Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][CH2:8][C:9]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:10]=2[CH2:11][O:12][C:13]2[CH:18]=[C:17]([CH3:19])[N:16]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:23](O)=[O:24])[C:15](=[O:30])[CH:14]=2)=[O:6])[CH2:3][CH2:2]1.ClC(OCC(C)C)=O.[CH3:44][N:45]1CCOCC1.CN>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH:1]1([NH:4][C:5]([NH:7][CH2:8][C:9]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:10]=2[CH2:11][O:12][C:13]2[CH:18]=[C:17]([CH3:19])[N:16]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:23]([NH:45][CH3:44])=[O:24])[C:15](=[O:30])[CH:14]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2CNC(=O)NC2CC2)cc1=O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: CN
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3CNC(=O)NC3CC3)cc2=O)c1
Reaction time: 0.33 h

Procedure:
To a cooled (−15° C.) solution of 3-[4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (see Example 651) (0.30 g, 0.63 mmol) and isobutyl chloroformate (0.10 mL, 0.75 mmol) in DMF (3.00 mL) was added 4-methylmorpholine (0.08 mL, 0.75 mmol). The solution instantly turned yellow and was dark brown within minutes. After 20 min, methylamine (0.47 mL of 2.0M solution in THF, 0.94 mmol) was added. The reaction was carried out at RT. After 2.5 h, a catalytic amount of DMAP and additional methylamine (0.47 mL, 0.94 mmol) were added. After an additional 2.5 h, the reaction was concentrated to a dark red oil. The crude product was purified by preparatory HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHCO3 (20 mL) and extracted in DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated to an off-white solid, dried in vacuo (0.06 g, 19%). 1H NMR (CD3OD/400 MHz) δ 7.85 (m, 1H), 7.58 (s, 1H), 7.48 (m, 2H), 7.14 (m, 1H), 7.02 (m, 1H), 6.23 (s, 1H), 6.09 (s, 1H), 5.20 (s, 2H), 4.45 (s, 2H), 2.90 (s, 3H), 2.49 (m, 1H), 2.11 (s, 3H), 1.91 (s, 3H), 0.71 (m, 2H), 0.48 (m, 2H). ES HRMS m/z 493.2260 (M+H calculated for C27H30N4O4F requires 493.2246).
Reaction SMILES: C(=O)(O)[O-].[K+].Cl.[C:7](=[NH:10])([NH2:9])[CH3:8].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([Br:22])[CH:16]=1)=O>O1CCCC1.O>[Br:22][C:17]1[CH:16]=[C:15]([C:13]2[NH:9][C:7]([CH3:8])=[N:10][CH:12]=2)[CH:20]=[CH:19][C:18]=1[CH3:21]
Reactant: CC(=N)N
Reactant: Cc1ccc(C(=O)CBr)cc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncc(-c2ccc(C)c(Br)c2)[nH]1
Temperature: 70 °C
Reaction time: 3 h
Yield: 4.2 %

Procedure:
Potassium bicarbonate (2.10 g, 20.7 mmol) was added portionwise to a solution of acetimidamide hydrochloride (1.06 g, 11.2 mmol) in tetrahydrofuran (20 mL) and water (5 mL). The resulting mixture was heated to reflux and 2-bromo-1-(3-bromo-4-methylphenyl)ethanone (preparation 58a, 2.74 g, 9.4 mmol) was added dropwise over a period of 20 minutes. After 3 hours, further acetamidamide hydrochloride (1.06 g, 11.2 mmol) and potassium bicarbonate (1.03 g, 10.1 mmol) were added and the was mixture refluxed overnight. The mixture was evaporated to dryness and partitioned between 2M aqueous hydrochloric acid and ethyl acetate. The acidic aqueous layer was bascified with solid sodium hydroxide and extracted with ethyl acetate. The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure to give a semi solid. This semi solid was heated in vacuo at 70° C. for one hour in order to remove excess acetamidamide to give the pure title compound (0.10 g, 5%) as a white solid.
Reaction SMILES: [CH3:1][C:2](=[O:6])[C:3](=[O:5])[CH3:4].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>CCOCC>[C:23]([O:5][C:3](=[CH2:4])[C:2](=[O:6])[CH3:1])(=[O:25])[CH3:24]
Reactant: CC(=O)C(C)=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(OC(C)=O)C(C)=O
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of 19.6 g. (228 mol) of 2,3-butanedione in 200 ml. of ether was added 3.34 g. (27 mmole) of dimethylamino pyridine, and 23 g. (228 mmole) of triethylamine. The solution was cooled to 0° and 23.24 g. (228 mmol) of acetic anhydride was added dropwise with vigorous stirring. The clear yellow solution was allowed to warm to 25° and was stirred 3 hours. The reaction mixture was transferred to a separatory funnel, washed with water (3x) and dried over MgSO4. Filtration and evaporation in vacuo afforded 17.6 g. of crude 3-acetoxy-3-buten-2-one (assayed by 1H-NMR with internal standard as 91% pure, 56% yield): 1H-NMR (CDCl3) delta 2.06 (s, 3), 2.25 (s, 3), 5.42, 5.49, 5,79, 5.82 (AB, 2).
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:64][O:65][C:66](=[O:78])[CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH3:77])[CH2:16][S:17][CH2:18][C@H:19]([NH:46]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:20](=[O:45])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1CCCCC1>C(#N)C>[C:66]([O:65][CH2:64][C@@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:16][S:17][CH2:18][C@H:19]([NH2:46])[C:20]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[O:45])(=[O:78])[CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH3:77]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCCCNC(=O)OCC1c2ccccc2-c2ccccc21)OC(=O)CCCCCCCCCCC
Solvent: CC#N
Solvent: C1CCNCC1
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCCCCN)OC(=O)CCCCCCCCCCC
Reaction time: 0.5 h

