Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:4]=1[CH2:5][NH:6][CH2:7][C:8]#[CH:9].I[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>CN(C)C=O.C(N(CC)CC)C.[Cu]I.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>[CH3:1][O:2][C:3]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:4]=1[CH2:5][NH:6][CH2:7][C:8]#[C:9][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1
Reactant: C#CCNCc1ccc(OC)cc1OC
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CNCC#Cc2ccc([N+](=O)[O-])cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 23A (12.47 g, 60.83 mmol) in a mixture of N,N-dimethylformamide (150 mL) and triethylamine (150 mL) was added 1-iodo-4-nitrobenzene (18.18 g, 73 mmol), CuI (2.33 g, 12.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.51 g, 3.04 mmol). The reaction mixture was stirred at room temperature overnight, and partitioned between ethyl acetate and brine. The organic phase was washed with brine, and concentrated. The crude material was purified by flash chromatography (20% ethyl acetate in hexane) to afford the title compound 1H NMR (400 MHz, dimethylsulfoxide-d6): δ 2.36 (br s, 1H), 3.59 (s, 2H), 3.72 (s, 2H), 3.74 (s, 3H), 3.77 (s, 3H), 6.48 (dd, J=6.0, 2.4 Hz, 1H), 6.53 (d, J=2.0 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.8 Hz, 2H), 8.22 (d, J=8.8 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][C:5]2[C:7]([N:12]=[CH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[OH:20])=[CH:8][CH:9]=[C:10]([OH:11])[C:4]=2[O:3]1.[CH3:22][N:23]=[C:24]=[O:25].C(Cl)Cl>C(N(CC)CC)C>[CH3:22][NH:23][C:24](=[O:25])[O:11][C:10]1[C:4]2[O:3][C:2]([CH3:21])([CH3:1])[CH2:6][C:5]=2[C:7]([N:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])=[CH:8][CH:9]=1
Reactant: CC1(C)Cc2c(N=Cc3ccccc3O)ccc(O)c2O1
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1ccc(N=Cc2ccccc2O)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 66 h
Yield: 92.9 %

Procedure:
To a 350 milliliter glass pressure bottle equipped with a magnetic stirrer was added 6.00 grams (0.021 moles) of 2,3-dihydro-2,2-dimethyl-4-(2-hydroxybenzylideneamino)benzofuran-7-ol prepared in part A, 1.4 grams (0.024 moles) of methyl isocyanate, 100 milliliters of methylene chloride and 0.1 milliliters of triethylamine. The resulting reaction mixture was stirred for 66 hours at room temperature and then concentrated under reduced pressure to give a yellow solid material. The yellow solid material was washed with hexane and dried to yield 6.64 grams (0.0195 moles) of 2,3-dihydro-2,2-dimethyl-4-(2-hydroxybenzylideneamino)benzofuran-7-yl methylcarbamate in the form of a yellow solid having a melting point of 201°-203° C. and the following structural formula: ##STR18##
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.C([Li])CCC.[F:23][C:24]([F:37])([F:36])[C:25]([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)=[O:26]>C1COCC1.CCCCCC>[F:37][C:24]([F:23])([F:36])[C:25]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2)([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[OH:26]
Reactant: Fc1ccc(-n2ncc3cc(Br)ccc32)cc1
Reactant: O=C(c1c[nH]c2ccccc12)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)(c1c[nH]c2ccccc12)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a chilled (−78° C.) solution of 2.67 g (9.20 mmol) 5-bromo-1-(4-fluorophenyl)-1H-indazole in 10 mL of anhydrous THF was added 7.36 mL (18.40 mmol) of a 2.5 M solution of n-butyllithium in hexane followed by a solution of 1.00 g (4.69 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-yl)ethanone in 5 mL of THF in one portion. The reaction was then stirred at −78° C. for 30 minutes and quenched with 5 mL of water. The mixture was warmed to room temperature and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (20%-40% ethyl acetate in hexanes). The major fractions were combined and concentrated to afford 978 mg of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-(1H-indol-3-yl)ethanol. MS m/z 426.39 (MIT).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:16]([CH3:17])[S:18][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:15]
Reactant: COC(=O)C(=O)C(Cl)c1ccc(Cl)cc1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1ccc(Cl)cc1

