Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][CH2:6][CH:7]([OH:22])[CH2:8][O:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17](=[NH:20])[NH:18][OH:19])=[CH:12][C:11]=1[CH3:21])=[O:4].[CH:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=O)=[CH:27][CH:26]=1)=[O:24].C(C1C=C(C2ON=C(C3C=C(C)C(OCC(O)CNC(=O)CO)=C(C)C=3)N=2)C=CC=1)=O>>[CH:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29]2[O:19][N:18]=[C:17]([C:13]3[CH:14]=[C:15]([CH3:16])[C:10]([O:9][CH2:8][CH:7]([OH:22])[CH2:6][NH:5][C:3](=[O:4])[CH2:2][OH:1])=[C:11]([CH3:21])[CH:12]=3)[N:20]=2)=[CH:27][CH:26]=1)=[O:24]
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC(O)CNC(=O)CO
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cc1cc(-c2noc(-c3cccc(C=O)c3)n2)cc(C)c1OCC(O)CNC(=O)CO
Product: Cc1cc(-c2noc(-c3ccc(C=O)cc3)n2)cc(C)c1OCC(O)CNC(=O)CO

Procedure:
The title compound was prepared from rac-2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide and 4-formyl-benzoic acid in analogy to (rac)-N-(3-{4-[5-(3-formyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide. LC-MS: tR=0.88 min; [M+1]+=426.36.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(OCC)C.[OH:16][S:17](O)(=[O:19])=[O:18].O=S(=O)=O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([S:17]([OH:19])(=[O:18])=[O:16])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=S(=O)(O)O
Reactant: Nc1ccccc1C(=O)O
Agent: O=S(=O)=O
Solvent: CCOCC
Product: Nc1ccc(S(=O)(=O)O)cc1C(=O)O
Yield: 57 %

Procedure:
A solution of 2-aminobenzoic acid (2g, 15 mM) in oleum (30 ml) was heated at 80°, under argon atmosphere for 2 hours. The mixture was poured into diethyl ether (400 ml) and the resulting precipitate was filtered, washed with diethyl ether and dried under vacuum to give 2-amino-5-sulphobenzoic acid (1.8 g, 57%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[N:11]([CH2:22][C:23](O)=[O:24])[C:10](=[O:26])[C@@H:9]1[CH2:27][CH:28]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=O)(C)(C)C.[NH2:35][C:36]1[CH:37]=[C:38]2[C:51](=[CH:52][CH:53]=1)[CH2:50][C@:40]1([C:48]3[C:43](=[N:44][CH:45]=[CH:46][CH:47]=3)[NH:42][C:41]1=[O:49])[CH2:39]2.Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH:28]1([CH2:27][C@@H:9]2[NH:8][CH2:13][CH:12]([C:14]3[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([F:20])[CH:19]=3)[N:11]([CH2:22][C:23]([NH:35][C:36]3[CH:37]=[C:38]4[C:51](=[CH:52][CH:53]=3)[CH2:50][C@:40]3([C:48]5[C:43](=[N:44][CH:45]=[CH:46][CH:47]=5)[NH:42][C:41]3=[O:49])[CH2:39]4)=[O:24])[C:10]2=[O:26])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)[C@@H]1CC1CCCCCC1
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)[C@H](CC2CCCCCC2)NCC1c1cc(F)cc(F)c1)Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
100 mg (0.21 mmol) 2-((3S)-4-(tert-butoxycarbonyl)-3-(cycloheptylmethyl)-6-(3,5-difluorophenyl)-2-oxopiperazin-1-yl)ethanoic acid, 58 mg (0.23 mmol) (R)-5-amino-1,3-dihydrospiro[inden-2,3′-pyrrol[2,3-b]pyridin]-2′(1′H)-one, 56 mg (0.29 mmol) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-hydrochloride, 39 mg (0.29 mmol) HOBT, 0.03 ml (0.23 mmol) TEA and 1.50 ml DMF were stirred overnight at RT. The mixture was concentrated by rotary evaporation. The residue was combined with 15 ml of a 1.25M methanolic hydrochloric acid and stirred for 2 h at 50° C. The diastereomers were separated by RP-HPLC. The fractions containing the product were lyophilised.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C@H:19]([N:26]=[C:27]=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C@@H:19]([NH:26][C:27](=[O:28])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)[CH3:18])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@H](N=C=O)c1ccccc1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Product: C[C@H](NC(=O)Oc1ccc2c(c1)CCN2Cc1ccccc1)c1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (35.0 mg, 0.155 mmol) using the same procedure employed for Example 2 (2), but with (S)-α-methylbenzylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (14.8 mg, 27%) having the following characteristics.
Reaction SMILES: [CH3:1][C:2]([CH3:39])([C:6](=[O:38])[C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[N:14]=2)[N:9]([Si](C(C)C)(C(C)C)C(C)C)[CH:8]=1)[CH2:3][C:4]#[N:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]([CH3:39])([C:6](=[O:38])[C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=3)[N:14]=2)[NH:9][CH:8]=1)[CH2:3][C:4]#[N:5]
Reactant: COc1cc(-c2cnc3c(n2)c(C(=O)C(C)(C)CC#N)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C(C)(C)CC#N)c3n2)cc(OC)c1OC
Yield: 8.9 %

