Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.Cl.[N:44]1([CH2:50][CH:51]([N:55]2[CH:59]=[C:58]([C:60]3[C:61]4[CH:68]=[CH:67][N:66](COCC[Si](C)(C)C)[C:62]=4[N:63]=[CH:64][N:65]=3)[CH:57]=[N:56]2)[CH2:52][C:53]#[N:54])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:8]([N:47]2[CH2:46][CH2:45][N:44]([CH2:50][CH:51]([N:55]3[CH:59]=[C:58]([C:60]4[C:61]5[CH:68]=[CH:67][NH:66][C:62]=5[N:63]=[CH:64][N:65]=4)[CH:57]=[N:56]3)[CH2:52][C:53]#[N:54])[CH2:49][CH2:48]2)=[O:10])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4)c3)ncnc21
Reactant: O=C(O)c1ncc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CCC(CN1CCN(C(=O)c2ncc(Cl)cc2F)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 0.25 h

Procedure:
To a solution of 5-chloro-3-fluoropyridine-2-carboxylic acid (23.5 mg, 0.134 mmol, prepared as described in Eur. J. Org. Chem. (24), 4174-4180; 2002) and triethylamine (86.2 uL, 0.618 mmol) in THF (1.1 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (47.0 mg, 0.124 mol). After stirring for 15 minutes, 4-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (61 mg, 0.10 mmol; from Example 12, Step 2) was added. The reaction was stirred for two hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed successively with water, 0.1 N NaOH and brine, dried over sodium sulfate and concentrated. The residue was stirred in a 1:1 mixture of DCM:TFA for 1 hour, concentrated, and stirred in methanol (1 mL) containing ethylenediamine (0.2 mL) for 1 hour. Preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH, was used to purify the product (29 mg, 57%). 1H NMR (300 MHz, d6-dmso): δ □12.10 (br s, 1H), 8.81 (s, 1H), 8.61 (s, 1H), 8.55 (dd, 1H), 8.37 (s, 1H), 8.24 (dd, 1H), 7.60 (d, 1H), 6.97 (d, 1H), 4.98 (tt, 1H), 3.65-3.56 (m, 2H), 3.26-3.12 (m, 4H), 2.92-2.77 (m, 2H), 2.64-2.25 (m, 4H); LCMS (M+H)+: 494.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][CH:14]3[CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:15]3=O)=O)=[CH:8][C:7]=2[CH:22]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[S:24][C:15]4[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:14]=4[N:13]=3)=[CH:8][C:7]=2[CH:22]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1ccc2oc(C(=O)NC3CCCCNC3=O)cc2c1
Solvent: c1ccncc1
Product: COc1ccc2oc(-c3nc4c(s3)NCCCC4)cc2c1
Temperature: 0 °C
Yield: 66.6 %

Procedure:
A mixture of DL-α-(5-methoxybenzofuran-2-yl)carbonylamino-ε-caprolactam (0.2 g) and phosphorus pentasulfide (0.2 g) in pyridin (2 ml) was stirred under reflux for 6.5 hours. After being cooled, the resulting mixture was poured into ice-water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give crude crystal, which was collected by filtration and washed with ethanol to give 2-(5-methoxybenzofuran-2-yl)-4,5,6,7-tetrahydro-8H-thiazolo[5,4-b]azepine (0.09 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]2[S:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[C:6](=[O:18])[N:5]=[C:4](SC)[N:3]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]1>O1CCOCC1>[OH:27][CH:24]1[CH2:25][CH2:26][N:21]([C:4]2[N:3]=[C:2]([CH3:1])[N:7]([CH2:8][C:9]3[S:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=3)[C:6](=[O:18])[N:5]=2)[CH2:22][CH2:23]1
Reactant: OC1CCNCC1
Reactant: CSc1nc(C)n(Cc2ccc(C(F)(F)F)s2)c(=O)n1
Solvent: C1COCCO1
Product: Cc1nc(N2CCC(O)CC2)nc(=O)n1Cc1ccc(C(F)(F)F)s1
Yield: 99.9 %