Procedure:
prepared by reaction of 3-chloro-3-(4-chloro-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.94 min; [M+H]+=267
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15].C(N(C(C)C)C(C)C)C.[NH4+].[Cl-]>CS(C)=O>[OH:16][CH:13]([CH2:14][OH:15])[CH2:12][NH:11][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1F
Reactant: NCC(O)CO
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1ccc(F)cc1NCC(O)CO
Yield: 41.4 %

Procedure:
A mixture of 2,4-Difluoro-benzonitrile (1.39 g, 10 mmol), 3-amino-propane-1,2-diol (0.911 g, 10 mmol), and ethyl-diisopropyl-amine (1.74 mL) in DMSO (10 mL) was microwaved at 200° C. for 7 min. Then the reaction mixture was poured into a saturated NH4Cl aq. solution (100 mL), extracted with EtOAc (3×100 mL), dried over Na2SO4, filtered, concentrated. The crude mixture was purified by flash silica gel chromatography (EtOAc-Hexane 1:1) to give 2-(2,3-Dihydroxy-propylamino)-4-fluoro-benzonitrile (0.87 g, 41.4% yield). LCMS (m/z): M+H=211.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:23])=[C:4]([C:8]2[CH:9]=[C:10]([CH3:22])[C:11]([N:14]([CH3:21])[C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.[CH2:28]([O:30][C:31]1(O[Si](C)(C)C)[CH2:33][CH2:32]1)C>CO>[CH3:28][O:30][C:31]1([NH:1][C:2]2[C:3]([CH3:23])=[C:4]([C:8]3[CH:9]=[C:10]([CH3:22])[C:11]([N:14]([CH3:21])[C:15](=[O:20])[C:16]([CH3:18])([CH3:19])[CH3:17])=[N:12][CH:13]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:33][CH2:32]1
Reactant: Cc1cc(-c2cccc(N)c2C)cnc1N(C)C(=O)C(C)(C)C
Reactant: CCOC1(O[Si](C)(C)C)CC1
Solvent: CC(=O)O
Solvent: CO
Product: COC1(Nc2cccc(-c3cnc(N(C)C(=O)C(C)(C)C)c(C)c3)c2C)CC1
Yield: 100 %

Procedure:
To a suspension of 5.70 g of N-[5-(3-amino-2-methyl-phenyl)-3-methyl-2-pyridyl]-N,2,2-trimethylpropanamide in 34.2 ml of methanol were added 4.40 g of acetic acid and 4.32 g of 1-ethoxy-1-trimethylsilyloxycyclopropane and the mixture was refluxed for 7 hours under a nitrogen atmosphere. Concentration of the reaction mixture under reduced pressure afforded 6.98 g of N-(5-{3-[(1-methoxycyclopropyl)amino]-2-methylphenyl}-3-methyl-2-pyridyl)-N,2,2-trimethylpropanamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([I:10])[CH:9]=1)[CH:5]=O.[C:11]([O:17][CH3:18])(=[O:16])[CH2:12]C([O-])=O.N1CCCC1>N1C=CC=CC=1>[CH3:18][O:17][C:11](=[O:16])[CH:12]=[CH:5][C:4]1[CH:7]=[C:8]([I:10])[CH:9]=[C:2]([F:1])[CH:3]=1
Reactant: O=Cc1cc(F)cc(I)c1
Reactant: COC(=O)CC(=O)[O-]
Solvent: C1CCNC1
Solvent: c1ccncc1
Product: COC(=O)C=Cc1cc(F)cc(I)c1

Procedure:
3-Fluoro-5-iodobenzaldehyde, monomethyl malonate, and a catalytic amount of pyrrolidine are heated in pyridine. After cooling, the solvent is distilled off in vacuo. 2N HCl and ethyl acetate are added to the residue, and the phases are separated. The organic layer is washed with brine and dried over Na2SO4. After evaporation, the residue is purified by CC on silica gel with EtOAc/hexane. Evaporation of appropriate fractions yields the title compound.
Reaction SMILES: Br[C:2]1[C:3]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].O.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>[Cl:25][C:22]1[S:21][C:20]([C:3]2[C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][N:11]3[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]3=[O:19])[N:4]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccccc1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2ccc(Cl)s2)n1
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: O
Solvent: C1COCCO1
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(-c2ccccc2)c(-c2ccc(Cl)s2)n1
Temperature: 140 °C

