Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:5]1[S:25][C@H:24]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.[NH:35]1[CH:42]=[CH:41][C:39]([NH2:40])=[N:38][C:36]1=[O:37].C(#N)C.C[Si](C)(C)N[Si](C)(C)C.Cl[Si](C)(C)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>>[CH2:8]([O:7][C@H:6]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:24]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:25][CH:5]1[N:35]1[CH:42]=[CH:41][C:39]([NH2:40])=[N:38][C:36]1=[O:37])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)OC1S[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: Nc1cc[nH]c(=O)n1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: Nc1ccn(C2S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)c(=O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1-O-acetyl 2,3,5-tri-O-benzyl-4-thio-D-arabinofuranose (478 mg, 1 mmol) and cytosine (111.0 mg, 1 mmol) in anhydrosis acetonitrile (25 mmol) were added consecutively hexamethyldisilazane (HMDS, 162 mg, 1 mmol) and chlorotrimethylsilane (TMSCl, 434 mg, 4 mmol), and the mixture was stirred at room temperature for 0.5 hours. This solution was cooled to −78° C. Trimethylsilyltrifluoromethane sulfonate (267 mg, 1.2 mmol) was added and the resulting solution was stirred at −78° C. for another 2.5 h, after which time the reaction was essentially complete. The mixture was warmed to room temperature, concentrated to a small volume (5 mL), diluted with methylene chloride (50 mL) and then washed with water (20 mL) followed by saturated sodium bicarbonate and water. The organic layer was dried over MgSO4 and evaporated to dryness. The residue was purified by chromatography over silica gel (50 g. elution with CHCl3/MEOH 98:2) to afford 7 (412 mg 77.5%) as a colorless syrup TLC (95:5 CHCl3/MEOH)Rf 0.65; MS z/e 536 (M+Li)+.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1([CH3:19])[C@H:10](/[CH:11]=[CH:12]/[C:13](=[O:15])[CH3:14])[C@H:9]1[C:16](Cl)=[O:17].[CH2:20]([OH:22])[CH3:21].Cl>C1C=CC=CC=1>[CH3:7][C:8]1([CH3:19])[C@H:10](/[CH:11]=[CH:12]/[C:13](=[O:15])[CH3:14])[C@H:9]1[C:16]([O:22][CH2:20][CH3:21])=[O:17]
Reactant: CC(=O)/C=C/[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Reactant: CCO
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCOC(=O)[C@@H]1[C@@H](/C=C/C(C)=O)C1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2 ml of pyridine, 2.9 g of (1R,trans) 2,2-dimethyl-3-[(E)-3-oxo-1-butenyl]-cyclopropane-1-carboxylic acid chloride, 1 ml of ethanol and 25 ml of benzene was stirred at 0° to 5° C. for 20 minutes and at room temperature for 2 hours and was then poured into iced aqueous N/6 hydrochloric acid solution. The mixture was extracted with ether and the organic phase was washed with water, dried and evaporated to dryness at 40° C. under reduced pressure. The 4.19 g of oil residue were chromatographed over silica gel and eluted with a 7-3 cyclohexane-ethyl acetate mixture to obtain 1.43 g of ethyl (1R,trans) 2,2-dimethyl-3-[(E)-3-oxo-1-butenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+82°±3° (c=0.5% in benzene).
Reaction SMILES: [NH2:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([C:9]([CH2:19][PH:20]([OH:22])=[O:21])([S:13][C:14]3[NH:18][N:17]=[N:16][N:15]=3)[O:10][CH2:11][CH3:12])[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[F:35][C:36]([F:45])([F:44])[CH2:37][S:38]([CH2:40][C:41](O)=[O:42])=[O:39]>CN(C)C=O>[F:35][C:36]([F:45])([F:44])[CH2:37][S:38]([CH2:40][C:41]([NH:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([C:9]([CH2:19][PH:20]([OH:22])=[O:21])([S:13][C:14]3[NH:18][N:17]=[N:16][N:15]=3)[O:10][CH2:11][CH3:12])[CH2:7][S:8][C@H:3]12)=[O:42])=[O:39]
Reactant: O=C(O)CS(=O)CC(F)(F)F
Reactant: CCOC(C[PH](=O)O)(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(C[PH](=O)O)(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CS(=O)CC(F)(F)F)[C@H]2SC1
Reaction time: 0.25 h