Procedure:
To a 1,4-dioxane solution (1.0 mL) of 6-methyl-4-(methylthio)-1-{[5-(trifluoromethyl)thiophen-2-yl]methyl}-1,3,5-triazin-2(1H)-one (321 mg, 1.00 mmol) synthesized in Reference Synthesis Example 292, 4-piperidinol (202 mg, 2.00 mmol) was added and the resultant mixture was stirred under reflux by heating for 10 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol=1/0→10/1) to obtain the title compound (374 mg, yield 100%).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH3:9])=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][C:4]=12)[CH3:2].[CH2:17]([C:19]1[CH:24]=[C:23]([CH:25]=O)[CH:22]=[C:21]([CH3:27])[C:20]=1[CH:28]=[CH:29][C:30]([OH:32])=[O:31])[CH3:18].Cl>[OH-].[Na+]>[CH2:17]([C:19]1[CH:24]=[C:23]([CH:25]=[CH:9][C:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]3[CH2:14][C:13]([CH3:15])([CH3:16])[CH2:12][CH2:11][C:5]=23)=[O:10])[CH:22]=[C:21]([CH3:27])[C:20]=1[CH:28]=[CH:29][C:30]([OH:32])=[O:31])[CH3:18]
Reactant: CCc1cc(C=O)cc(C)c1C=CC(=O)O
Reactant: CCc1sc(C(C)=O)c2c1CC(C)(C)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc(C=CC(=O)c2sc(CC)c3c2CCC(C)(C)C3)cc(C)c1C=CC(=O)O
Yield: 60.1 %

Procedure:
A solution of 1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (200 mg, 0.846 mmol) and 3-(2-ethyl-4-formyl-6-methyl-phenyl)-acrylic acid (203 mg, 0.931 mmol) in methanolic NaOH (8 mL, 10 g NaOH in 100 mL methanol) is stirred at rt for 3 h before it is carefully acidified to pH 1 by adding 2 N aq. HCl. The mixture is extracted twice with DCM and the organic extracts are washed with water and brine, dried over MgSO4, filtered and evaporated. The crude product is crystallised from acetonitrile (40 mL) to give 3-{2-ethyl-4-[3-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propenyl]-6-methyl-phenyl}-acrylic acid (222 mg) as yellow crystals. From the mother liquor a second crop (29 mg) of product can be obtained after purification by prep. HPLC (Grom-Sil 120 ODS-4-HE, 30×75 mm, 10 μm, acetonitrile/water (0.5% HCOOH), 20% to 95% acetonitrile); LC-MS: tR=1.20 min, [M+1]=437.31.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:21]=[C:22]([S:29](=[O:33])(=[O:32])[NH:30][CH3:31])[C:23]=2[C:24]([O:26]CC)=[O:25])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[C:24]([C:23]1[C:22]([S:29](=[O:33])(=[O:32])[NH:30][CH3:31])=[N:21][N:12]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:9]=[N:10][C:11]=12)([OH:26])=[O:25]
Reactant: CCOC(=O)c1c(S(=O)(=O)NC)nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CNS(=O)(=O)c1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.7 %

Procedure:
To a solution of the compound obtained in Example B1 (524 mg) in ethanol/tetrahydrofuran (7 mL/7 mL) was added an aqueous 2N sodium hydroxide solution (1.04 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was weakly acidified with an aqueous 2N hydrochloric acid. The mixture was concentrated in vacuo and extracted with chloroform. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 3-carboxy-6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-(N-methylsulfamoyl)-pyrazolo[1,5-a]pyrimidine (543 mg) as a crude product.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:23][CH2:22][C:21]([C:29]([O:31]C)=[O:30])=[CH:20][C:19]=3[CH:33]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1.O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:23][CH2:22][C:21]([C:29]([OH:31])=[O:30])=[CH:20][C:19]=3[CH:33]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.3 %

Procedure:
To a solution of methyl 7-[4-(2-butoxyethoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.94 g) in THF-water (20-20 ml) was added 1N aqueous solution of sodium hydroxide (8.0 ml) at room temperature and the mixture was stirred for 20 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and to the residue was added 1N hydrochloric acid (10 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with diisopropylether, to give 7-[4-(2-butoxyethoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1.23 g) as colorless crystals.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([C:19]3[S:20][CH:21]=[C:22]([CH2:24][C:25](O)=[O:26])[N:23]=3)[CH:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[O:61]1[CH2:66][CH2:65][CH:64]([CH2:67][NH2:68])[CH2:63][CH2:62]1>CN(C=O)C.O>[CH:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([C:19]3[S:20][CH:21]=[C:22]([CH2:24][C:25]([NH:68][CH2:67][CH:64]4[CH2:65][CH2:66][O:61][CH2:62][CH2:63]4)=[O:26])[N:23]=3)[CH:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1CCOCC1
Reactant: O=C(O)Cc1csc(-c2cnn(C3CCCCC3)c2-c2ccc(F)cc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1csc(-c2cnn(C3CCCCC3)c2-c2ccc(F)cc2)n1)NCC1CCOCC1
Yield: 71.5 %

