Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.Cl.C(N1CC(C2C=CC([Cl:37])=C(Cl)C=2)(CCN2CCC(O)(C3C=CC=CC=3)CC2)[O:13]CC1=O)C1C=CC=CC=1.[CH2:40]([N:47]1[CH2:52][C:51]([CH2:61][CH2:62]N2CCC(C3C=CC=CC=3)(O)CC2)([C:53]2[CH:58]=[CH:57][C:56]([Cl:59])=[C:55]([Cl:60])[CH:54]=2)[O:50][CH2:49][C:48]1=[O:76])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:89]([N:92]([C:94]1([C:100]2[CH:105]=[CH:104][CH:103]=[CH:102][CH:101]=2)[CH2:99][CH2:98][NH:97][CH2:96][CH2:95]1)[CH3:93])(=[O:91])[CH3:90].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl.CCOCC.O>[OH2:13].[ClH:37].[C:89]([N:92]([C:94]1([C:100]2[CH:101]=[CH:102][CH:103]=[CH:104][CH:105]=2)[CH2:95][CH2:96][N:97]([CH2:62][CH2:61][C:51]2([C:53]3[CH:58]=[CH:57][C:56]([Cl:59])=[C:55]([Cl:60])[CH:54]=3)[CH2:52][N:47]([CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:48](=[O:76])[CH2:49][O:50]2)[CH2:98][CH2:99]1)[CH3:93])(=[O:91])[CH3:90]
Reactant: O=C1COC(CCN2CCC(O)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)CN1Cc1ccccc1
Reactant: CC(=O)N(C)C1(c2ccccc2)CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(=O)N(C)C1(c2ccccc2)CCN(CCC2(c3ccc(Cl)c(Cl)c3)CN(Cc3ccccc3)C(=O)CO2)CC1
Temperature: 90 °C
Yield: 101.6 %

Procedure:
A mixture of 1.1 g of the compound obtained in step B of EXAMPLE 14, 1.85 g of 4-(acetyl-N-methylamino)-4-phenylpiperidine p-toluenesulfonate and 1.3 g of K2CO3 in 3 ml of DMF is heated at 80-100° C. for 2 hours. After cooling to RT, the reaction mixture is poured into water and extracted with ether, the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a DCM/HeOH mixture (from 100/1; v/v to 100/4; v/v) as the eluent. The product obtained is dissolved in DCM, a saturated solution of hydrochloric acid in ether is added until the pH is 1, and the precipitate formed is wrung to give 0.62 g of the expected product. M.p.=148-150° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-])=O>CO.[Ni]>[NH2:11][C:3]1[CH:4]=[C:5]([C:8](=[O:10])[CH3:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Product: CC(=O)c1ccc(F)c(N)c1

Procedure:
39 g of 4'-fluoro-3'-nitroacetophenone, melting point: 44° C, were hydrogenated in 390 ml of methanol at 20 atm. and 40° C in the presence of Raney-Nickel to give the 3'-amino-4'-fluoro-acetophenone, melting point: 70° C).
Reaction SMILES: CO[C:3](=[O:17])[C:4]([C:6]1[C:14]2[C:9]3=[C:10]([CH2:15][CH2:16][N:8]3[CH:7]=1)[CH:11]=[CH:12][CH:13]=2)=O.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27][C:28]([NH2:30])=[O:29])=[CH:19]1.CC(C)([O-])C.[K+].Cl>O1CCCC1.C(OCC)(=O)C>[C:6]1([C:4]2[C:3](=[O:17])[NH:30][C:28](=[O:29])[C:27]=2[C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:18][CH:19]=2)[C:14]2[C:9]3=[C:10]([CH2:15][CH2:16][N:8]3[CH:7]=1)[CH:11]=[CH:12][CH:13]=2
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CC2
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CC3)=C1c1c[nH]c2ccccc12
Reaction time: 0.33 h
Yield: 49.3 %