Procedure:
A suspension of 4.36 g (0.01 mol) of 7β-amino-3-(1-ethoxyhydroxyphosphinylmethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid in 50 ml of dry dimethylformamide is treated with 4 ml of triethylamine and the mixture is stirred for 15 minutes at 25°. A slight excess of 0.01 mol of the activated ester of 2,2,2-trifluoroethylsulfinylacetic acid is added to the mixture and it is stirred an additional hour. The reaction mixture is evaporated to dryness and water and ethyl acetate are added to the residue. The layers are separated, the ethyl acetate layer is discarded, fresh ethyl acetate is added to the aqueous phase and it is acidified to pH 2.5 by addition of 6N hydrochloric acid. The mixture is filtered, the layers are separated and the aqueous phase is treated with Amberlite IR-120H ion-exchange resin and lyophilized to give the title compound.
Reaction SMILES: I[CH3:2].[CH3:3][S:4](=S)(OC)=O.Br[C:10]1[N:11]([CH3:28])[N:12]=[C:13]2[C:18]=1[CH2:17][CH2:16][CH2:15][N:14]2[C:19]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=1Cl>>[CH3:28][N:11]1[C:10]([S:4][CH3:3])=[C:18]2[C:13]([N:14]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:2])[CH2:15][CH2:16][CH2:17]2)=[N:12]1
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3Br)c(Cl)c1
Reactant: COS(C)(=O)=S
Reactant: CI
Product: CSc1c2c(nn1C)N(c1c(C)cc(C)cc1C)CCC2
Yield: 48 %

Procedure:
2-Methyl-3-methylsulfanyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine (2-20) was prepared according to Example 5 except iodomethane was replaced with methyl methanethiosulfonate (A. I. Meyers and M. A. Sturgess, Tetrahedron Lett. 1988 29:5339) as the electrophile and compound 1-1 was replaced with compound 1-3 to afford 2-20 as a white solid (48% theory; mp=90.3-91.7° C.).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([NH:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)[CH2:8][CH3:9].[Cl:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[F:27].Cl>CN1C(=O)CCC1.CCCCCCC.O>[ClH:20].[F:27][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:21]=1[N:10]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCNn1ccc2ccccc21
Reactant: Fc1cnccc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCCCCCC
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCN(c1ccncc1F)n1ccc2ccccc21
Temperature: 20 °C

Procedure:
Prepare a solution of 18.0 g potassium tert-butoxide in 53 mL NMP and stir the suspension at 20° C. until a clear solution is obtained. Cool the solution to −20° C. Add to the cooled solution a mixture of 9.3 g (53.4 mmol) N-propyl-1H-indol-1-amine, 7.4 g (53.4 mmol) 4-chloro-3-fluoropyridine and 53 mL NMP while maintaining the internal reaction temperature around −15° C. After the addition is over, the reaction mixture is stirred for ˜30 min at −20° C. The reaction mixture is then added to 100 mL water and 13 mL HCl (37%). Then, add 50 mL n-heptane (2×) and separate the phases. Add to the water phase 10 mL NaOH (32%) and extract the water phase twice with 50 mL n-butyl acetate, wash the combined n-butyl acetate phase with 50 mL water. Add to the resulting n-butyl acetate phase 4.5 mL HCl (37%). Distill the mixture using Dean-Stark trap to remove completely the water. During the distillation a solid precipitates. The suspension is cooled to 5° C. and filtered. After drying at 60–70° C., there remains 10.8 g (3-fluoro-pyridin-4-yl)-(indol-1-yl)-propylamine hydrochloride (75%) as a slightly yellow solid.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[CH2:5]([O:7][P:8]([CH:13]([F:19])[C:14](OCC)=[O:15])([O:10][CH2:11][CH3:12])=[O:9])[CH3:6]>CCO.CCO.CCO.CCO.[Ti]>[CH2:5]([O:7][P:8]([CH:13]([F:19])[C:14]([O:4][CH2:1][C:2]#[CH:3])=[O:15])([O:10][CH2:11][CH3:12])=[O:9])[CH3:6]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: C#CCO
Agent: [Ti]
Solvent: CCO
Product: C#CCOC(=O)C(F)P(=O)(OCC)OCC
Temperature: 100 °C
Reaction time: 10 h
Yield: 86 %

