Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29]C)=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[C:37]([CH3:38])=[CH:36][CH:35]=[C:34]([F:39])[C:33]=3[F:40])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=[O:28])([CH3:25])[CH3:26])[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[C:37]([CH3:38])=[CH:36][CH:35]=[C:34]([F:39])[C:33]=3[F:40])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2c(C)ccc(F)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(F)c(F)c1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C
Yield: 9.4 %

Procedure:
A mixture of racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(2,3-difluoro-6-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (110 mg, 0.18 mmol), NaOH (15 mg, 0.375 mmol), H2O (2 mL) and methanol (5 mL) was heated at 80° C. for 2 h. After cooled to room temperature, the solution was acidified to “pH” 1-2 by addition of concentrated aqueous HCl solution. The aqueous phase was extracted with EtOAc. The organic layer was separated, washed with water, dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude product was washed with ether twice to give the title compound as a white solid (10 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:17][O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[Br:28]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([Br:28])[O:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: COC(=O)CCCCCNc1ncnc2occ(-c3ccc(OC)cc3)c12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)CCCCCNc1ncnc2oc(Br)c(-c3ccc(OC)cc3)c12
Temperature: 25 °C

Procedure:
Dissolve 4.1 g (11.1 mmol) 6-{[5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester at room temperature in 150 ml carbon tetrachloride and add 2.2 g (12.2 mmol) N-bromosuccinimide. Stir the mixture under reflux for three hours, then filter after cooling to room temperature and concentrate the filtrate by vacuum evaporation. 4.8 g (96% of theor.) of the title compound is obtained.
Reaction SMILES: [P:1]([O:6]C)([O:4][CH3:5])[O:2][CH3:3].I[CH2:9][C:10]([CH2:12]I)=[CH2:11]>C1C=CC=CC=1>[CH3:3][O:2][P:1]([CH2:9][C:10](=[CH2:11])[CH2:12][P:1]([O:2][CH3:3])([O:4][CH3:5])=[O:6])([O:4][CH3:5])=[O:6]
Reactant: COP(OC)OC
Reactant: C=C(CI)CI
Solvent: c1ccccc1
Product: C=C(CP(=O)(OC)OC)CP(=O)(OC)OC
Yield: 92 %

Procedure:
400 ml of trimethyl phosphite was placed into a 2-1 flask equipped with an addition funnel, a gas inlet tube, and a Vigreux column with distilling head. The phosphite was heated at reflux, then a solution of 131 g (0.425 Mole) of 2-iodomethyl-3-iodopropene [see J. Amer. Chem. Soc., 89, 4688 (1967)] in 200 ml of benzene was added dropwise over a period of 2 h, followed by an additional 100 ml of trimethyl phosphite within 30 min. The reaction was run under nitrogen, and approx. 150 ml of distillate was allowed to collect. Distillation of the reaction mixture afforded 106 g (92%) of the title compound, b.p. 125°-7°/0.08 Torr;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:13]([C:24]3[CH:28]=[CH:27][N:26]([Si](C(C)C)(C(C)C)C(C)C)[CH:25]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:13]([C:24]3[CH:28]=[CH:27][NH:26][CH:25]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)n2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2cc[nH]c2)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.4 %