Procedure:
A solution of the compound (50 mg, 0.13 mmol) obtained in step 4, HATU (74.0 mg, 0.19 mmol), DIEA (0.034 ml, 0.19 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (0.022 ml, 0.19 mmol) in DMF (2 mL) was stirred at room temperature for 2 days. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was crystallized from ethyl acetate and hexane to give the title compound (45 mg, 0.093 mmol, 71.9%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]([C:12]([OH:14])=[O:13])[CH2:9][C:10](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[CH:8]([C:12]([OH:14])=[O:13])[CH2:9][CH2:10]2
Reactant: Cc1cccc2c1C(C(=O)O)CC2=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2c1C(C(=O)O)CC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.7 %

Procedure:
To a solution of 12a (100 g) in trifluoroacetic acid is added trietylsilane (141 g). The mixture was stirred for 72 hours at room temperature and was then evaporated in vacuo the residue was dissolved in ethyl acetate and was extracted with dilute NaOH solution. The aqueous phase was washed with ethyl acetate and was then acidified with concentrated hydrochloric acid. Conventional work up with ethyl acetate gave 80.4 g of crude product. Purification on silica gel eluted with ethyl acetate-heptane-acetic acid gave the title compound (76.6 g).
Reaction SMILES: O/[C:2](=[CH:8]\[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH3:17])[CH:16]=1)=O)/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[CH:27]=[C:26]([NH2:28])[O:25][N:24]=1>C(O)(=O)C>[CH3:17][C:15]1[CH:16]=[C:11]([C:9]2[CH:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:27]3[C:23]([C:19]4[S:18][CH:22]=[CH:21][CH:20]=4)=[N:24][O:25][C:26]=3[N:28]=2)[CH:12]=[N:13][CH:14]=1
Reactant: CCOC(=O)/C(O)=C/C(=O)c1cncc(C)c1
Reactant: Nc1cc(-c2cccs2)no1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2cncc(C)c2)nc2onc(-c3cccs3)c12
Temperature: 25 °C

Procedure:
A mixture of 1-3 (150 mg, 0.638 mmol) and 1-4 (106 mg, 0.638 mmol) in acetic acid (3 mL) was heated at reflux for 3 h. The mixture was cooled to rt and concentrated. The residue was purified by column chromatography (0-100% EtOAc in hexane) to give 1-5 as a white solid: 1H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 8.59 (s, 1H), 8.36 (s, 1H), 8.15 (s, 1H), 7.58 (m, 1H), 7.39 (m, 1H), 7.22 (m, 1H), 4.21 (q, J=7.2 Hz, 2H), 2.48 (s, 3H), 1.07 (t, J=7.2 Hz, 3H); ESI+ MS [M+H]+ C19H16N3O3S=366.0.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:17][CH2:16][C:15]([CH3:19])([CH3:18])[CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:33]1[C:41]2[C:36](=[C:37](B3OC(C)(C)C(C)(C)O3)[C:38]([F:42])=[CH:39][CH:40]=2)[CH:35]=[CH:34]1)(C(C)(C)C)(C)C>>[CH3:18][C:15]1([CH3:19])[CH2:16][CH2:17][N:13]([CH2:12][C:10]2[CH:9]=[CH:8][C:6]3[N:7]=[C:2]([C:37]4[C:38]([F:42])=[CH:39][CH:40]=[C:41]5[C:36]=4[CH:35]=[CH:34][NH:33]5)[N:3]=[C:4]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:5]=3[N:11]=2)[CH2:14]1
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: CC1(C)CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)C1
Product: CC1(C)CCN(Cc2ccc3nc(-c4c(F)ccc5[nH]ccc45)nc(N4CCOCC4)c3n2)C1

