Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:5](=[O:21])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:3])[CH3:2].[C:30](Cl)(=[O:35])[CH2:31][C:32](Cl)=[O:33]>C1COCC1>[O:33]=[C:32]1[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:21])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:30](=[O:35])[CH2:31]1
Reactant: O=C(Cl)CC(=O)Cl
Reactant: COc1ccc(N(C(=O)CNc2ccccc2Nc2ccccc2)C(C)C)cc1
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
To 100 mL of THF at 0° C. is added dropwise over 20 min simultaneously a solution of 8.0 g (20.5 mmol) of N-isopropyl-N-(4-methoxy-phenyl)-2-(2-phenylamino-phenylamino) acetamide, prepared as in Intermediate 43, in 100 mL of THF and 2.40 mL (24.6 mmol, 1.2 equiv) of malonyl dichloride in 100 mL of THF. The resulting solution is stirred at RT for 20 h and the solvent removed in vacuo. Purification of the resulting brown oil by silica gel flash column chromatography afforded 7.5 g of the title compound as a light tan solid: 1H NMR (CDCl3, 300 MHz) δ7.44-6.86 (m, 13H), 5.02 (m, 1H), 4.38 (d, 1H, J=16.6), 4.04 (d, 1H, J=16.6), 3.84 (s, 3H), 2.55 (m, 2H), 1.10 (d, 6H, J=6.8); Rf =0.15 in hexane/EtOAc 1/1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9]([O:11]CC)=[O:10].O.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)CCCOc1cccc(Br)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCOc1cccc(Br)c1
Temperature: 50 °C

Procedure:
Ethyl 4-(3-bromophenoxy)butanoate 6 from Example 5 was taken up in 100 mL THF and 50 mL water and treated with lithium hydroxide LiOH (hydrate, 4.9 g). see FIG. 1. The whole was heated at 50° C. for 2 days. The mixture was cooled to room temperature and acidified to pH 1 with 2N HCl. The aqueous was extracted with ethylacetate. The combined organics were washed with brine and dried over sodium sulfate to give crude 4-(3-Bromophenoxy)butanoic acid as a sticky solid. 1H NMR (DMSO-d6, 500 MHz) 7.24 (m, 1H), 7.13 (m, 1H), 7.11 (m, 1H), 6.95 (m, 1H), 3.99 (m, 2H), 2.37 (m, 2H), 1.94 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([S:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=[N:22]2)[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:43])C=1>O1CCCC1>[C:29]1([S:28]([C:24]2[CH:23]=[N:22][N:21]([CH:7]([CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]([NH:10][C:11]3[CH:15]=[CH:14][N:13]([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[N:12]=3)=[O:9])[C:26](=[O:27])[CH:25]=2)=[O:43])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Sc3ccccc3)cc2=O)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(S(=O)c3ccccc3)cc2=O)n1
Temperature: 25 °C
Yield: 23.1 %