Procedure:
305 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)-6-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]pyrimidine-2,4-diamine was dissolved in 3 ml of tetrahydrofuran, and 0.86 ml of 1M tetrabutylammoniumfluoride/tetrahydrofuran solution was added under ice water cooling, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was added with water. The solution was subjected to extraction with ethyl acetate. The organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 199 mg of the objective compound as pale brown powder.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)[CH2:4][C@H:3]1[O:18][CH3:19].[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.C(OCC)(=O)C>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[S:12][C:11]([CH3:13])=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=3)[CH2:4][C@H:3]2[O:18][CH3:19])=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)sc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cc(C(=O)OC)c(C)s3)C[C@H]2OC)nc1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
Methyl cis(±)-5-(4-amino-3-methoxypiperidin-1-yl)-2-methylthiophene-3-carboxylate obtained in Example (188d) (20 mg, 0.07 mmol) and 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (15 mg, 0.07 mmol) were dissolved in DMA (2 ml). WSC hydrochloride (40 mg, 0.21 mmol) and HOBt (10 mg, 0.07 mmol) were added, and the mixture was stirred at 70° C. for one hour and at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=0, 9, 17%) to obtain 16 mg of the title compound as a glassy solid. mass spectrum (ESI): m/z 441 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([OH:11])[CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1>ClCCl>[Br:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([O:11][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][O:29]2)[CH:3]=1
Reactant: C1=COCCC1
Reactant: Oc1cc(Br)c2occc2c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Brc1cc(OC2CCCCO2)cc2ccoc12
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Combine 7-bromo-5-hydroxybenzofuran (5.0 g, 0.0235 mol) with pyridinium para-toluenesulfonate (0.59 g, 0.1 equivalent) and dissolve in 60 mL dichloromethane under nitrogen. Add via syringe 3,4-dihydro-2H-pyran (3.2 mL, 1.5 equivalents) and stir at 20° C. overnight Dilute with dichloromethane then extract with 1N sodium hydroxide and wash with brine. Dry over sodium sulfate, filtered, and then concentrate to afford the title compound as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([N:21]=[C:22]=[O:23])[CH2:19][CH3:20]>>[CH2:18]([NH:21][C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23])[CH2:19][CH3:20]
Reactant: CCCN=C=O
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CCCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 28.2 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 11.1 mg (0.131 mMol) propyl isocyanate, 5.8 mg of the title compound were recovered.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].N1C=CC=CC=1.[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[Cl-].[NH4+]>O1CCCC1>[C:11]([O:4][CH2:3][CH2:2][Br:1])(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: OCCBr
Reactant: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-bromoethanol (0.36 mL) and pyridine (0.61 mL) in tetrahydrofuran (5 mL) was added pivaloyl chloride (0.62 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give (2-bromoethyl) pivalate (1.04 g). A mixture of 4-bromo-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (0.93 g), (2-bromoethyl)pivalate (0.82 g), cesium carbonate (1.27 g) and sodium iodide (0.2 g) in N,N-dimethylformamide (10 mL) was stirred at 65° C. for 6 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−3/1) to give the title compound (0.73 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:22])[C:14]([C:18]([NH:20][OH:21])=[NH:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH3:2].C(N(CC)CC)C.[C:38]([C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][C:48]=1[O:49][CH:50]([CH3:52])[CH3:51])[C:43](Cl)=O)#[N:39]>CN(C)C=O>[C:38]([C:40]1[CH:41]=[C:42]([C:43]2[O:21][N:20]=[C:18]([C:14]3[C:13]([CH3:22])=[C:12]4[C:17](=[CH:16][CH:15]=3)[CH:8]([CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:30])[N:9]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:10][CH2:11]4)[N:19]=2)[CH:46]=[CH:47][C:48]=1[O:49][CH:50]([CH3:51])[CH3:52])#[N:39]
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1C#N
Reactant: CCOC(=O)CCCC1c2ccc(C(=N)NO)c(C)c2CCN1C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCC1c2ccc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)c(C)c2CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.6 %

Procedure:
To a solution of 1,1-dimethylethyl 1-[4-(ethyloxy)-4-oxobutyl]-6-[(hydroxyamino)(imino)methyl]-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 27; 240 mg, 0.572 mmol) in N,N-dimethylformamide (DMF) (4 ml) was added triethylamine (0.119 ml, 0.858 mmol) followed by 3-cyano-4-[(1-methylethyl)oxy]benzoyl chloride (WO 2008128951; 141 mg, 0.629 mmol) in DMF (2 ml) dropwise over one minute at room temperature under nitrogen. The resulting mixture was stirred for 1 h at room temperature, then warmed up to 120° C. After 2 h at 120° C., most of the solvent was removed, and the residue diluted with ethyl acetate. The solution was washed with sodium bicarbonate then brine, dried over MgSO4 and concentrated in vacuo to give the crude product (ca. 300 mg). Purification by flash chromatography on silica gel, eluting with 8-38% ethyl acetate in cyclohexane, gave the title compound (120 mg) as a white foam.
Reaction SMILES: [C:1]([N:9]1[C@@H:13]([CH:14]([CH3:16])[CH3:15])[C:12](=[O:17])OC1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([CH3:28])[CH:24]=[CH:23][C:22]([C@@H:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1.CN1CCOCC1.Cl>C(OCC)(=O)C>[C:19]1([CH3:28])[CH:24]=[CH:23][C:22]([C@@H:25]([NH:27][C:12](=[O:17])[C@H:13]([CH:14]([CH3:15])[CH3:16])[NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc([C@H](C)N)cc1
Reactant: CC(C)[C@H]1C(=O)OC(=O)N1C(=O)c1ccccc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: Cc1ccc([C@H](C)NC(=O)[C@@H](NC(=O)c2ccccc2)C(C)C)cc1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
(S)-3-Benzoyl-4-isopropyl-2,5-oxazolidinedione (N-benzoyl-L-valine-NCA) (100 mg, 0.40 mmol) was dissolved in ethyl acetate (2.0 mL), followed by the addition of a solution of (S)-1-(p-tolyl)ethylamine (55 mg, 0.40 mmol) and N-methylmorpholine (61 mg, 0.60 mmol) in ethyl acetate (2.0 mL) at 0° C. The resulting mixture was stirred for 30 minutes. The reaction mixture was poured into 1 N hydrochloric acid (10 mL), followed by extraction with ethyl acetate (10 mL). The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate (10 mL) and a saturated aqueous solution of sodium chloride (10 mL), and was then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to afford the title compound (134 mg, 98%) as white crystals.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[C:13]1([CH:19](O)[CH2:20][CH2:21][CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(F)(F)F.CCOCC>O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:20][CH2:21][CH3:22]
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: CCCC(O)c1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCCC(c1ccccc1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.7 %