Procedure:
A solution of (12R,16R)-12-(((9H-fluoren-9-yl)methoxy)carbonylamino)-1-(9H-fluoren-9-yl)-3,11-dioxo-2-oxa-14-thia-4,10-diazaheptadecane-16,17-diyl didodecanoate in acetonitrile (0.1M) was stirred at room temperature. Piperidine (final conc. 20%) was then added and the reaction stirred for 30 minutes. After concentration, the product was purified by flash chromatography on an ISCO COMBIFLASH® system using a 0-20% MeOH (1% NH3)/DCM gradient to give (R)-3-((R)-2-amino-3-(5-aminopentylamino)-3-oxopropylthio)propane-1,2-diyl didodecanoate. 1H NMR (DMSO d-6): δ 7.91 (t, 1H), 5.09 (m, 1H), 4.26-4.32 (dd, 1H), 4.08-4.12 (m, 1H), 3.24-3.36 (m, 8H), 3.05-3.08 (m, 2H), 3.06 (m, 1H), 2.80 (m, 1H), 2.74 (t, 1H), 2.67 (dd, 1H), 2.60 (dd, 1H), 2.29-2.34 (q, 4H), 1.48-1.54 (m, 4H), 1.32-1.40 (m, 4H), 1.21-1.34 (m, 32H), 0.88 (t, 6H). LRMS [M+H]=645.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][C:6](=[O:12])[C:5]2=[CH:13][N:14]([CH3:16])C.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH:19]1C1C=CC(N)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][C:6](=[O:12])/[C:5]/2=[CH:13]\[NH:14][C:16]1[CH:4]=[CH:3][C:2]([N:21]2[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]2)=[CH:11][CH:10]=1
Reactant: CN(C)C=C1C(=O)NCc2ccc(Br)cc21
Reactant: CN1CCNCC1c1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc(N/C=C3\C(=O)NCc4ccc(Br)cc43)cc2)CC1
Yield: 50.5 %

Procedure:
A toluene solution (0.75 mL) of 6-bromo-4-[(dimethylamino)methylene]-1,4-dihydroisoquinolin-3(2H)-one (60 mg, 0.213 mmol) and 4-(N-methylpiperazinyl)aniline (42.9 mg, 0.224 mmol) is heated at 110° C. for 3 h. It is dried up and triturated with ether and hexane to yield 23 mg (25%) of the title compound as a light-brown solid.
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]([O:11]CC)=O)=[CH:7][N:6]=[C:5]2[N:14]([CH2:17][C:18]3[O:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[CH:16][C:4]=12)[NH2:2].C([N:25]1[C:29]2=NC=[C:32](C(OCC)=O)[C:33](NN)=[C:28]2C=N1)C.C(N1N2C3C4C=NNC=4N=CC=3C(=O)N(C3C=CC=CC=3)C2=CC1C)C1OC=CC=1.C(N1C2N=CC3C(=O)NC4N(N=C(C)C=4)C=3C=2C=N1)C>>[CH2:17]([N:14]1[C:5]2[N:6]=[CH:7][C:8]3[C:9](=[O:11])[NH:25][C:29]4[N:1]([N:2]=[C:33]([CH3:32])[CH:28]=4)[C:3]=3[C:4]=2[CH:16]=[N:15]1)[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccco2)c1NN
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1NN
Agent: CC1C=C2N(c3ccccc3)C(=O)c3cnc4[nH]ncc4c3N2N1Cc1ccco1
Agent: CCn1ncc2c1ncc1c(=O)[nH]c3cc(C)nn3c12
Product: Cc1cc2[nH]c(=O)c3cnc4c(cnn4Cc4ccco4)c3n2n1