Procedure:
A biphasic mixture of 30 mg (0.068 mmol) of 1-{2-[5-bromo-4-(5-chlorothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione, 10 mg (0.081 mmol) of phenylboronic acid, 4.0 mg (0.0034 mmol) of tetrakis(triphenylphosphine)palladium(0) in 2 mL of 1,4-dioxane and 0.5 mL of 2 M aqueous Na2CO3 was heated in a microwave at 140° C. for 20 min. The reaction mixture was cooled to rt, diluted with 5 mL of water and extracted twice with CH2Cl2 and twice with a 3:1 mixture of CHCl3 and iPrOH. The combined organic extracts were concentrated and the crude products separated by C-18 prep HPLC to give 1-{2-[4-(5-chlorothiophen-2-yl)-5-phenylpyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione: MS (M+H)+ 442; and 5,5-dimethyl-1-{2-[5-phenyl-4-(5-phenylthiophen-2-yl)pyrimidin-2-ylamino]ethyl}imidazolidine-2,4-dione: MS (M+H)+ 484.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: CN1CCNCC1
Solvent: CCO
Solvent: CN(C)C=O
Product: CN1CCN(C[C@@H](O)COc2ccc(-c3noc4cc(F)ccc34)cc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1-methylpiperazine in ethanol essentially as described above in Example 21. Purity by LC/MS=90%, [M+H]+=386. Remaining 10% identified as N(CH3)2 adduct.
Reaction SMILES: [N+:1]([C:4]1([N+:20]([O-:22])=[O:21])[CH2:11][NH:10][CH2:9][C:8]([N+:15]([O-:17])=[O:16])([N+:12]([O-:14])=[O:13])[CH2:7][N:6]([N:18]=[O:19])[CH2:5]1)([O-:3])=[O:2].[N+:23]([O-])(O)=[O:24]>>[N+:20]([C:4]1([N+:1]([O-:3])=[O:2])[CH2:11][N:10]([N:23]=[O:24])[CH2:9][C:8]([N+:15]([O-:17])=[O:16])([N+:12]([O-:14])=[O:13])[CH2:7][N:6]([N:18]=[O:19])[CH2:5]1)([O-:22])=[O:21]
Reactant: O=NN1CC([N+](=O)[O-])([N+](=O)[O-])CNCC([N+](=O)[O-])([N+](=O)[O-])C1
Reactant: O=[N+]([O-])O
Product: O=NN1CC([N+](=O)[O-])([N+](=O)[O-])CN(N=O)CC([N+](=O)[O-])([N+](=O)[O-])C1

Procedure:
nitrosating the 3,3,7,7-tetranitro-1-nitrosoperhydro-1,5-diazocine in from about 55 to about 70 percent nitric acid to form 3,3,7,7-tetranitro-1,5-dinitrosoperhydro-1,5-diazocine product; and
Reaction SMILES: [O:1]([C@H:19]1[C@@H:26]2[N:22](/[C:23](=[N:27]/[C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([Cl:36])[C:29]=3[CH3:37])/[O:24][CH2:25]2)[CH2:21][CH2:20]1)[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C1COCC1>[OH:1][C@H:19]1[C@@H:26]2[N:22](/[C:23](=[N:27]/[C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([Cl:36])[C:29]=3[CH3:37])/[O:24][CH2:25]2)[CH2:21][CH2:20]1
Reactant: Cc1c(/N=C2\OC[C@@H]3[C@H](O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CCN23)ccc(C#N)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1c(/N=C2\OC[C@@H]3[C@H](O)CCN23)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
To a solution of 1I (29.0 mg, 0.0550 mmol) in THF (2 mL) at 0° C. was added HF/pyridine mixture (˜2.3:1, 0.120 mL) and the reaction was stirred at rt overnight. Saturated aqueous NaHCO3 was added (5 mL), and the product was extracted with EtOAc (3×5 mL). The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, then filtered and concentrated. Purification via flash chromatography (silica gel, 0-90% EtOAc in hexane) provided the title compound (10.0 mg). LCMS: niz 292 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9](=[O:11])[CH3:10])[CH:4]=1.[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH2:16]([O:15][C:13](=[O:14])[C:12](=[O:18])[CH2:10][C:9]([C:5]1[CH:4]=[C:3]([S:2][CH3:1])[CH:8]=[CH:7][N:6]=1)=[O:11])[CH3:17]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CSc1ccnc(C(C)=O)c1
Product: CCOC(=O)C(=O)CC(=O)c1cc(SC)ccn1
Yield: 58 %