Procedure:
To a solution of (4,5-dihydro-pyrrolo[3,2,1-hi]indol-1-yl)-oxo-acetic acid methyl ester (150 mg, 0.66 mmol) and 2-(1H-indol-3-yl)-acetamide (114 mg, 0.66 mmol) in anhydrous tetrahydrofuran (10 ml) at 0° C. was added potassium tert-butoxide (2.6 ml, 2.6 mmol; 1M solution in tetrahydrofuran). The mixture was stirred at room temperature for 1 hour before concentrated hydrochloric acid (3 ml) was added and the mixture stirred for an additional 20 minutes. The mixture was poured into ethyl acetate (200 ml) washed with water (700 ml) and brine (100 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by flash column chromatography (SiO2, 40% EtOAc in hexanes) to afford 3-(4,5-dihydro-pyrrolo[3,2,1-hi]indol-1-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione as a red solid (115 mg). 400 MHz 1H NMR (DMSO-d6) δ: 11.63 (s, 1H), 10.84 (s, 1H), 7.98 (s, 1H), 7.62 (d, J=2.8 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.05-7.01 (m, 2H), 6.78-6.74 (m, 2H), 6.53 (t, J=7.2 Hz, 1H), 6.08 (d, J=8.0 Hz, 1H), 4.58 (t, J=7.2 Hz, 2H), 3.71 (t, J=6.8 Hz, 2H); LCMS: 354 [M+H].
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]1[CH:36]=O>>[CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:36][C:28]3[N:27]([CH3:26])[C:35]4[C:30]([CH:29]=3)=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: Cn1c(C=O)cc2ccccc21
Product: Cn1c(CNc2cccc(-c3c(Cc4ccccc4)nnc4c(Cl)cccc34)c2)cc2ccccc21

Procedure:
The title compound was prepared from [3-(3-benzyl-8-chlorocinnolin-4-yl)phenyl]amine and 1-methyl-1H-indole-2-carbaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 489.1.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([O:22][CH3:23])[CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[O:24]=[C:25]1[C:28]2([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:27](O)=[CH:26]1>C(Cl)Cl>[O:24]=[C:25]1[C:28]2([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:27]([NH:1][C@@H:2]([CH2:7][C:8]2[CH:9]=[C:10]([O:22][CH3:23])[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([O:14][CH3:15])[CH:13]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:26]1
Reactant: O=C1C=C(O)C12CCCCC2
Reactant: COC(=O)[C@@H](N)Cc1cc(OC)c(-c2ccccc2)c(OC)c1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cc(OC)c(-c2ccccc2)c(OC)c1)NC1=CC(=O)C12CCCCC2
Reaction time: 48 h
Yield: 93.4 %

Procedure:
To a solution of methyl(2S)-2-amino-3-(2,6-dimethoxy[1,1′-biphenyl]-4-yl)propanoate (0.80 g, 2.5 mmol) in DCM (10 ml) at room temperature was added 1-keto-3-hydroxyspiro[3,5]-non-2-ene (0.38 g, 2.5 mmol) and the mixture stirred for 48 h. Volatiles were removed in vacuo and the residue purified by column chromatography (SiO2, EtOAc) to give the title compound as a white solid (1.05 g, 92%). δH (CDCl3): 7.32-7.26 (3H, m), 7.12 (2H, d, J 8.2 Hz), 6.92 (2H, d, J 8.3 Hz), 5.90 (1H, br d, J 8.2 Hz), 4.60 (1H, s), 4.33 (1H, br), 3.86 (3H,s), 3.73 (6H, s), 3.30 (1H, dd, J 13.9, 5.3 Hz), 3.13 (1H, dd, J 13.9, 6.3 Hz), 1.82-1.33 (10H, m); m/z (ES+, 70V) 450.1 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=2)[O:9][N:8]=1.[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:21]3[CH:22]=[CH:23][S:19][CH:20]=3)[CH:17]=2)[O:9][N:8]=1
Reactant: OB(O)c1ccsc1
Reactant: Brc1cncc(-c2nc(-c3ccccn3)no2)c1
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
Product: c1ccc(-c2noc(-c3cncc(-c4ccsc4)c3)n2)nc1
Yield: 7.5 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-pyrid-3-yl)-1,2,4-oxadiazole (42 mg, 0.1385 mmol), 3-thiopheneboronic acid (26.6 mg, 0.208 mmol), and Pd(PPh3)4 (24.0 mg, 0.021 mmole) in a solution of 2M sodium carbonate (1.5 mL) and ethylene glycol dimethyl ether (1.5 mL) was heated overnight at 105° C. Standard work up afforded 3.2 mg (8%) of 3-(2-pyridyl)-5-[5-(3-thienyl)-pyrid-3-yl]-1,2,4-oxadiazole.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH2:15])=[CH:10][N:9]=2)[CH2:4][CH2:3]1.I[C:17]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]=[O:27])=[CH:23][CH:24]=2)[N:19]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:18]=1>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:17]3[C:25]4[C:20](=[CH:21][C:22]([CH:26]=[O:27])=[CH:23][CH:24]=4)[N:19]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:18]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: C=Cc1ccc(N2CCN(C)CC2)nc1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Product: CN1CCN(c2ccc(/C=C/c3nn(COCC[Si](C)(C)C)c4cc(C=O)ccc34)cn2)CC1
Temperature: 90 °C