Procedure:
4-(2-chloro-6-((3,3-dimethylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine (0.28 g) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 70.2 mg of 144 following reverse phase HPLC purification. MS (Q1) 461.2 (M)+
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:9][CH:8]=1)=[O:5].CC1(C)C(C)(C)OB([C:35]2[CH:36]=[CH:37][C:38]([C:41]([NH:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])=[O:42])=[N:39][CH:40]=2)O1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:4]([C:3]2[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:2]=2[C:35]2[CH:36]=[CH:37][C:38]([C:41]([NH:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])=[O:42])=[N:39][CH:40]=2)=[O:5])=[CH:8][CH:9]=1
Reactant: O=C(Nc1ccc(-c2ccc(Cl)cc2Cl)cc1)c1cc(F)c(F)cc1Br
Reactant: CCOC(=O)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(F)c(F)cc2C(=O)Nc2ccc(-c3ccc(Cl)cc3Cl)cc2)cn1

Procedure:
2-Bromo-N-(2′,4′-dichloro-[1,1′-biphenyl]-4-yl)-4,5-difluorobenzamide (100 mg, 0.22 mmol), ethyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamido)propanoate (114 mg, 0.33 mmol), Pd(dppf)Cl2 (24 mg, 0.03 mmol), and K2CO3 (60 mg, 0.44 mmol) were dissolved in 1,4-dioxane (1 mL) and water (0.5 mL) and the resulting mixture was heated to 85° C. After 2 h the resulting mixture directly purified via column chromatography to yield the title compound.
Reaction SMILES: C([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[C@H:13]([O:28]C(=O)C)[CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=O)C.[OH-].[Na+].O.Cl>C(O)C>[CH3:26][CH2:25][C:24]([NH:23][C@H:14]1[C@H:13]([OH:28])[CH2:12][C@H:11]2[C@H:10]3[C@H:19]([CH2:18][CH2:17][C@:15]12[CH3:16])[C:20]1[CH:21]=[CH:22][C:5]([OH:4])=[CH:6][C:7]=1[CH2:8][CH2:9]3)=[O:27]
Reactant: CCC(=O)N[C@H]1[C@H](OC(C)=O)C[C@H]2[C@@H]3CCc4cc(OC(C)=O)ccc4[C@H]3CC[C@@]21C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(=O)N[C@H]1[C@H](O)C[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@@]21C
Temperature: 25 °C

Procedure:
17β-Methylacetamido-oestra-1,3,5(10)-triene-3,16α-diol diacetate (19.7 g) was dissolved in ethanol (394 ml) and sodium hydroxide (50.9 ml; 2 N) was added. The resulting solution was refluxed for 1 h., cooled to room temperature and water (4 l) was added. The mixture was acidified with hydrochloric acid (2 N) and the precipitated product was filtered off and washed with water. Crystallisation from methanol-ether gave an isomeric mixture of 17β-methylacetamido-oestra-1,3,5(10)-triene-3,16α-diols (13.1 g; 83%).
Reaction SMILES: Cl.C([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])C1C=CC=CC=1.C([NH:34][C@H:35]([C:37](O)=[O:38])[CH3:36])(OCC1C=CC=CC=1)=O>>[NH2:34][C@@H:35]([CH3:36])[C:37]([NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19][P:10]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:11])[OH:9])=[O:38]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Agent: Cl
Product: C[C@H](N)C(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1

Procedure:
Step 4, Method B of Example 1 was substantially repeated in this Example 3 except for employing ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride and N-Cbz-L-alanine as the starting materials. Subsequent hydrogenation of the resulting benzyl ester in accordance with the procedures of Step 5, Method A of Example 1 and RP-HPLC purification yielded the title compound. 1H NMR (CD3OD, 300 MHz): δ 4.18-3.99 (m, 1H), 3.93 (q, 1H), 3.42-3.25 (m, 2H), 1.98-1.85 (m, 2H), 1.83-1.61 (m, 6H), 1.59-1.55 (m, 2H), 1.52 (d, 3H), 1.42-0.98 (m, 5H). 31P NMR (CD3OD, 300 MHz): δ 42.98. LCMS m/z: [M+H]+=307.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH2:10][CH:9]([C:13]([O:15]CC)=[O:14])[CH2:8]2)=[CH:3][CH:2]=1.[ClH:18]>O1CCOCC1>[ClH:18].[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:12][CH2:11][CH2:10][CH:9]([C:13]([OH:15])=[O:14])[CH2:8]2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CCCN(c2ccncc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C1CCCN(c2ccncc2)C1