Procedure:
A solution of 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(6-oxo-4-phenylsulfanyl-6H-pyridazin-1-yl)-propionamide (30 mg, 0.06 mmol) in tetrahydrofuran (1 mL) was treated with m-chloroperbenzoic acid (10.8 mg, 0.06 mmol). In a separate flask, a solution of 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(6-oxo-4-phenylsulfanyl-6H-pyridazin-1-yl)-propionamide (30 mg, 0.06 mmol) in tetrahydrofuran (1 mL) was treated with m-chloroperbenzoic acid (21.5 mg, 0.12 mmol). Both reactions were stirred at 25° C. for 3 nights. At this time, each reaction was individually concentrated in vacuo. Two separate HPLC purifications (30-100% acetonitrile/water, C18 Pursuit Agilient, 20×150mm, 30 ml/min) were combined to afford 2-(4-benzenesulfinyl-6-oxo-6H-pyridazin-1-yl)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (6.9 mg, 11%) as a white solid; ES+-HRMS m/e calcd for C25H31N5O4S [M+H+] 498.2170 found 498.2171. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (2×s, 6H), 1.19-1.70 (m, 9H), 1.88-2.01 (m, 1H), 2.10-2.26 (m, 1H), 3.87 (s, 2H), 4.66 (s, 1H), 5.47 (dd, J=10.6, 4.2 Hz, 1H), 6.35 (d, J=2.4 Hz, 1H), 7.51 (dd, J=2.4 Hz, 1H), 7.54 (dd, J=2.4 Hz, 1H), 7.73 (t, J=7.5 Hz, 2H), 7.85 (t, J=7.5 Hz, 1H), 8.14 (d, J=7.5 Hz, 2H), 8.47 (d, J=2.4 Hz, 1H), 10.87 (s, 1H); and 2-(4-benzenesulfonyl-6-oxo-6H-pyridazin-1-yl)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (14.9 mg, 23%) as a white solid; ES+-HRMS m/e calcd for C25H31N5O5S [M+H+] 514.2119 found 514.2121. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (s, 3H), 1.04 (s, 3H), 1.20-1.70 (m, 9H), 1.86-2.02 (m, 1H), 2.07-2.31 (m, 1H), 3.87 (s, 2H), 4.66 (s, 1H), 5.47 (dd, J=10.4, 4.4 Hz, 1H), 6.35 (d, J=2.4 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.52 (d, J=2.4 Hz, 1H), 7.73 (t, J=7.5 Hz, 2H), 7.85 (t, J=7.5 Hz, 1H), 8.14 (d, J=7.5 Hz, 2H), 8.47 (d, J=2.4 Hz, 1H), 10.87 (s, 1H).
Reaction SMILES: [CH2:1]([NH:8]/[CH:9]=[CH:10]/[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C1(C)C=CC=CC=1>[CH2:1]([N:8](/[CH:9]=[CH:10]/[CH2:11][CH3:12])[C:20](=[O:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC/C=C/NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC/C=C/N(Cc1ccccc1)C(C)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 62a (3.22 g, 20 mmol) in 10 mL of toluene, was added triethylamine (2.79 mL, 20 mmol). The mixture was cooled to 0° C. and acetic anhydride (1.89 mL, 20 mmol) was added dropwise. The mixture was warmed to room temperature and stirred overnight. It was then concentrated on high vacuum to give crude 62b.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O.Cl[C:16]1[N:21]=[C:20]([N:22]2[C:26]([CH3:27])=[CH:25][C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:23]2)[CH:19]=[CH:18][CH:17]=1.C(O)CC.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:27][C:26]1[N:22]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][C:2]([F:14])([F:13])[F:1])[N:21]=2)[N:23]=[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: CCOC(=O)c1cc(C)n(-c2cccc(Cl)n2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C)n(-c2cccc(-c3ccccc3OC(F)(F)F)n2)n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 12.3 %

Procedure:
To the solution of 2-trifluoromethoxyphenyl boronic acid (0.192 g, 0.92 mmol) and the 2-chloropyridine compound from Step 1 (0.165 g, 0.62 mmol) in toluene:n-propanol (3 mL:3 mL) were added tetrabis(triphenylphosphine)palladium (0.072 g, 0.062 mmol) and aqueous sodium bicarbonate (2.0M, 0.62 mL, 1.2 mmol). The reaction mixture was stirred at 90° C. for 16 hours. After cooling to room temperature, the mixture was filtered through a Celite pad, and washed with ethyl acetate (3 times). The filtrate was concentrated. The resulting residue was dissolved in ethyl acetate and washed with saturated sodium carbonate aqueous solution and brine, the organic layer was dried over anhydrous sodium sulfate. After concentration, the crude product was applied to column chromatography on silica gel to afford the titled compound, as yellow oil, 30 mg, 12.3% yield.
Reaction SMILES: [OH:1][C@@H:2]([C:21]([CH3:27])([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])/[CH:3]=[CH:4]/[C@H:5]1[C@@H:9]([CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:19])[CH2:7][C@H:6]1[CH3:20].[C:28](OC(=O)C)(=[O:30])[CH3:29]>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[C:28]([O:1][C@@H:2]([C:21]([CH3:26])([CH3:27])[CH2:22][CH2:23][CH2:24][CH3:25])/[CH:3]=[CH:4]/[C@H:5]1[C@@H:9]([CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:19])[CH2:7][C@H:6]1[CH3:20])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC(C)(C)[C@H](O)/C=C/[C@@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CCCCC(C)(C)[C@@H](/C=C/[C@@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)O)OC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
A mixture of 156 mg of (8R,11R,12S,15R,5Z,13E)-15-hydroxy-11,16,16-trimethyl-9-oxoprosta-5,13-dien-1-oic acid, 100 mg of acetic, anhydride, 21 mg of 4-(dimethylamino)pyridine, and 2 ml of triethylamine was stirred at room temperature under a positive nitrogen atmosphere. After 16 hr, the reaction mixture was partitioned between ethyl acetate-water and the organic layer separated, dried (MgSO4), and condensed by rotary evaporation. The residual material was purified by chromatography over Sephadex LH-20 (hydroxypropylated beaded dextran) using chloroform/hexane (3:2) as the eluant to yield 112 mg (65%) of (8R,11R,12S,15R,5Z,13E)-15-acetyloxy-11,16,16-trimethyl-9-oxoprosta-5,13-dien-1-oic acid. [α]D25 -78.52 (CHCl3, c 1.02).
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([CH:12]2[C:19]([Cl:21])([CH3:20])[CH2:18][S:17][CH:16]3[N:13]2[C:14](=[O:32])[CH:15]3[NH:22][C:23](=[O:31])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:11])=CC=1)([O-])=O>C(OCC)(=O)C.[Pd]>[Cl:21][C:19]1([CH3:20])[CH2:18][S:17][CH:16]2[N:13]([C:14](=[O:32])[CH:15]2[NH:22][C:23](=[O:31])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]1[C:10]([OH:11])=[O:9]
Reactant: CC1(Cl)CSC2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(Cl)CSC2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O