Procedure:
The title compound was synthesized according to the method of Example A15A, utilizing 1-methyl-4-(5-vinylpyridin-2-yl)piperazine (65 mg, 0.32 mmol) and 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (100 mg, 0.25 mmol), with heating in a sealed tube at 90° C. overnight instead of with microwave irradiation. Purified by prepTLC (SiO2 10% MeOH/DCM) to provide the title compound to as a pale orange material (46 mg, 39%). 1H NMR (400 MHz, CD3OD) δ ppm 10.14 (s, 1 H), 8.34 (d, J=2.26 Hz, 1.0H), 8.24-8.28 (m, 2H), 8.00 (dd, J=8.91, 2.38 Hz, 1H), 7.80 (d, J=8.78 Hz, 1H), 7.51 (d, J=16.56 Hz, 1H), 7.36 (d, J=16.56 Hz, 1H), 6.97 (d, J=9.29 Hz, 1H), 5.85 (s, 2H), 3.77-3.87 (m, 4H), 3.63 (t, J=7.91 Hz, 2H), 3.06-3.15 (m, 4H), 2.75 (s, 3H), 0.88 (t, J=8.03 Hz, 2H), −0.09 (s, 9H); MS ESI 478.3 [M+H]+, calcd for [C26H35N5O2Si+H]+ 478.7.
Reaction SMILES: Cl[C:2](=O)[CH2:3][C:4](=[N:10][O:11][CH2:12][C:13]#[CH:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:16][C:17]([NH2:19])=[S:18].O>C(O)C>[NH2:19][C:17]1[S:18][CH:2]=[C:3]([C:4](=[N:10][O:11][CH2:12][C:13]#[CH:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:16]=1
Reactant: NC(N)=S
Reactant: C#CCON=C(CC(=O)Cl)C(=O)OCC
Solvent: CCO
Solvent: O
Product: C#CCON=C(C(=O)OCC)c1csc(N)n1
Temperature: 40 °C
Reaction time: 1.25 h
Yield: 53.5 %

Procedure:
A mixture of ethyl 4-chloro-4-oxo-2-propargyloxyiminobutyrate (syn isomer, 61 g), thiourea (20 g), sodium acetate 3-hydrate (35.8 g), water (150 ml), and ethanol (180 ml) was stirred at 40° C. for 1.25 hrs. The reaction mixture was treated in a conventional manner to give ethyl 2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetate (syn isomer, 35.6 g).
Reaction SMILES: [P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:26]3[N:25]=[C:23]([NH2:24])[NH:22][C:20](=[O:21])[C:19]=3[N:18]=[CH:17]2)[C@H:13]([OH:27])[CH2:12]1)([O:4][P:5]([OH:8])([OH:7])=[O:6])(=[O:3])[OH:2].[CH3:28]S(C)=O.CN(C=O)C.CI>O>[P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:26]3[N:25]=[C:23]([NH2:24])[NH:22][C:20](=[O:21])[C:19]=3[N:18]([CH3:28])[CH2:17]2)[C@H:13]([OH:27])[CH2:12]1)([O:4][P:5]([OH:7])([OH:8])=[O:6])(=[O:2])[OH:3]
Reactant: CS(C)=O
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)C[C@H]2O)c(=O)[nH]1
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)C[C@H]2O)c2nc(N)[nH]c(=O)c21
Yield: 28 %

Procedure:
Compound 5 (34 mg, 0.055 mmol) was mixed with 1 mL of dimethylsulfoxide, 1 mL of DMF, and 100 μL of methyl iodide at room temperature. After 3 h the reaction mixture was treated with 30 mL of cold water and extracted three times with 10-mL portions of diethyl ether. After neutralization with NaHCO3, chromatographic separation of the aqueous phase on DEAE-Sephadex, using a linear gradient of 0 to 0.8 M TEAB, gave Compound 7 (yield: 10 mg, 28%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24]CC)=[O:23])=[CH:18][CH:17]=2)=[CH:12][C:11]=1[C:27]1[CH:36]=[CH:35][C:34]2[C:33]([CH3:38])([CH3:37])[CH2:32][CH2:31][C:30]([CH3:40])([CH3:39])[C:29]=2[CH:28]=1)[CH3:4]>O1CCCC1>[CH2:3]([NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=2)=[CH:12][C:11]=1[C:27]1[CH:36]=[CH:35][C:34]2[C:33]([CH3:38])([CH3:37])[CH2:32][CH2:31][C:30]([CH3:39])([CH3:40])[C:29]=2[CH:28]=1)[CH3:4]
Reactant: CCNCCCOc1ccc(-c2ccc(C(=O)OCC)cc2)cc1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCNCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 85.6 %