Procedure:
To a mixture of 792 mg of 4-hydroxycoumarin and 809 mg of 1-phenyl- 1 -butanol of Preparation 12 in 25 mL of dioxane under an argon atmosphere is added 2.6 mL of boron trifluoride etherate. The resulting yellow solution is left to stir at room temperature overnight. The volatiles are removed under reduced pressure and the residue is partioned between diethyl ether and 1N sodium hydroxide. The basic aqueous phase is washed with diethyl ether, acidified to pH=1 with 6N hydrochloric acid. The resulting precipitant is repeatedly extracted with dichloromethane (methanol-chloroform co-solvents). The combined dichloromethane extracts are washed once with dilute sodium bicarbonate to remove most of the unreacted 4-hydroxycoumarin, then brine, dried (magnesium sulfate), and finally concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed with 40% to 50% ethyl acetate in hexane to yield 183 mg of the title product as white crystals.
Reaction SMILES: [NH:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:19]([N:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: C1COCCOCCOCCOCCOCCN1
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)(C)C(=O)N1CCOCCOCCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1-aza-4,7,10,13,16-pentaoxacyclooctadecane and pivalyl chloride.
Reaction SMILES: [CH2:1]1[O:10][C:4]([CH2:6][CH2:7][CH2:8]Cl)([CH3:5])[O:3][CH2:2]1.[CH3:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH2:1]1[O:10][C:4]([CH2:6][CH2:7][CH2:8][N:12]([CH3:11])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH3:5])[O:3][CH2:2]1
Reactant: CNc1ccccc1
Reactant: CC1(CCCCl)OCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCCC1(C)OCCO1)c1ccccc1

Procedure:
Combine 5-chloro-2-pentanone ethylene ketal (80 g=0.49 mol), N-methylaniline (52 g=0.49 mol), potassium carbonate (67 g=0.49 mol) and potassium iodide (8.1 g) in 250 ml dimethylformamide and heat at 100° C. for 16 hours. Allow to cool, partition between ether and water, and wash the ether twice with water. Dry, concentrate and distill to obtain 5-(N-methylanilino)-2-pentanone ethylene ketal, boiling point 104°-109° C./0.1 mm. Dissolve this (47 g=0.20 mol) in 400 ml 1.0 N hydrochloric acid with 100 ml ethanol. Let stand 2 hours, concentrate and adjust pH to about 8. Extract with ethyl ether, dry, concentrate and distill to obtain the product, having a boiling point 100°-104° C./0.1 mm pressure.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.Cl[CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][S:47](=[O:51])(=[O:50])[CH2:46][CH2:45]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.[I-].[K+]>[O:50]=[S:47]1(=[O:51])[CH2:48][CH2:49][N:44]([CH2:43][CH2:42][NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)[CH2:45][CH2:46]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=S1(=O)CCN(CCCl)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 120 °C
Yield: 73 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (600 mg, 1.10 mmol), 4-(2-chloroethyl)thiomorpholine 1,1-dioxide (600 mg, 2.56 mmol) (prepared as described in WO2002045652), anhydrous potassium phosphate (3.00 g, 14.1 mmol) and potassium iodide (10 mg, 0.060 mmol) in acetonitrile (50 mL) was placed in 150 mL AceGlass resealable pressure vessel. The white suspension was blanketed with nitrogen. The vessel was sealed and warmed to 115-125° C. for 48 h. The crude reaction was filtered through a short bed of silica gel and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified by silica gel chromatography eluted with ethyl acetate and hexanes (0-50%) to afford the title compound as a colorless foam (566 mg, 73%). 1H NMR (500 MHz, CHLOROFORM-d) δ 7.95 (d, J=8.2 Hz, 2H), 7.22 (d, J=8.2 Hz, 2H), 5.31 (d, J=4.6 Hz, 1H), 4.74 (d, J=1.8 Hz, 1H), 4.62 (s, 1H), 3.93 (s, 3H), 3.22-2.99 (m, 9H), 2.79-2.55 (m, 4H), 2.52-2.42 (m, 1H), 2.18-2.09 (m, 1H), 1.99-1.02 (m, 20H), 1.72 (s, 3H), 1.11 (s, 3H), 1.01 (s., 3H), 1.10 (s, 3H), 0.95 (s, 3H), 0.95 (s., 3H). LCMS: m/e 705.51 (M+H)+, 3.01 min (method 10).
Reaction SMILES: CO[C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].[NH2:11][C:12](N)=[O:13]>O>[NH:10]1[C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3](=[O:4])[NH:11][C:12]1=[O:13]
Reactant: COC(=O)c1sccc1N
Reactant: NC(N)=O
Solvent: O
Product: O=c1[nH]c(=O)c2sccc2[nH]1
Temperature: 180 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
A solid mixture of methyl-3-aminothiophene-2-carboxylate (76 g, 480 mmol) and urea (189 g, 3140 mmol) was heated, with stirring, to 180° C. for 5 h. The mixture was cooled to 90° C. and water (1000 ml) added. After stirring at room temperature for 16 h, a cream coloured solid was filtered and washed twice with further water. The solid was dried in vacuo at 40° C. to give the title compound in 94% yield, >95% purity. LC-MS m/z=169.0 [M+H]+; RT=1.29 min; LC-MS method 2. 1H NMR: δH (400 MHz, D6-DMSO) 6.90 (1H, d, J=5.5 Hz), 8.04 (1H, d, J=5.5 Hz), 11.10-11.80 (2H, b).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[OH:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:2]([OH:3])[C:1]([OH:5])=[O:4]
Reactant: Oc1ccccc1
Reactant: O=CC(=O)O
Product: O=C(O)C(O)c1ccccc1O