Procedure:
A mixture of 1.8 g of ethyl 1-(4-pyridyl)-piperidine-3-carboxylate, 50 ml of dioxane and 20 ml of 1 M hydrochloric acid was heated under reflux for 5 hours. The solvent was evaporated, and the residue was washed with ethyl acetate to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[C:19]([NH:22][NH2:23])(=O)[CH3:20]>C(O)CCC>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]1=[N:23][N:22]=[C:19]([CH3:20])[N:3]1[N:4]=[C:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1ccc2c(Cl)nnc(-c3ccccc3)c2c1
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2c3ccc(Cl)cc3c(-c3ccccc3)nn12

Procedure:
A mixture of 1,6-dichloro-4-phenyl-phthalazine (8 g), acetyl hydrazine (4.4 g) and butanol (100 ml) is refluxed for 25 hours. Then the solvent is evaporated off and the residue is washed carefully with a small amount of water and crystallized from ethanol yielding 6 g of the compound of the title. M.p. 236°-38° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[C:10](=[O:18])[CH:9]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:25]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH:25]([N:38]1[CH2:43][CH2:42][N:41]([C:15](=[O:17])[CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH:9]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:10]2=[O:18])[CH2:40][CH2:39]1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)O)C(=O)C1c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCN(C(c3ccccc3)c3ccccc3)CC2)C(=O)C1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-(tert-butoxycarbonyl)-2-oxo-3-phenylpiperazin-1-yl)acetic acid (Example 101C, 0.334 g, 1 mmol) and 1-benzhydrylpiperazine (0.252 g, 1 mmol) in methylene chloride (10 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.38 g, 1 mmol) and diisopropylethylamine (0.8 mL). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with methylene chloride, and then washed sequentially with 1 N HCl, water, 1 N NaOH, and water. The organic layer was dried over magnesium sulfate and concentrated in vacuo to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.44 (m, 6H), 7.30 (m, 7H), 7.19 (m, 2H), 5.74 (m, 1H), 4.51 (d, J=15.60 Hz, 1H), 4.23 (s, 1H), 4.12 (q, J=7.12 Hz, 1H), 3.96 (d, J=15.94 Hz, 1H), 3.59 (m, 3H), 2.38 (m, 5H), 1.44 (s, 9H); MS (ESI+) m/z 569 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:28][C:29]3[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(CC(O)C(F)(F)F)c2=O)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
An amount of 305 mg (0.99 mmol) of the compound from Example 19A and 355 mg (1.09 mmol) of caesium carbonate were suspended in 10 ml of acetone and admixed with 227 mg (0.99 mmol) of methyl 4-(bromomethyl)benzoate. The mixture was stirred at 50° C. for 3 h. The suspension was diluted with water. It was extracted with twice 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. Purification by flash chromatography over silica gel with elution with cyclohexane/ethyl acetate (gradient 10:1→2:1) gave 284 mg (63% of theory) of the target compound.
Reaction SMILES: [C:1]([C:4]1[CH2:8][O:7][CH2:6][C:5]=1[C:9]1[CH:10]=[C:11]([C:15]2[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=2)[CH:12]=[CH:13][CH:14]=1)(=O)[NH2:2].O>ClCCl>[C:1]([C:4]1[CH2:8][O:7][CH2:6][C:5]=1[C:9]1[CH:10]=[C:11]([C:15]2[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=2)[CH:12]=[CH:13][CH:14]=1)#[N:2]
Reactant: CC1(C)COC(c2cccc(C3=C(C(N)=O)COC3)c2)=N1
Solvent: O
Solvent: ClCCl
Product: CC1(C)COC(c2cccc(C3=C(C#N)COC3)c2)=N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-[3-(4-carbamoyl-2,5-dihydrofuran-3-yl)phenyl]-4,4-dimethyl-4,5-dihydrooxazole (0.1 g) in dichloromethane (1 ml) was added dropwise bis(trifluoromethanesulfonic)anhydride (0.0588 ml) at 0° C. and the mixture was stirred at room temperature for two hours. Then water was added to the reaction mixture and the stirring was continued for thirty minutes. The product was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with chloroform. The fractions containing the desired product were collected and evaporated in vacuo to give 2-[3-(4-cyano-2,5-dihydrofuran-3-yl)phenyl]-4,4-dimethyl-4,5-dihydrooxazole.