Procedure:
In a manner similar to that of Example 2a, by reaction of 380 mg (9.5 mmol) of sodium hydroxide with 490 mg (0.95 mmol) of ethyl 4′-(3-ethylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate (Example 15a) in 30 ml of tetrahydrofuran. 395 mg of 4′-(3-ethylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid are obtained in the form of a white solid (m.p.=233° C., yield=85%).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]([F:38])([F:37])[O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1.O>CN(C=O)C>[CH2:17]([NH:16][C:11]1=[N:12][C:13](=[O:15])[S:14]/[C:10]/1=[CH:9]\[CH:6]1[CH2:7][CH2:8][N:3]([CH2:33][C:32]2[CH:35]=[CH:36][C:29]([O:28][C:27]([F:26])([F:37])[F:38])=[CH:30][CH:31]=2)[CH2:4][CH2:5]1)[C:18]#[CH:19]
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) was added a solution of potassium carbonate (345 mg) and 4-(trifluoromethoxy)benzyl bromide (0.113 mL) in DMF (2 mL). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (48.5 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([NH:14][CH3:15])=[O:13])[CH:5]=[CH:4][N:3]=1.Cl.[F:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH:26]2[CH2:29][NH:28][CH2:27]2)=[CH:23][CH:22]=1.C(N(C(C)C)C(C)C)C>CC(O)C>[F:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH:26]2[CH2:27][N:28]([C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=4)[C:12]([NH:14][CH3:15])=[O:13])[CH:5]=[CH:4][N:3]=3)[CH2:29]2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(OC2CNC2)cc1
Reactant: CNC(=O)c1cccc(Nc2ccnc(Cl)n2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CNC(=O)c1cccc(Nc2ccnc(N3CC(Oc4ccc(F)cc4)C3)n2)c1
Temperature: 84 °C
Yield: 75.8 %

Procedure:
To 3-(2-chloropyrimidin-4-ylamino)-N-methylbenzamide (90.0 mg, 0.343 mmol) and 3-(4-fluorophenoxy)azetidine hydrochloride (73.3 mg, 0.360 mmol) in a disposable sealed tube in 2-propanol (2.00 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.028 mmol). The resulting reaction mixture was heated at 84° C. for 48 h, cooled to RT, filtered, rinsed with IPA, and concentrated under reduced pressure to afford 3-(2-(3-(4-fluorophenoxy)azetidin-1-yl)pyrimidin-4-ylamino)-N-methylbenzamide (102.3 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[OH:39][CH2:38][C:37]([NH:36][S:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)=[N:8][C:7]=23)[CH:28]=1)(=[O:35])=[O:34])([CH3:41])[CH3:40]
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (355 mg, 1.0 mmol) and 3-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.6) (308 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (560 mg, 96%). MS (ISN) 581.1 [(M−H)−]; mp 132° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:12]([CH2:18][C:19]1([CH3:22])[CH2:21][CH2:20]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:12]([CH2:18][C:19]2([CH3:22])[CH2:20][CH2:21]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CCOC(=O)C(Br)CC1(C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC1(C)CC1)Sc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice cold solution of 4-bromothiophenol (455 mg, 2.4 mmol) in DRY (3 mL) was added sodium hydride (101 mg of 60% oil disp., 2.5 mmol). The resulting suspension was stirred at 0° C. for 30 min. A solution of ethyl 2-bromo-3-(1-methylcyclopropyl)propanoate (465 mg, 2.0 mmol) in DMF (2 mL) was added dropwise and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography using Et2O in hexane to afford ethyl 2-[(4-bromophenyl)thio]-3-(1-methylcyclopropyl)propanoate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:18][CH3:19]>CN(C)C=O>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH2:18][CH3:19])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCO[C@@H]1CC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of cyclopent-3-enecarboxylic acid (2.25 g), diphenylphosphoryl azide (4.7 mL), and triethylamine (2.8 mL) in 25 mL toluene was refluxed for 7 h. The mixture was cooled to rt and treated with 10 mL of tert-butanol. The resulting mixture was refluxed for an additional 16 h. The solvents were evaporated and the crude residue was chromatographed with silica gel (1:10 ethyl acetate:hexanes) to give Cyclopent-3-enylcarbamic acid tert-butyl ester (racemic): (2.37 g). Borane-tetrahydrofuran (1.5 M in THF, 20 mL) was added dropwise to a solution of cyclopent-3-enylcarbamic acid tert-butyl ester (1.83 g) in tetrahydrofuran (30 mL) at 0° C. The solution was gradually warmed to rt and stirred for 16 h. The reaction solution was cooled to 0° C. and sodium hydroxide (1 N, 33 mL) was slowly added followed by 30% hydrogen peroxide (33 mL). The resulting mixture was stirred at rt for an additional 5 h and diluted with ethyl acetate (70 mL). The aqueous layer was separated and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated via rotary evaporator. Silica gel chromatography (1:1 ethyl acetate:hexanes) provided 0.25 g of cis-(3-hydroxycyclopentyl)carbamic acid tert-butyl ester (racemic) followed by 1.07 g of the trans isomer. A solution of cis-(3-hydroxycyclopentyl)-carbamic acid tert-butyl ester (201 mg) in dimethylformamide (3 mL) was treated with sodium hydride (60% in mineral oil, 95 mg) at 0° C. After gas evolution had ceased, the mixture was stirred for 30 min at rt. Iodoethane (88 μL) was added to the mixture and the reaction was stirred at rt for 16 h. The excess sodium hydride was destroyed at 0° C. by the careful addition of aqueous ammonium chloride. The resulting mixture was partitioned between ethyl acetate and ammonium chloride and the organic layer was separated and washed with brine. The organic layer was dried over Na2SO4 and concentrated via rotary evaporator. Silica gel chromatography (1:4 ethyl acetate:hexanes) provided cis-(3-ethoxycyclopentyl)carbamic acid tert-butyl ester (racemic) (102 mg). Cis-(3-ethoxycyclopentyl)carbamic acid tert-butyl ester was stirred in 1:1 trifluoroacetic acid:dichloromethane for 0.5 h. The solvent was removed by evaporation to provide cis-3-ethoxycyclopentylamine (racemic).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][CH2:17][C:18]([N:20]1[CH2:58][CH2:57][CH2:56][C@H:21]1[C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:46]([N:48]1[CH2:55][CH2:54][CH2:53][C@H:49]1[C:50]([NH2:52])=[O:51])=[O:47])[C@@H:39]([CH3:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:23])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]>CO.[Pd]>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][CH2:17][C:18]([N:20]1[CH2:58][CH2:57][CH2:56][C@H:21]1[C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:46]([N:48]1[CH2:55][CH2:54][CH2:53][C@H:49]1[C:50]([NH2:52])=[O:51])=[O:47])[C@@H:39]([CH3:45])[O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:23])=[O:19])=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(N)=O
Agent: [Pd]
Solvent: CO
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CN)C(=O)N1CCC[C@H]1C(N)=O