Procedure:
reacting glyoxylic acid with a boric acid ester of a phenol of the formula: ##STR9## under acid conditions to form a boric acid ester of a 2-hydroxymandelic acid;
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)CCC>C1(C)C=CC=CC=1.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:15][C:10]1[CH:9]=[C:8]([C:6]2[N:7]([C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)[CH2:2][N:3]=[C:4]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)[CH:5]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: Fc1ccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(Cl)n2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(C2=CC(N3CCN(c4ncccc4C(F)(F)F)CC3)=NCN2c2cccnc2)cc1Cl
Temperature: 25 °C

Procedure:
Heat a mixture of 2-chloro-4-(3-chloro-4-fluoro-phenyl)-6-[4-(3-trifluoromethylpyridin-2-yl)-piperazin-1-yl]-pyrimidine, (47 mg, 0.1 mmol), 3-tri-n-butylstannylpyridine (92 mg, 0.25 mmol), Pd(PPh3)4 (6 mg, 0.005 mmol), in toluene (5 mL) at 110° C. for 16 hours. Let cool to room temperature, filter off the catalyst, and add water (5 mL). Extract with EtOAc, dry (Na2SO4), and evaporate. Purify using flash chromatography (9:1 hexanes/EtOAc) to give pure 4-(3-chloro-4-fluorophenyl)-3-pyridin-3-yl-6-[4-(3-trifluoromethylpyridin-2-yl)-piperazin-1-yl]-pyrimidine as a tan solid. 1H NMR (DMSO D6): 9.75 (s, 1H). 9.21 (d, 1H), 8.97 (d, 1H), 8.62 (d, 1H), 8.58 (d, 1H), 8.40 (dd, 1H), 8.19 (d, 1H), 8.00 (d, 1H), 7.61 (d, 1H), 7.58 (s, 1H), 7.21 (dd, 1H), 4.01 (br m, 8H).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:30][CH2:31][CH2:32][C:33]([CH2:44][CH3:45])([O:36][Si](CC)(CC)CC)[CH2:34][CH3:35])[CH2:12][C@@H:11]([O:46][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH2:34]([C:33]([OH:36])([CH2:44][CH3:45])[CH2:32][CH2:31][CH2:30][O:29][CH2:28][C:20]1[C@:21]2([CH2:23][CH2:24][C@H:25]3[C:16](=[CH:15][CH:14]=[C:13]4[C@:26]3([CH3:27])[C@@H:9]([OH:8])[CH2:10][C@H:11]([OH:46])[CH2:12]4)[C@@H:17]2[CH2:18][CH:19]=1)[CH3:22])[CH3:35]
Reactant: CCC(CC)(CCCOCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)O[Si](CC)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(O)(CC)CCCOCC1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 92.5 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-17-{4-ethyl-4-(triethylsilyloxy)hexyloxymethyl}androsta-5,7,16-triene (559 mg, 0.710 mmol) and a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (6 ml) were subjected to reaction using a procedure similar to that of Example 5(2) (4 hours), worked up and purified by column chromatography (ethyl acetate:dichloromethane=4:1 and then ethyl acetate) to give the titled compound (292 mg, 93%) as a colorless foam.