aminopropylphosphonous acid in 10.4 ml (50 mmol) of hexamethyldisilazane is heated to reflux under argon for 24 hours. 5 ml of diethylene glycol dimethyl ether are added to the clear solution obtained and the mixture is heated for additional 2 hours and then cooled to 0°. 8.5 ml (50 mmol) of N-ethyl-N,N-diisopropyl-amine are added, followed by slow addition of 3.8 ml (50 mmol) of propargyl bromide over a period of 40 minutes. The mixture is stirred for 1 hour at 0° and 4 hours at room temperature, filtered and evaporated under high vacuum. The residue is dissolved in 10 ml of dichloromethane and extracted with 3×10 ml of 1 N hydrochloric acid solution. The water layer is evaporated under high vacuum and the residue obtained dissolved in 4 ml of methanol at 0°. 20 ml of propylene oxide are added during a period of 1 hour, after which time a crude product precipitates. Chromatography (silicagel Merck 230-400 ASTM, methanol) followed by recrystallization (methanol/ether) yields 3-aminopropyl(propargyl)-phosphinic acid, m.p. 172°-173°.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:10][C:11]([F:25])([F:24])[C:12]1[CH:13]=[C:14]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:15]=[CH:16][CH:17]=1>C1(C)C=CC=CC=1>[CH2:8]([O:7][C:5](=[O:6])[C:4]([N:21]1[CH2:20][CH2:19][N:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:24])([F:25])[F:10])[CH:13]=2)[CH2:23][CH2:22]1)=[CH:3][CH3:2])[CH3:9]
Reactant: CCOC(=O)/C=C/CBr
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Solvent: Cc1ccccc1
Product: CC=C(C(=O)OCC)N1CCN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
Over a period of 20 minutes 29 g of ethyl 4-bromocrotonate are added to 69 g of 1-(3-trifluoromethylphenyl)-piperazine dissolved in 300 ml of anhydrous toluene. The mixture is then heated at reflux for 1 hour. After cooling, the hydrobromide is filtered with suction and the filtrate is concentrate to dryness in vacuo. In this manner crude 4-(3-trifluoromethylphenyl)piperazin-1-ylbut-2-enoic acid ethyl ester is obtained in theoretical yield.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:62][CH3:63])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]6[CH2:54][CH2:53][CH2:52][N:51](C(OC(C)(C)C)=O)[CH2:50][CH2:49]6)[CH:42]=5)[CH:36]=[C:37]([O:39][CH3:40])[CH:38]=4)=[O:30])[CH:26]=[CH:27][CH:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:62][CH3:63])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]6[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]6)[CH:42]=5)[CH:36]=[C:37]([O:39][CH3:40])[CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(OC)cc(-c3cccc(CN4CCCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(OC)cc(-c3cccc(CN4CCCNCC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.2 %

Procedure:
236(b) A mixture of 1,1-dimethylethyl 4-{[3′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]phenyl}carbonyl)-amino]methyl}-5′-(methyloxy)-3-biphenylyl]methyl}hexahydro-1H-1,4-diazepine-1-carboxylate (130 mg, 0.19 mmol) in 25% TFA in DCM (3 mL) was stirred at RT for 2 h. It was purified by preparative hplc (NH2OH condition), eluting with 10 to 90% CH3CN in water. The product-containing fractions were dried under GeneVac to give a solid. It was purified using a Gilson HPLC (with 0.1% TFA condition) and eluting with 10 to 90% CH3CN in water. Product-containing fractions were combined and then converted to the free base with saturated NaHCO3. The organic layer was dried over sodium sulfate, filtered and then concentrated to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-(hexahydro-1H-1,4-diazepin-1-ylmethyl)-5-(methyloxy)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide as a white solid (45 mg, 31%). LC-MS m/z 759 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[C:7][C:8]1[S:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[CH:12]=1.C([Li])CCC.CN(C)[CH:24]=[O:25]>O1CCCC1>[CH:24]([C:5]1[S:1][C:2]([C:6]#[C:7][C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)=[CH:3][CH:4]=1)=[O:25]
Reactant: C(#Cc1cc2ccccc2s1)c1cccs1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(C#Cc2cc3ccccc3s2)s1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 18.6 %

Procedure:
A stirred solution of 10 grams (0.042 mole) of 2-(thien-2-ylethynyl)benzothiophene (prepared as in Example 2, Steps A and B) in 100 ml of tetrahydrofuran was cooled to -70° C., and 20 ml (0.050 mole) of n-butyl lithium (2.5 molar in hexane) was added portionwise, keeping the reaction mixture below -60°C. Upon completion of addition, the reaction mixture was stirred for 45 minutes as the reaction mixture temperature returned to -70°C. After this time 3.8 grams (0.052 moles) of dimethylformamide as added. Upon completion of addition, the reaction mixture was stirred at -70°C. for 5 minutes and then was allowed to warm to ambient temperature. The reaction mixture was then quenched with an aqueous solution saturated with ammonium chloride, and washed in sequence with water and then with an aqueous solution saturated with sodium chloride. The organic layer was absorbed into 15 grams of silica gel which was in turn placed on a 2.5 cm long silica gel column. Elution was accomplished with a 1:1 hexane and ethyl acetate mixture. The eluate was concentrated under reduced pressure to a brown solid residue. The dried solid residue was suspended in hexane, and the hexane was decanted from the solid. The solid was dried, yielding 2.1 grams of 2-(5-formylthien-2-ylethynyl)benzothiophene. The nmr spectrum was consistent with the proposed structure.