Procedure:
By substituting 4-hydrazino-1-furfurylpyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester for the 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester in Example 1(a) and proceeding as in parts (a) and (b), 8-furfuryl-2-methyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one is obtained. This compound is now processed as in Example 1, part (c), substituting bromobenzene for the methyl iodide. A small amount of copper catalyst is added to obtain 1-furfuryl-2-methyl-4-phenyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7]3=[CH:13][C:14]([C:16]([O:18]CC)=[O:17])=[N:15][N:6]3[C:5](=[O:21])[C:4]=2[CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7]3=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[N:15][N:6]3[C:5](=[O:21])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1cc2n(C)c3ccc(Cl)cc3c(=O)n2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c2ccc(Cl)cc2c(=O)n2nc(C(=O)O)cc12

Procedure:
From 0.6 g of 7-chloro-4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid, ethyl ester, 22 ml of 0.1 N aqueous sodium hydroxide and 66 ml of methanol, following the procedure of Example 14, there is obtained 7-chloro-4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid; mp 280° C., after crystallization from dimethylformamide/methanol.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:16]=[C:17]([CH2:19][OH:20])[N:18]=2)=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCl.CS(C)=O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:23][CH:22]=3)[CH:16]=[C:17]([CH:19]=[O:20])[N:18]=2)=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)c1ccc(-n2cc(CO)nc2-c2ccc(Cl)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(-n2cc(C=O)nc2-c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49.4 %

Procedure:
To 8 ml of a 1:1 mixture of dimethyl sulfoxide and dichloromethane stirring in a dry ice/isopropanol bath under nitrogen was added dropwise oxalyl chloride (321 μl, 3.69 mmol). After stirring for 10 minutes, a solution of 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-4-methanol (Example 158) (670 mg, 1.85 mmol) in 25 ml of a 1:1 mixture of dimethyl sulfoxide and dichloromethane. Stirring was continued while warming to 0° C., where it was maintained for 15 minutes. Triethylamine (1.87 g, 18.5 mmol) was added, and the mixture was stirred overnight while warming to room temperature. The mixture was partitioned between dichloromethane and water, the organic layer was washed with water and then brine, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue. over silica gel using mixtures of ethyl acetate and hexane gave the title compound as an off-white solid (330 mg): mp (DSC) 203° C. Anal. Calc'd. for C17H13ClN2O3S (MW 360.82): C, 56.59; H, 3.63; N, 7.76. Found: C, 56.24; H, 3.62; N, 7.50.
Reaction SMILES: O.[OH-].[Li+].[C:4]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([O:25]C)=[O:24])=[N:21][CH:22]=3)=[CH:14][CH:15]=2)[C@H:10]([NH:27][C:28]2[CH:33]=[N:32][C:31]([C:34]#[N:35])=[CH:30][N:29]=2)[CH2:9][C@@H:8]1[CH3:36])(=[O:6])[CH3:5].C(O)(=O)C>O.O1CCOCC1>[C:4]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([OH:25])=[O:24])=[N:21][CH:22]=3)=[CH:14][CH:15]=2)[C@H:10]([NH:27][C:28]2[CH:33]=[N:32][C:31]([C:34]#[N:35])=[CH:30][N:29]=2)[CH2:9][C@@H:8]1[CH3:36])(=[O:6])[CH3:5]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2cnc(C#N)cn2)C[C@H](C)N3C(C)=O)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)O)nc3)cc2[C@H](Nc2cnc(C#N)cn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 43 %