Procedure:
A solution of 3,3-dimethyl-4-oxo-4-[5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-butyronitrile (0.093 g, 0.17 mmol) and 0.3 mL of trifluoroacetic acid in 2 mL of dichloromethane was stirred for 15 h, then concentrated. The resulting residue was redissolved in dichloromethane and washed with a sat. aq. NaHCO3 solution, dried over MgSO4, filtered and concentrated to a residue. Column chromatography (0->100% EtOAc/hexanes) afforded 0.006 g (9%) of 3,3-dimethyl-4-oxo-4-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-butyronitrile as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[C:10]([NH:17][CH2:18][CH2:19][CH2:20]O)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:13]([O:12][C:10](=[O:11])[NH:17][CH2:18][CH2:19][CH2:20][O:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1])([CH3:16])([CH3:15])[CH3:14]
Reactant: Oc1cc(F)ccc1F
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCOc1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The solution of 2.50 g of 2,5-difluorophenol, 3-(Boc-amino)-1-propanol, 7.26 g of triphenylphosphine and tetrahydrofuran (30 ml) is cooled to 0° C. and admixed dropwise with 5.65 ml of diisopropyl azodicarboxylate. The reaction mixture is stirred at room temperature for a further 2 hours and subsequently concentrated by evaporation. The title compound is obtained as a yellowish solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.34 (1:2 EtOAc-heptane); Rt=4.69.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1.[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O>C1COCC1>[C:16]([O:15][C:13]([NH:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:6]=1)=[O:12])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COCOc1cccc(N)c1
Solvent: C1CCOC1
Product: COCOc1cccc(NC(=O)OC(C)(C)C)c1
Temperature: 65 °C
Yield: 99.9 %