Procedure:
45.31 g (826 mmol) of propargyl alcohol and 0.94 g (4.1 mmol of tetraethyl titanate were added to 10.00 g (41.3 mmol) of ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate, and heated under reflux at 100° C. for 10 hours. Subsequently, ethanol and propargyl alcohol were evaporated away under reduced pressure at a temperature falling within a range of from 70° C. to 100° C., taking 10 hours, and then the residue was cooled down to room temperature. 0.18 g of water was added to the reaction liquid, the formed precipitate was filtered away, and the filtrate was purified through silica gel column chromatography (ethyl acetate/hexane=1/1 for elution) to give 8.96 g (yield 86%) of the intended 2-propynyl 2-(diethoxyphosphoryl)-2-fluoroacetate. The obtained 2-propynyl 2-(diethoxyphosphoryl)-2-fluoroacetate was analyzed through 1H-NMR to confirm the structure thereof. The results are shown below.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=[O:7].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[F:14][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28]([CH:30]4[CH2:31][CH2:32]4)=[O:29])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(CCCCCl)c1cccc(F)c1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: O=C(CCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1cccc(F)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(3-fluorophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 423.2 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[O:11][C:12]([CH3:36])=[C:13]([CH2:15][N:16]3[C:24]4[C:19](=[CH:20][C:21]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:22][CH:23]=4)[CH2:18][CH:17]3[CH3:35])[N:14]=2)[CH:5]=1.CC1OC(C2C=C(C=CC=2)C(O)=O)N(CN2C3C(=CC(C(O)(C(F)(F)F)C(F)(F)F)=CC=3)C=C2C)C=1>>[CH3:36][C:12]1[O:11][C:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:37])=[O:2])=[N:14][C:13]=1[CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:27])([F:28])[F:29])=[CH:22][CH:23]=2)[CH:18]=[C:17]1[CH3:35]
Reactant: COC(=O)c1cccc(-c2nc(CN3c4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4CC3C)c(C)o2)c1
Agent: CC1=CN(Cn2c(C)cc3cc(C(O)(C(F)(F)F)C(F)(F)F)ccc32)C(c2cccc(C(=O)O)c2)O1
Product: Cc1oc(-c2cccc(C(=O)O)c2)nc1Cn1c(C)cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21

Procedure:
In analogy to example 91, from 3-{5-methyl-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-2,3-dihydro-indol-1-ylmethyl]-oxazol-2-yl}-benzoic acid methyl ester (example 120) was prepared 3-{5-methyl-3-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-oxazol-2-yl}-benzoic acid, brown solid, MS: 513 (MH+).
Reaction SMILES: [CH:1]1[C:17]2[C:16]([C:18]([O:20][CH3:21])=[O:19])=[C:15]3[C:7](=[C:8]4[C:13](=[N:14]3)[CH:12]=[CH:11][CH:10]=[CH:9]4)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:22][I:23]>>[IH:23].[CH3:22][NH+:6]1[C:7]2[C:15]([N:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[CH:12]3)=[C:16]([C:18]([O:20][CH3:21])=[O:19])[C:17]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: COC(=O)c1c2nc3ccccc3c-2[nH]c2ccccc12
Reactant: CI
Product: COC(=O)C1=C2N=c3ccccc3=C2[NH+](C)c2ccccc21
Product: I
Yield: 24.7 %