Procedure:
Lithium hydroxide monohydrate (83 mg, 1.97 mmol) in water (5 mL) was added to methyl 5-((2S,4R)-1-acetyl-4-((5-cyanopyrazin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)picolinate (for a preparation, see Intermediate 52) (435 mg, 0.983 mmol) in 1,4-dioxane (5 mL) and the reaction mixture stirred at room temperature for 70 mins. Acetic acid (0.169 mL, 2.95 mmol) was added and the resulting mixture stirred for 10 mins. The mixture was filtered, the solid collected was washed with water, then dried in a vacuum oven to give 5-((2S,4R)-1-acetyl-4-((5-cyanopyrazin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)picolinic acid (181 mg, 0.422 mmol, 43% yield) as a brown solid. LCMS: (Formate, 2 min) Rt=0.66 mins, MH+=429.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH3:32][O-:33].[Na+]>CO>[CH3:32][O:33][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1
Reactant: C[O-]
Reactant: COc1cnc2c(Sc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Agent: [Na+]
Solvent: CO
Product: COc1cnc2c(Sc3ccc(Nc4nnc(OC)c5ccccc45)cc3)ccnc2c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
In a 100 ml RBF was added 4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine (158 mg, 0.354 mmol) to a solution of sodium methoxide (96 mg, 1.772 mmol) in MeOH. The mixture was heated to reflux with a water condenser attached. The solution was stirred for 16 hours. A white solid precipitated. The mixture was cooled to 0° C., quenched with excess methoxide, followed by saturated NH4Cl, and the resulting solids were filtered and washed with water. The crude solids were purified by Gilson Reverse Phase HPLC eluting with a 15-70% gradient of ACN in water with 0.1% TFA. The product fractions were combined, neutralized with saturated sodium bicarbonate, extracted with 15 ml of methylene chloride (3×), dried organics over Na2SO4, filtered and concentrated filtrate in vacuo to afford 4-methoxy-N-(4-(7-methoxy-1,5-naphthyridin-4 ylthio)phenyl)phthalazin-1-amine as an off-white solid. MS: [M+H]=442.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pt]=O.C(Cl)(Cl)Cl>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:17][CH2:18]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: Cc1ccccc1N1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1N1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Yield: 58 %

Procedure:
A mixture of 5.00 g (0.0142 m) of 1-[(p-nitrophenyl)sulfonyl]-4-(o-methylphenyl)piperazine, 0.3 g of platinum oxide, and 150 ml of chloroform is shaken under pressure on a Parr hydrogenator until hydrogen uptake ceases (25 minutes). The catalyst is removed on a fine sintered glass funnel and the filtrate is taken to dryness. Crystallization from ethyl acetate/methylene chloride/Skellysolve® B hexanes gives 2.66 g (57%) of 1-[(p-aminophenyl)-sulfonyl]-4-(o-methylphenyl)piperazine.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:17]3=[N:18][C:19]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[N:20][CH:21]=[C:16]3[CH2:15][N:14]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][CH:31]=3)[C:13]2=[O:38])[CH2:8]1)(C)(C)C.N1C=CC=CC=1.F>N1C=CC=CC=1>[CH2:36]([C:33]1[CH:34]=[CH:35][C:30]([N:14]2[CH2:15][C:16]3[C:17](=[N:18][C:19]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[N:20][CH:21]=3)[N:12]([C@H:9]3[CH2:10][CH2:11][C@H:7]([OH:6])[CH2:8]3)[C:13]2=[O:38])=[CH:31][CH:32]=1)[CH3:37]
Reactant: CCc1ccc(N2Cc3cnc(Nc4ccc(F)cc4)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)C3)C2=O)cc1
Agent: F
Solvent: c1ccncc1
Product: CCc1ccc(N2Cc3cnc(Nc4ccc(F)cc4)nc3N([C@H]3CC[C@H](O)C3)C2=O)cc1

Procedure:
A solution of (±)-1-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-3-(4-ethyl-phenyl)-7-(4-fluoro-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (47 mg, 0.08 mmol) in pyridine (1 mL) (Fisher) was treated at room temperature with hydrogen fluoride-pyridine (0.6 mL) (Aldrich) for 20 minutes. The reaction mixture was quenched with 1 N aqueous hydrochloric acid at 0° C., then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (50% ethyl acetate in hexanes) to give (±)-3-(4-ethyl-phenyl)-7-(4-fluoro-phenylamino)-1-(trans-3-hydroxy-cyclopentyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a white solid. (Yield 32 mg, 87%).
Reaction SMILES: CS(C)=O.[F-].[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C-:22]#[N:23].[Na+]>O>[C:6]([C:16]1[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=1)(=[O:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCC(=O)c1ccccc1
Reactant: [C-]#N
Agent: [F-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCC(=O)c1ccc(C#N)cc1
Yield: 100 %