Procedure:
A solution of crude 12 (4.13 g, 27 mmol) in 135 mL anhydrous THF was treated with BOC2O (12.14 g, 54 mmol) and the reaction mixture was warmed at reflux (65° C.) for 18 h. The solvents were removed under reduced pressure, and flash chromatography (SiO2, 4×15 cm, 20% EtOAc/hexane) provided pure 13 (6.83 g, 100%) as a yellow oil: 1H NM (CDCl3, 250 MHz) δ 7.15 (m, 2H), 6.94 (m, 1H), 6.68 (m, 1H), 6.58 (br s, 1H), 5.13 (s, 2H), 3.44 (s, 3H), 1.50 (s, 9H); 13C NMR (CDCl3, 62.5 MHz) δ 157.7, 152.5, 139.5, 129.6, 111.9, 110.7, 106.6, 94.2, 80.5, 55.9, 28.2; IR (film) νmax 3337, 2977, 1728, 1605, 1537, 1236, 1153, 1015 cm−1; FABHRMS (NBA/NaI) m/z 276.1203 (C13H19NO4+Na+ requires 276.1212)
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([C:63]1[CH:91]=[CH:90][C:66]([CH2:67][O:68][C:69]([NH:71][CH2:72][CH2:73][CH2:74][C@H:75]([NH:82][C:83]([O:85][C:86]([CH3:89])([CH3:88])[CH3:87])=[O:84])[C:76](OCC#N)=[O:77])=[O:70])=[CH:65][CH:64]=1)=[N+:61]=[N-:62]>C(#N)C>[N:60]([C:63]1[CH:91]=[CH:90][C:66]([CH2:67][O:68][C:69]([NH:71][CH2:72][CH2:73][CH2:74][C@@H:75]([NH:82][C:83]([O:85][C:86]([CH3:87])([CH3:89])[CH3:88])=[O:84])[C:76]([O:40][C@H:39]2[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36][C@H:35]2[CH2:34][O:33][P:30]([O:29][C@H:28]2[CH2:27][C@H:26]([N:52]3[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]3=[O:59])[O:25][C@@H:24]2[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:77])=[O:70])=[CH:65][CH:64]=1)=[N+:61]=[N-:62]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 23.8 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (143 mg, 0.224 mmol) and (S)-cyanomethyl 5-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk58) (400 mg, 0.896 mmol) in acetonitrile (1 mL) was added to buffer A (33 mL), and the mixture was stirred at room temperature for 1.5 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk59) (54.7 mg, 24%).
Reaction SMILES: [O-:1][Si:2]([O-:4])=[O:3].[Na+:5].[Na+].[OH2:7]>>[Si:2]([O-:7])([O-:4])([O-:1])[O-:3].[Na+:5].[Na+:5].[Na+:5].[Na+:5]
Reactant: O=[Si]([O-])[O-]
Reactant: O
Agent: [Na+]
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
A reaction mixture having the molar composition 0.303 Na2O:0.0052 Al2O3 :SiO2 :XH2O is first prepared by adding 83.5 parts by weight of soda waterglass (27% of SiO2, 8.43% of Na2O and 0.24% of Al2O3 to 149 parts of water. Thereafter, some of a filter-moist crystalline sodium silicate from a previous experiment (71% weight loss as a result of heating to 1,200° C.; only the amount of water was taken into account in calculating the molar composition) is added. 4.93 parts of 96% strength sulfuric acid are then added slowly, while stirring. The reaction mixture then has the following molar composition: 0.174 Na2O:0.0052 Al2O3 :SiO2 :0.129 Na2SO4 :30 H2O.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([S:28][CH:29]5[CH2:31][CH2:30]5)=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CN(C)C(N(C)C)=N.[F:40][C:41]([F:48])([F:47])[C:42](OCC)=[O:43]>CO>[CH:29]1([S:28][C:25]2[CH:24]=[CH:23][C:22]([C@@H:18]([O:17][C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[CH:10]4)[C@@H:19]([NH:21][C:42](=[O:43])[C:41]([F:48])([F:47])[F:40])[CH3:20])=[CH:27][CH:26]=2)[CH2:31][CH2:30]1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(SC2CC2)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: CN(C)C(=N)N(C)C
Solvent: CO
Product: C[C@H](NC(=O)C(F)(F)F)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(SC2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1R,2S)-1-{[1-(4-Fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(cyclopropylthio)phenyl]propan-2-amine (62 mg, 0.14 mmol) was dissolved in MeOH (2 mL), 1,1,3,3-tetramethylguanidine (100 μL, 0.8 mmol) and ethyl trifluoroacetate (83 μL, 0.7 mmol) was added. The mixture was stirred at r.t. for 2 h, the solvents was removed by evaporation and the residual material was treated with water and a few drops of dilute HCl(aq) until slightly acidic. The formed slurry was extracted with DCM and EtOAc, the combined organic phases was concentrated and purified by semi-preparative HPLC using a Kromasil® C18 250×20 mm, 5 μm column. Flow 10 mL/min, 15 min gradient of 50%-90% MeCN in water followed by isocratic final concentration until product had eluted. UV=254 nm was used for detection. Fractions with product was combined and lyophilized to afford the title compound as a colourless solid.
Reaction SMILES: [CH2:1]([C:9]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:23])=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([C:9]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([Cl:23])=[O:17])=[CH:14][CH:13]=1)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCC(=O)Oc1ccc(C(=O)Cl)cc1

Procedure:
2.5 g of 4-octylcarbonyloxybenzoic acid was dispersed in 50 ml carbon tetrachloride, after dropping 10 ml of thionyl chloride to this solution, refluxed for three hours. After reducing the solvent, 4-octylcarbonyloxybenzoic chloride (CK) was obtained.
Reaction SMILES: O=[C:2]([C:6]1([C:9]([F:12])([F:11])[F:10])[CH2:8][CH2:7]1)[CH2:3][C:4]#[N:5].Cl.[C:14]1([NH:20][NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO.O>[C:14]1([N:20]2[C:4]([NH2:5])=[CH:3][C:2]([C:6]3([C:9]([F:10])([F:11])[F:12])[CH2:8][CH2:7]3)=[N:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNc1ccccc1
Reactant: N#CCC(=O)C1(C(F)(F)F)CC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(C2(C(F)(F)F)CC2)nn1-c1ccccc1
Temperature: 90 °C
Yield: 43.1 %