Procedure:
A solution of methyl quindoline-11-carboxylate (0.16 g, 0.58 mmol) from Example 15 in methyl iodide (3 mL, 30.2 mmol) was stirred at rt for 48 hours. The excess of CH3I was removed in vacuo and the residue was washed thoroughly with diethyl ether to afford the 0.06 g (25.0%) of the title compound as a red solid, mp 246.5°-247.0° C.; 1H NMR (DMSO-d6) δ 12.70 (s, 1H, NH), 8.92-8.80 (m, 3H), 8.22 (t, J=8.0, 1H), 8.09-7.95 (m, 2H), 7.94 (d, J=8.0, 1H), 7.58 (t, J=7.6, 1H); 13C NMR (DMSO-d6) δ 164.01, 146.47, 141.01, 135.35, 135.14, 132.10, 131.94, 128.40, 126.89, 126.37, 122.88, 122.09, 118.60, 113.86, 113.54, 95.02, 54.20, 41.29; MS (LSIMS, m/z) 291 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:63][O:64][C:65](=[O:83])[C@@H:66]([NH2:82])[CH2:67][C:68]1[CH:73]=[CH:72][C:71]([C:74]2[CH:79]=[CH:78][N:77]=[C:76]([CH3:80])[C:75]=2[CH3:81])=[CH:70][CH:69]=1.CN1CCOCC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:19])[NH:82][C@H:66]([C:65]([O:64][CH3:63])=[O:83])[CH2:67][C:68]2[CH:69]=[CH:70][C:71]([C:74]3[CH:79]=[CH:78][N:77]=[C:76]([CH3:80])[C:75]=3[CH3:81])=[CH:72][CH:73]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccnc(C)c2C)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCC2CCCCC2)cc1)O3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
(3S,8S)-3-(4-Cyclohexylmethoxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (72 mg), EDCl (33 mg), HOBt (24 mg), and (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (59 mg) were suspended in 3 mL DCM and NMM (0.067 mL) added. The mixture was stirred at room temperature for 3 hours and the mixture was directly purified over silica (hexanes to 1:1 hexanes/EtOAc to 1:1 hexanes/EtOAc+1% MeOH) to give (3S,8S)-3-(4-cyclohexylmethoxy-phenyl)-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (86 mg). LCMS: (m/z)791.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[N:11]=2)[C:6](=[O:14])[C:5]([C:15]([OH:17])=O)=[CH:4]1)[CH3:2].[NH2:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[N:11]=2)[C:6](=[O:14])[C:5]([C:15]([NH:18][C:19]2[NH:23][N:22]=[N:21][N:20]=2)=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(C)nc21
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)Nc2nnn[nH]2)c(=O)c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (4.1g) and N,N'-carbonyldiimidazole (2.85g) in dimethylformamide (30 ml) were stirred and heated at 100° for 3 hours and cooled. 5-Amino-1H-tetrazole (3.6 g) was added and the mixture was stirred at room temperature for 16 hours. The solid was collected and dissolved in aqueous dimethylaminoethanol and the solution was acidified to pH2 with dilute hydrochloric acid. The solid was filtered off and dried, m.p. above 289° (d), (60%)
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:16]=[C:17]([C:28]4[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][C:27]=4[CH3:26])[CH:18]=[CH:19][CH:20]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C)c(B(O)O)c1
Reactant: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2)CC1c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C)c(-c2cccc(C3CN(S(=O)(=O)c4ccccc4)C(=O)N3C(C)C)c2)c1

Procedure:
In analogy to example 1, step 3,1-benzenesulfonyl-4-(3-bromo-phenyl)-3-isopropyl-imidazolidin-2-one (example 12, step 1) was reacted with 2,5-dimethylphenylboronic acid in the presence of dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give 1-benzenesulfonyl-4-(2′,5′-dimethyl-biphenyl-3-yl)-3-isopropyl-imidazolidin-2-one as a light yellow oil. MS: 449.2 ([M+H]+)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]([OH:15])[C:13]3[S:16][CH2:17][CH2:18][S:19][C:12]=3[C:11]2=[O:20])=[N:8][CH:9]=1.Cl[C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH3:31])[CH2:26][CH2:25]1)=[O:23]>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:11]([O:20][C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH3:31])[CH2:26][CH2:25]3)=[O:23])[C:12]3[S:19][CH2:18][CH2:17][S:16][C:13]=3[C:14]2=[O:15])=[N:8][CH:9]=1
Reactant: O=C1C2=C(SCCS2)C(O)N1c1ccc(Cl)cn1
Reactant: CCN1CCN(C(=O)Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCN(C(=O)OC2C3=C(SCCS3)C(=O)N2c2ccc(Cl)cn2)CC1
Temperature: 5 °C
Reaction time: 4 h
Yield: 28.8 %

Procedure:
A suspension of sodium hydride (1.11 g.) in anhydrous tetrahydrofuran (120 cc.) is treated for 20 minutes at about 10°-15° C. with 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (11.6 g.), and a solution of 1-chlorocarbonyl-4-ethylpiperazine (20.4 g.) in anhydrous tetrahydrofuran (160 cc.) is then added, at 5° C. The reaction mixture is stirred for 4 hours at 5° C. After evaporating the solvent under reduced pressure (20 mm. Hg), the residue is dissolved in diethyl ether (400 cc.). The ether solution is washed twice with ice-cold normal sodium hydroxide solution (total 300 cc.) and three times with distilled water (total 300 cc.), treated with decolourising charcoal (0.2 g.), dried over anhydrous sodium sulphate, filtered and evaporated. The residue (13.8 g.; m.p. 140° C.) is dissolved in boiling ethanol (25 cc.). After cooling for 3 hours at 2° C, the crystals which have appeared are filtered off, washed twice with ice-cold ethanol (total 20 cc.) and dried under reduced pressure (20 mm. Hg). 6-(5-Chloropyrid-2-yl)-5-(4-ethylpiperazin-1-yl)carbonyloxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (4.9 g.), melting at 163° C, is thus obtained.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[O:22]=[C:6]1[CH2:5][CH2:4][C@@:3]2([CH:2]=[O:1])[C:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=[O:21])=[CH:7]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C=O)[C@@H]1CCC2=O