Procedure:
The general procedure of Referential Example 17 was repeated through use of 1-(4-methylthio-2-pyridyl)ethanone (1.76 g) and diethyl oxalate (2.86 mL), to thereby give the title compound as a solid (1.64 g, 58%).
Reaction SMILES: Cl[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([CH3:48])([CH3:47])[C@H:12]3[C@:25]([CH3:28])([CH2:26][CH:27]=2)[CH:24]2[C@:15]([CH3:46])([C@@:16]4([CH3:45])[C@H:21]([CH2:22][CH2:23]2)[C@H:20]2[C@H:29]([C:32]([CH3:34])=[CH2:33])[CH2:30][CH2:31][C@:19]2([C:35]([O:37]CC2C=CC=CC=2)=[O:36])[CH2:18][CH2:17]4)[CH2:14][CH2:13]3)=[CH:6][CH:5]=1)=[O:3].[CH3:49][S:50]([NH2:53])(=[O:52])=[O:51]>>[CH3:45][C@:16]12[C@@:15]3([CH3:46])[CH:24]([C@:25]4([CH3:28])[C@@H:12]([CH2:13][CH2:14]3)[C:11]([CH3:47])([CH3:48])[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:2](=[O:3])[NH:53][S:50]([CH3:49])(=[O:52])=[O:51])=[CH:5][CH:6]=3)=[CH:27][CH2:26]4)[CH2:23][CH2:22][C@@H:21]1[C@H:20]1[C@H:29]([C:32]([CH3:34])=[CH2:33])[CH2:30][CH2:31][C@:19]1([C:35]([OH:37])=[O:36])[CH2:18][CH2:17]2
Reactant: CS(N)(=O)=O
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC=C(c6ccc(C(=O)Cl)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC=C(c6ccc(C(=O)NS(C)(=O)=O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared from the procedure described above for (1R,3aS,5aR,5bR,7aR,11aS,13aR,13bR)-benzyl 9-(4-(chlorocarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate using methanesulfonamide as the reactant sulfonamide. The title compound was isolated as a white solid (3.2 mg, 7%). LCMS: m/e 636.51 (M+H)+, 2.13 min (method 7). 1H NMR (500 MHz, DMSO-D6) δ ppm 0.88 (d, J=3.05 Hz, 6H), 0.94 (s, 6H), 0.98 (s, 3H), 1.11-1.62 (m, 15H), 1.63-1.72 (m, 5H), 1.77-1.88 (m, 2H), 2.03-2.17 (m, 2H), 2.24-2.35 (m, 1H), 2.97 (d, J=4.58 Hz, 1H), 3.57 (s, 3H), 4.58 (s, 1H), 4.71 (d, J=1.83 Hz, 1H), 5.23 (d, J=4.58 Hz, 1H), 7.17 (d, J=8.24 Hz, 2H), 7.86 (d, J=8.24 Hz, 2H), 12.03 (s, 1H), 12.10 (br. s., 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[N:5]=[C:4]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:34][CH2:33][N:32]([CH:35]([CH3:37])[CH3:36])[CH2:31][CH2:30]4)=[O:28])=[CH:23][CH:22]=3)[CH:18]=[N:19][CH:20]=2)[CH:3]=1.[CH3:38][OH:39]>>[CH:35]([N:32]1[CH2:33][CH2:34][N:29]([C:27]([C:24]2[CH:25]=[CH:26][C:21]([C:17]3[CH:18]=[N:19][CH:20]=[C:15]([C:4]4[CH:3]=[C:2]([O:39][CH3:38])[N:7]=[C:6]([C:8]5[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=5)[N:5]=4)[CH:16]=3)=[CH:22][CH:23]=2)=[O:28])[CH2:30][CH2:31]1)([CH3:37])[CH3:36]
Reactant: Cc1cccc(-c2nc(Cl)cc(-c3cncc(-c4ccc(C(=O)N5CCN(C(C)C)CC5)cc4)c3)n2)n1
Reactant: CO
Product: COc1cc(-c2cncc(-c3ccc(C(=O)N4CCN(C(C)C)CC4)cc3)c2)nc(-c2cccc(C)n2)n1