Procedure:
To 3-oxo-3-(1-(trifluoromethyl)cyclopropyl)propanenitrile (230 mg, 1.3 mmol) in EtOH (5 mL, 200 proof) was added H2O (3.7 mL), 1NaOH(aq) (1.3 mL), and phenylhydrazine hydrochloride (188 mg, 1.3 mmol) and the mixture heated at 90° C. overnight. After cooling to room temperature, the mixture was diluted with H2O, extracted with EtOAc, the org layer concentrated in vacuo, and purified by column chromatography (5-25% EtOAc/hexanes) to give 1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine (150 mg, 0.56 mmol, 43%). LC-MS (ESI) m/z 268 (M+H)+.
Reaction SMILES: O.[N+:2]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]=1[OH:18])([O-])=O>[Pd].CO>[NH2:2][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]=1[OH:18]
Reactant: O=[N+]([O-])c1cc(Oc2ccccc2)ccc1O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: Nc1cc(Oc2ccccc2)ccc1O
Reaction time: 8 h

Procedure:
10% Palladium on carbon, 50% water wet (1.43 g, 1.34 mmol) and 2-nitro-4-phenoxyphenol (3.10 g, 13.4 mmol) were combined under nitrogen and 30 mL MeOH was added. The mixture was exposed to H2 from a balloon and was stirred rapidly overnight. In the morning the reaction was flushed with nitrogen and filtered and concentrated in vacuo to give 2-amino-4-phenoxyphenol as a light brown solid. MS (ESI) m/z: Calculated: 201.1; Observed: 202.1 (M++1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:30])=[CH:24][CH:23]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)C(Cc1ccc(OC)c(CO)c1)C(=O)OC
Product: COC(=O)C(Cc1ccc(OC)c(COC(=O)Nc2ccc(Cl)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)-4-methoxybenzyl]malonate and 4-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)=[O:2].[CH3:12][C:13]1[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=1.N1C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:12][C:13]1[CH:17]=[C:16]([CH3:18])[N:15]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:1]=[O:2])[N:14]=1
Reactant: O=Cc1ccccc1B(O)O
Reactant: Cc1cc(C)[nH]n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C)n(-c2ccccc2C=O)n1
Reaction time: 96 h
Yield: 15 %

Procedure:
To a solution of 2-formylphenylboronic acid (500 mg, 3.33 mmol) in CH2Cl2 (30 mL) are added 3,5-dimethyl-1H-pyrazole (160 mg, 1.67 mmol), Cu(OAc)2 (909 mg, 5.0 mmol), pyridine (528 mg, 6.67 mmol) and molecular sieves (1.0 g) at room temperature. The mixture is stirred at the same temperature for 4 days with loose cap. The mixture is filtered through a short pad of diatomaceous earth and the solids are washed with CH2Cl2. The combined filtrates are concentrated and purified via flash chromatography (12 g silica gel, CH2Cl2 then 20% EtOAc/heptane) to afford 2-(3,5-dimethyl-pyrazol-1-yl)-benzaldehyde (50 mg, 8%).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)[N:3]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CN1C(=O)CCC1.C(Cl)Cl>[N:20]1([C:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:4]3[N:3]=[C:2]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:10]=[CH:9][C:5]=3[C:6]([NH2:8])=[O:7])=[CH:13][CH:14]=2)=[O:19])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: NC(=O)c1ccc(Cl)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: C1CNCCN1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: NC(=O)c1ccc(N2CCNCC2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Yield: 63.3 %

Procedure:
A solution of 6-chloro-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (100 mg, 0.277 mmol) and piperazine (477 mg, 5.54 mmol) in NMP (2 mL) was heated to 120° C. overnight. The reaction mixture was diluted with CH2Cl2, washed with satd NaHCO3, separated, and concentrated. The residue was purified by MPLC chromatography (ISCO, 8% NH4OH/MeOH/CH2Cl2, 40 g silica gel column) to give 72 mg of 2-(4-(morpholine-4-carbonyl)phenylamino)-6-(piperazin-1-yl)nicotinamide as a white solid. LCMS: (M+H)+=411.35. 1H NMR (400 MHz, CDCl3) δ ppm 11.20 (1H, s), 7.70 (2H, d, J=8.56 Hz), 7.54 (1H, d, J=9.06 Hz), 7.38 (2H, d, J=8.56 Hz), 6.04 (1H, d, J=8.81 Hz), 5.58 (2H, s), 3.58-3.78 (12H, m), 2.92-3.01 (4H, m).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl[CH:22]([F:24])[F:23]>[OH-].[Na+].O1CCOCC1.O>[F:23][CH:22]([F:24])[S:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1cnc2ccc(S)cc2c1-c1ccccc1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnc2ccc(SC(F)F)cc2c1-c1ccccc1