Procedure:
3-Chloro-3-methyl-8-oxo-7-(2-phenylacetamido)-5-thia-1-azabicyclo[4.2.0]octane-2-carboxylic acid p-nitrobenzyl ester (1.06 g, 2.1 mmoles) was hydrogenated in 60 ml of ethyl acetate over 1 g. of 10 per cent palladium on charcoal. The catalyst was filtered and washed with ethyl acetate. The filtrate was extracted with ice cold saturated sodium bicarbonate (100 ml.). The aqueous phase was covered with fresh ethyl acetate (100 ml.) and was acidified with concentrated hydrochloric acid to pH 1.5. The organic phase was separated, dried and flash concentrated to a total of 10 ml. The obtained solution was added to pentane to give 475 mg. (61 per cent yield) of the desired acid, which did not melt but slowly decomposed above 90° C., nmr (DMSO--D6) ppm (δ), 1.75 (s, 3, CH3), 3.32 (ABq, δ 0.675 ppm, J 14.2 cps, 2--CH2), ##STR9## 4.55 (s, 1, 4--H), 5.22 (2, 1, 6H), 5.51 (q, 1, 7H), 7.34 (s, 5, C6H5), 9.1 (d, 1, NH).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([C:13]2[NH:18][C:17](=[O:19])[C:16]3=[CH:20][N:21]=[C:22]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[N:15]3[N:14]=2)[CH:10]([CH3:29])[CH2:9]1)=O)(C)(C)C.[ClH:30]>C(Cl)Cl.C(OCC)C>[ClH:30].[CH3:29][CH:10]1[CH2:9][NH:8][CH2:12][CH:11]1[C:13]1[NH:18][C:17](=[O:19])[C:16]2=[CH:20][N:21]=[C:22]([CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:15]2[N:14]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CC1c1nn2c(C3CCOCC3)ncc2c(=O)[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC1CNCC1c1nn2c(C3CCOCC3)ncc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of compound 8 (130 mg, 0.32 mmol) in CH2Cl2 (10 mL) was added a saturated solution of HCl in diethylether (20 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo to dryness to afford compound 9 (110 mg, 100% yield). LC-MS (free base): m/z 304.37 [M+1]+. 1H NMR (400 MHz, D2O-d2): δ 8.02 (s, 1H), 3.98˜3.95 (dd, J=2.8, 8.8 Hz, 2H), 3.64˜3.60 (m, 3H), 3.56˜3.50 (m, 3H), 3.15˜3.09 (m, 1H), 3.01˜2.96 (m, 1H), 2.72˜2.67 (m, 1H), 1.92˜1.87 (m, 4H), 1.09 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1.Cl.CCN(C(C)C)C(C)C.Br[C:24]1[N:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=1>CC(N(C)C)=O>[Br:30][C:27]1[CH:26]=[N:25][C:24]([N:2]([CH2:3][C@H:4]2[CH2:9][CH2:8][C@H:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]2)[CH3:1])=[N:29][CH:28]=1
Reactant: CNC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: Brc1cnc(Br)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](C(=O)O)CC1)c1ncc(Br)cn1
Temperature: 120 °C