Procedure:
This compound is prepared from (4-{5-[6-chloro-2-(6-methyl-pyridin-2-yl)-pyrimidin-4-yl]-pyridin-3-yl}-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone (Ex. 7) and methanol analogously to Example 2: [M+H]+=509 as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][C@@H:11]([CH3:21])[CH2:12][O:13][Si](C(C)(C)C)(C)C)[CH:7]=[C:6]([O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH:5]=1.[NH2:34][C:35]1[S:39][N:38]=[C:37]([CH3:40])[N:36]=1>>[OH:13][CH2:12][CH:11]([CH3:21])[O:10][C:8]1[CH:7]=[C:6]([O:22][C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:27][CH:28]=2)[CH:5]=[C:4]([CH:9]=1)[C:3]([NH:34][C:35]1[S:39][N:38]=[C:37]([CH3:40])[N:36]=1)=[O:2]
Reactant: Cc1nsc(N)n1
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1
Product: Cc1nsc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC(C)CO)c2)n1

Procedure:
The compound of Production Example 89 was obtained as a colorless amorphous substance using 200 mg (0.40 mmol) of the obtained 5-((1S)-2-(t-butyldimethylsiloxy)-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-benzoic acid methyl ester and 5-amino-3-methyl-[1,2,4]thiadiazole, by the same method as in Production Example 2, a corresponding method, or a combination thereof with an ordinary method.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][OH:12].[C:13](Cl)([Cl:15])=[O:14]>C1COCC1>[C:13]([Cl:15])(=[O:14])[O:12][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: O=C(Cl)Cl
Reactant: OCc1ccc2ccccc2c1
Solvent: C1CCOC1
Product: O=C(Cl)OCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of naphthalen-2-yl methanol (51.2 g, 324 mmol) dissolved in anhydrous THF (1 L) was treated with phosgene (205 mL, 20% solution in toluene, 388 mmol). The solution was stirred at ambient temperature for 45 minutes and then concentrated to afford the desired product as a solid, which was dried under vacuum and used directly in the next step.
Reaction SMILES: CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:12])=O.[CH2:15]([N:22]1[CH2:31][CH2:30][CH:29]2[C:24](=[N:25][C:26]([CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:27][C:28]2=O)[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:15]([N:22]1[CH2:31][CH2:30][C:29]2[C:28]([Cl:12])=[N:27][C:26]([CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:25][C:24]=2[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1N=C(CN2CCOCC2)N=C2CN(Cc3ccccc3)CCC12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Solvent: ClCCCl
Product: Clc1nc(CN2CCOCC2)nc2c1CCN(Cc1ccccc1)C2
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
N,N-Dimethylaniline (1.2 g, 10 mmol) and phosphorus oxychloride (12.2 g, 80 mmol) were added to the solution of 7-benzyl-5,6,7,8-tetrahydro-2-(morpholinomethyl)pyrido[3,4-d]pyrimidin-4(4aH)-one (˜10 mmol) in 1,2-dichloroethane (30 mL, anhydrous) and were stirred in a preheated oil bath at 90° C. for 30 min. Reaction mixture was poured into ice, neutralized by solid sodium bicarbonate, extracted by ethyl acetate and dried over sodium sulfate. Solvent was removed in vacuo and brown oil residue was directly gone to next step.
Reaction SMILES: [CH3:1][CH:2](Br)[C:3]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C(#N)C>[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:25][CH2:26][N:27]([CH:2]([CH3:1])[C:3]([C:5]3[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:28][CH2:29]2)=[CH:20][CH:19]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: COC(=O)COc1ccc(C(=O)C(C)Br)cc1
Solvent: CC#N
Product: COC(=O)COc1ccc(C(=O)C(C)N2CCN(c3ccncc3)CC2)cc1
Reaction time: 8 h