Procedure:
3.95 g of Z-Gly-Phe-Gly-Pro-Glu(OtBu)-Thr(tBu)-Pro-NH2 are dissolved in 80 ml of methanol and the solution is hydrogenated in the presence of 600 mg of palladium charcoal (10 % Pd). After completion of the hydrogenation the catalyst is filtered off, the filtrate is evaporated to a volume of 10 ml, 20 ml of benzene are added, the mixture again concentrated to 10 ml, and the product precipitated with 70 ml of petroleum ether. The smeary precipitate is triturated to give a powder, filtered and dried; yield 3.3 g. On thin layer chromatography on silica gel plates Rf43C = 0.27; Rf52 = 0.24; Rf in chloroform-methanol (8:2) = 0.10.
Reaction SMILES: CO.[OH-].[K+].[CH3:5][C@@:6]12[C:22](=[O:23])[CH2:21][CH2:20][C@H:19]1[C@H:18]1[C@@H:9]([C:10]3[CH:11]=[CH:12][C:13]([OH:24])=[CH:14][C:15]=3[CH2:16][CH2:17]1)[CH2:8][CH2:7]2.S(OC)(O[CH3:29])(=O)=O>O>[CH3:29][O:24][CH3:13].[CH3:5][C@@:6]12[C:22](=[O:23])[CH2:21][CH2:20][C@H:19]1[C@H:18]1[C@@H:9]([C:10]3[CH:11]=[CH:12][C:13]([OH:24])=[CH:14][C:15]=3[CH2:16][CH2:17]1)[CH2:8][CH2:7]2
Reactant: COS(=O)(=O)OC
Agent: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC
Reaction time: 2 h

Procedure:
Into a mixture of 20 ml of methanol and 16 ml of 30% aqueous solution of potassium hydroxide, 1.0 g of estrone was dissolved and the mixture was cooled in an ice bath and stirred while 4 ml of dimethyl sulfate was added. Stirring was continued for 2 hours. Water was added to the reaction mixture and the crystals which precipitated during the addition of water were filtered, washed with water and dried to obtain 0.341 g of the 96.3% purity methyl ether of estrone in a 34.2% yield.