Procedure:
To 1350 ml of dimethylsulfoxide were added 292.2 g (1.238 mol) of the above 4-nonanoyl-benzene fluoride and 67.4 g (1.374 mol) of sodium cyanide, which were reacted at 110°-125° C. for 12 hours. After the cooling up to room temperature, the reaction solution was poured into 2.7 l of water and extracted with 2 l of chloroform. The extract was washed with a saturated saline solution and dried on anhydrous magnesium sulfate. The solvent was distilled off to obtain 317.9 g (yield: 100%) of brown oily substance of 4-nonanoyl benzonitrile having an infrared absorption spectrum of 1680 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]([F:44])([F:43])[F:42])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]([F:43])([F:42])[F:44])=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: FC(F)(F)c1ccccc1Sc1ccc(Br)cc1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3ccccc3C(F)(F)F)cc2)c1C
Yield: 33 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-bromo-4-(2-(trifluoromethyl)-phenylsulfanyl)-benzene (0.279 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. Flash chromatography (0-3% ethyl acetate in hexanes) provided {6-fluoro-3-methyl-4-[4-(2-trifluoromethyl-phenylsulfanyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.088 g, 32%) as a solid. MS calcd. for C27H19F4O2S [(M−H)−] 483, obsd. 483.0.
Reaction SMILES: Br[C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:31]C(=O)OC(C)(C)C)[CH:26]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2]>[C:11]1([C:3]2[C:2]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH2:31])[CH:26]=3)=[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][N:5]3[N:4]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1c(-c2ccccc2)nn2cccnc12
Reactant: CC(C)(C)OC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(-c2c(-c3ccccc3)nn3cccnc23)ccn1
Temperature: 120 °C
Yield: 45.8 %

Procedure:
3-Bromo-2-phenylpyrazolo[1,5-a]pyrimidine (1.0 g, 3.65 mmol) and tert-butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (1.29 g, 4.01 mmol, 1.1 eq) are dissolved in 10 mL 1,4-dioxan. To this mixture bis(tricyclohexylphosphine)palladium(II)-dichloride (269 mg, 0.37 mmol, 0.1 eq) and 9.1 mL sodium carbonate solution (2 molar) are added. The reaction mixture is flushed with argon for 5 mins and then sealed. Next the mixture is heated for 90 min at 120° C. in the microwave (Biotage). Tert-butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (214 mg, 1.4 mmol, 0.37 eq) and bis(tricyclohexylphosphine)palladium(II)-dichloride (269 mg, 0.37 mmol, 0.1 eq) are then added and the mixture is heated for 2 h at 120° C. The reaction mixture is then poured in water and extracted with ethyl acetate (3×50 mL). The organic layer is dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material is purified by column chromatography using silica gel in heptane and ethyl acetate (1:0 to 1:1) as eluent and 0.48 g (44%) of 4-(2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-amine are obtained as a white solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:12]([OH:14])=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.N1([C:27](=O)[C:26]2N(C)C=N[C:21]=2N(C)C1=O)C>O>[CH:26]([O:13][C:12](=[O:14])[C@H:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)[NH2:2])([CH3:27])[CH3:21]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: Cn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: Cl
Solvent: O
Product: CC(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1

Procedure:
HCl (70 g) and tyrosine (7 g) were dissolved in water (1 L). Caffeine (50 g) was added into the mixture and the mixture was stirred for a few minutes. The mixture was filled into either spray bottles or roll-on bottles.
Reaction SMILES: C(O[C@@H:5]1[C@H:11]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:8]2([CH2:9][CH3:10])[C:7](=[O:26])[CH2:6]1)[C@@H:20]1[C:15]([CH:16]=[C:17]([O:24][CH3:25])[CH2:18][CH2:19]1)=[CH:14][CH2:13]3)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:25][O:24][C:17]1[CH2:18][CH2:19][C@H:20]2[C:15](=[CH:14][CH2:13][C@@H:12]3[C@@H:21]2[CH2:22][CH2:23][C@@:8]2([CH2:9][CH3:10])[C@H:11]3[CH:5]=[CH:6][C:7]2=[O:26])[CH:16]=1
Reactant: CC[C@]12CC[C@H]3[C@@H](CC=C4C=C(OC)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC[C@]12CC[C@H]3[C@@H](CC=C4C=C(OC)CC[C@@H]43)[C@@H]1C=CC2=O
Temperature: 50 °C
Yield: 80.2 %

Procedure:
A mixture of 15α-acetoxy-3-methoxy-18-methyl-estra-3,5-dien-17-one (1 g, 2.8 mmol) in suspension in a 1/1 MeOH/water solution (20 ml), and potassium carbonate (1 g, 7.23 mmol) was heated at 50° C. for 1 h. The mixture was allowed to cool to room temperature and the precipitate was filtered, washed with water and dried under vacuum to afford 3-methoxy-18-methyl-estra-3,5,15-trien-17-one (0.67 g, yield: 80%). mp: 159-161° C.; 1H-NMR δ=0.72 (t, 3H), 0.9-2.4 (m, 16H), 3.55 (s, 3H), 5.18 (s, 1H), 5.28 (d, 1H), 5.95 (m, 1H), 7.45 (d, 1H).