Procedure:
6-Mercapto-3-nitro-4-phenylquinoline (1.00 g) was dissolved in a mixture of 2N-sodium hydroxide (20 ml) and dioxane (20 ml), and into the solution was introduced chlorodifluoromethane gas for 2 hrs. at 75°-80° C. The reaction mixture was diluted with water and extracted with chloroform. The extract was washed with aqueous 2N-sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and distilled to remove the solvent. The residue was recrystallized from isopropyl ether to give 6-difluoromethylthio-3-nitro-4-phenylquinoline as yellow prisms. Yield 948 mg (80.5%). m.p. 101°-103° C.
Reaction SMILES: [C:1]([C@:3]1([OH:24])[CH:9]=[CH:8][C@H:7]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH2:5][CH3:6])[C@@H:18]1[C:13](=[CH:14][C:15](=[O:23])[CH2:16][C@@H:17]1[OH:22])[CH2:12][CH2:11]3)#[CH:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([O:22][C@@H:17]1[C@H:18]2[C:13]([CH2:12][CH2:11][C@@H:10]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH2:5][CH3:6])[C@H:7]3[CH:8]=[CH:9][C@:3]2([C:1]#[CH:2])[OH:24])=[CH:14][C:15](=[O:23])[CH2:16]1)(=[O:27])[CH3:26]
Reactant: C#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC(=O)C[C@H](O)[C@@H]4[C@H]3CC[C@@]21CC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC(=O)C[C@H](OC(C)=O)[C@@H]4[C@H]3CC[C@@]21CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg of 17α-ethynyl-1α,17-dihydroxy-18-methyl-4,15-estradien-3-one is dissolved in 10 ml of pyridine and combined under ice-cooling dropwise with 3 m of acetic anhydride. The solution is then allowed to warm up and agitated at room temperature overnight. Thereafter the reaction mixture is stirred into ice water, the precipitated, oily-crystalline product is vacuum-filtered, taken up in ethyl acetate, washed neutral, dried over Na2SO4, and concentrated to dryness under vacuum. The remaining residue is crystallized from ether/hexane, thus obtaining 165 mg of 1α-acetoxy-17α-ethynyl-17-hydroxy-18-methyl-4,15-estradien-3-one, mp 123°-126° C.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]=[O:13].C(N(CC)CC)C.[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[CH3:8][N:7]1[C:2]([N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)=[C:3]([CH:12]=[O:13])[C:4](=[O:11])[N:5]([CH3:10])[C:6]1=[O:9]
Reactant: Cn1c(Cl)c(C=O)c(=O)n(C)c1=O
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(N2CCN(c3ccccc3)CC2)c(C=O)c(=O)n(C)c1=O
Temperature: 25 °C

Procedure:
To an ice-cooled, stirred solution of 6-chloro-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (0.600 g, 2.96 mmol) and triethyl-amine (0.45 ml, 3.26 mmol) in dichloromethane (20 ml), a solution of N-phenylpiperazine (0.49 ml, 3.26 mmol) in dichloromethane (10 ml) was added dropwise. The resulting suspension was stirred at room temperature until the starting material was consumed (3.5 h, monitored by TLC). Then the reaction mixture was washed with water (3×10 ml), and the organic phase was dried over 20, anhydrous MgSO4. The solvent was evaporated in vacuo, and the brown oily crude product was purified by column chromatography with a mixture of dichloromethane:ethyl acetate (1:1) as the eluent and crystallized from ethanol.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]([OH:35])=[N:33][CH:34]=2)O1>>[OH:35][C:32]1[N:33]=[CH:34][C:29]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:30][CH:31]=1
Reactant: CC1(C)OB(c2ccc(O)nc2)OC1(C)C
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(O)nc3)ccn2c1=O

Procedure:
Methyl 8-(6-hydroxypyridin-3-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol (90.8 mg, 0.41 mmol). The precipitate was rinsed with DCM and dried in a vacuum stove to afford quantitatively the title compound as a yellow solid.