Procedure:
To a solution of 30 g of 19-hydroxyandrost-4-ene-3,17-dione in 3 liters of acetone cooled in an ice bath is added 28 ml of Jones reagent over a one hour period. The reaction mixture is stirred for an additional fifteen minutes, filtered and the solvent removed under reduced pressure at 35° C. The residue is taken up in a large volume of ether and 1.5 liters of water. The ether layer is collected, dried over magnesium sulfate, filtered and the solvent removed. The residue is crystallized from acetone-hexane to give 3,17-dioxoandrost-4-en-19-al, M.P. 126°-129° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[CH3:29][S:30](O)(=[O:32])=[O:31].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Reactant: CS(=O)(=O)O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CNS(C)(=O)=O)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
A round bottom flask was charged with (5)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3; 0.025 g, 0.065 mmol), methanesulfonic acid loaded TFP resin (0.9 mmol/g loading, 0.065 mmol), DIEA (0.017 g, 0.13 mmol), DMAP (0.09 g, 0.072 mmol), and THF (5 ml). The resulting solution was shaken vigorously at 60° C. for 8 hrs. The reaction was filtered and the resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.016 g, 53%). 1H NMR (400 MHz, CD3OD) δ 7.42-7.39 (m, 2H), 7.14 (d, J=10.7 Hz, 1H), 7.01-6.97 (m, 2H), 5.16-5.09 (m, 1H), 4.15-4.06 (m, 2H), 2.99 (s, 3H), 1.88-1.83 (m, 1H), 1.52 (d, J=6.8 Hz, 3H), 0.95-0.93 (m, 2H), 0.66-0.64 (m, 2H). MS: Calcd.: 462. Found: [M+H]+ 463.
Reaction SMILES: CO.[OH-].[K+].[Br:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[OH:13].[S:14]([O:24][CH2:25][C:26]#[C:27][CH2:28][CH2:29]OS(C1C=CC(C)=CC=1)(=O)=O)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>C(O)(=O)C>[S:14]([O:24][CH2:25][CH2:26][C:27]#[C:28][CH2:29][O:13][C:7]1[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=1[Br:5])([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:15])=[O:16]
Reactant: Cc1ccc(S(=O)(=O)OCC#CCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: Oc1ccc(F)cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)OCCC#CCOc2ccc(F)cc2Br)cc1
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To MeOH (140 mL) solution containing KOH (4.73 g, 84.3 mmol) at 22° C. was added 2-bromo-4-fluorophenol (16.09 g, 84.2 mmol) and 2-pentyne-1,5-diol ditosylate (11.47 g, 28.1 mmol). After stirring 20 h acetic acid (3.5 mL) was added and the reaction stirred 1 h. The reaction was concentrated in vacuo and the residue extracted with CH2Cl2 (75 mL) and saturated K2CO3 (75 mL). The organic phase was separated and washed with saturated K2CO3. The aqueous phase was washed with CH2Cl2 (2×30 mL). The combined CH2 Cl2 layers were dried with dried with MgSO4, filtered, concentrated in vacuo. Silica gel chromatography (9:1 Hexane:EtOAc) yielded the title compound as a viscous oil (8.39 g, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][S:12]2(=[O:17])=[O:16])[CH:3]=1.[CH2:18]([C:20]1[CH:21]=[C:22]([CH3:32])[C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:24][CH:25]=1)[CH3:19]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:29]2[CH2:30][CH2:31][N:26]([C:23]3[C:22]([CH3:32])=[CH:21][C:20]([CH2:18][CH3:19])=[CH:25][N:24]=3)[CH2:27][CH2:28]2)=[O:8])=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][S:12]2(=[O:17])=[O:16])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1N1CCCS1(=O)=O
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 94.1 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 90 and using 4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)benzoic acid (4.80 g) described in Preparation Example 178 and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (3.08 g) described in Preparation Example 53, the title compound (7.16 g) was obtained.