Procedure:
A solution of RS methyl 4-(2-methylbromoacetyl)phenoxyacetate (1.2 g) in acetonitrile (10 ml) was added dropwise over 30 minutes to a stirred solution of 1-(4-pyridyl)piperazine (1.3 g) in acetonitrile (30 ml) and the mixture stirred overnight. The mixture was then filtered and the filtrate evaporated to give an oil. Purification by flash chromatography, eluting first with dichloromethane then successively 2.5%, 3%, 4%, 5% and 10% v/v methanol/dichloromethane gave the title compound, 220 mg as a solid: m.p. 81°-83° C.; NMR (d6DMSO) δ 8.13(2H,d), 8.06(2H,d), 7.02(2H,d), 6.77(2H,d), 4.92(2H,s), 4.33(1H,q), 3.72(3H,s), 3.26(4H,t), 2.63(4H,t), 1.16(3H,d); m/e 384(M+H)+ ; calculated for C21H25N3O4 : C, 65.8; H, 6.6; N, 11.0. found C, 65.7; H, 6.8; N, 10.9%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[NH2:10][C:11]1[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: COc1ccc(N)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(Nc2cc(Cl)nc(Cl)n2)cn1
Yield: 53.2 %

Procedure:
A solution of 2,4,6-trichloropyrimidine (2.0 mL, 17.4 mmol), 3-amino-6-methoxypyridine (1.5 mL, 19.1 mmol) and diisopropylethylamine (6.1 mL, 34.8 mmol) in acetonitrile (100 mL) was stirred at 55° C. under N2 for 15 hours. The reaction mixture was then partitioned between EtOAc (400 mL) and NaHCO3(sat.) (100 mL). The organic layer was separated, washed with brine (75 mL), dried over Na2SO4, concentrated, and purified by silica gel chromatography (20-30% EtOAc/hexanes) to yield 2,6-dichloro-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (2.51 g, 53%) as an off-white solid. LCMS (m/z): 270.9 and 272.9 (MH+); 1H NMR (CDCl3): δ 8.13 (d, J=2.7 Hz, 1H), 8.55 (dd, J=8.5, 2.7 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.84(bs, 1H), 6.35 (s, 1H), 3.97 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.Cl.[CH2:15](O)[CH3:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:15][CH3:16])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CCO
Reactant: COc1cccc(/C=C/C(=O)O)c1
Agent: Cl
Product: CCOC(=O)/C=C/c1cccc(OC)c1

Procedure:
To a solution of (2E)-3-(3-methoxyphenyl)acrylic acid (25 g) in ethanol (150 mL) was added conc HCl (25 mL) and the solution refluxed for 3 hours. The solvent was evaporated and residue dissolved in ethyl acetate. The organic phase was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to give ethyl (2E)-3-(3-methoxyphenyl)acrylate as yellow oil in quantitative yield. To a solution of isopropyl(triphenyl)phosphonium iodide (75 g, 0.173 mol) in dry THF (200 mL) at −78° C. was added butyl lithium (1.6M in Hexanes, 119 mL, 0.191 mol). The reaction was stirred for 1 hour at room temperature and then cooled to −78° C. To the solution was added ethyl (2E)-3-(3-methoxyphenyl)acrylate (2.91 g, 0.014 mol) in THF (200 mL). The solution was stirred at room temperature for few hours and then refluxed overnight. The reaction mixture was poured into 5% aqueous citric acid and extracted with ethyl acetate. The organic portion washed with saturated aqueous sodium bicarbonate, brine, dried over Na2SO4 and concentrated. The concentrated residue was chromatographed on silica gel using 5% ethyl acetate/hexane to afford viscous yellow oil. To the solution ethyl 3-(3-methoxyphenyl)-2,2-dimethylcyclopropanecarboxylate (15 g) in ethanol (60 mL) and water (20 mL) was added LiOH (12.74 g). The reaction mixture was heated for 3 hours at 50° C. and concentrated to remove ethanol. The residue was dissolved in ethyl acetate, washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to give 3-(3-methoxyphenyl)-2,2-dimethylcycloprop-anecarboxylic acid as yellow oil. 1H NMR (CDCl3) δ 7.15 (m, 1H), 6.74 (m, 3H), 3.8 (s, 3H), 2.67 (m, 1H), 2.05 (m, 1H), 1.38 (s, 3H), 1.06 (s, 3H). M−=219. Step 2. Synthesis of [3-(3-methoxyphenyl)-2,2-dimethylcyclopropyl]methanol.