Procedure:
A mixture of 0.42 g (2.0 mmol) of trans-4-methylaminomethyl-cyclohexanecarboxylic acid•HCl, 1.85 mL (1.1 mmol) of Huenig's base and 0.57 g (2.4 mmol) of 2,5-dibromo-pyrimidine [Brown and Arantz, J. Chem. Soc. C Issue 10, 1889-1891 (1971)] in 2 mL of DMA was placed in the microwave and heated to 120° C. for 1 h. The solvent was evaporated, partitioned between Et2O (×3)/aqueous 10% KH2PO4, dried over Na2SO4 and evaporated to yield 0.604 g (92%) of trans-4-{[(5-bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-cyclohexanecarboxylic acid, MS: 326 (M−H−, 1Br), MP: 172-174° C.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:10]([CH:12]1[N:17](C(OCC2C=CC=CC=2)=O)[CH2:16][CH2:15][N:14]([CH3:28])[C:13]1=[O:29])[OH:11])C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C@@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:10]([CH:12]1[NH:17][CH2:16][CH2:15][N:14]([CH3:28])[C:13]1=[O:29])[OH:11]
Reactant: CN1CCN(C(=O)OCc2ccccc2)C(C(O)[C@H](Cc2ccccc2)N(Cc2ccccc2)Cc2ccccc2)C1=O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN1CCNC(C(O)[C@@H](N)Cc2ccccc2)C1=O

Procedure:
Treat a solution of 3-(2(S)-dibenzylamino-1-hydroxy-3-phenylpropyl)-4-benzyloxycarbonyl-1-methylpiperazin-2-one (Isomer-2) (210 mg, 0.36 mmol) in methanol (10 mL) with 20% palladium hydroxide on carbon (48 mg) in one portion and stir the mixture under 1 atmosphere of hydrogen gas for 24 h. Filter through a filtering agent, wash with methanol and concentrate to give the title compound as an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:15][C:16](=[O:30])[CH2:17][CH:18]1[C:22]2[CH:23]=[C:24]([F:29])[C:25]([OH:28])=[C:26]([F:27])[C:21]=2[O:20][CH2:19]1>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:28][C:25]3[C:24]([F:29])=[CH:23][C:22]4[CH:18]([CH2:17][C:16]([OH:30])=[O:15])[CH2:19][O:20][C:21]=4[C:26]=3[F:27])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccnc1SC1CCC1
Reactant: COC(=O)CC1COc2c1cc(F)c(O)c2F
Product: O=C(O)CC1COc2c1cc(F)c(OCc1cccnc1SC1CCC1)c2F
Yield: 79.8 %

Procedure:
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (18 mg, 0.08 mmol) obtained in Step C of Preparation Example 23 and (5,7-difluoro-6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (20 mg, 0.08 mmol) obtained in Preparation Example 51 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (26 mg, 78%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH2:4]Cl.[N-:12]=[N+]=[N-].[Na+].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CS(C)=O>[CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH2:4][NH2:12]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(C)c(CCl)c(C)c1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C)c(CN)c(C)c1
Temperature: 60 °C
Yield: 60.9 %

Procedure:
To a solution of 2,4,6-trimethylbenzyl chloride (5 g, 29.7 mmol) in DMSO (20 mL) was added sodium azide (2.9 g, 44.6 mmol). The mixture was heated at 60° C. for 3 h before it was allowed to cool to rt and poured to water (200 mL). The resulted precipitate was filtered dissolved in wet THF (50 mL) followed by the addition of triphenylphosphine (15.6, 59.4 mmol). The mixture was heated under reflux for 3 h and the volatiles were evaporated. The residue was added to 1 N HCl (200 mL) and the solids were filtered off. The filtrate was basified and the resulted precipitate was filtered, dried under vacuum to give 2,4,6-trimethylbenzylamine (2.7 g, 61% yleld).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([Si:9]([CH3:12])([CH3:11])[CH3:10])#[CH:8]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:10][Si:9]([CH3:12])([CH3:11])[C:7]#[C:8][C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1nccs1

Procedure:
A solution of 2-Bromothiazole (Aldrich, 5.0 g, 30.5 mmol), ethynyl-trimethyl-silane (Aldrich, 3.0 g, 30.5 mmol), PdCl2(PPh3)2 (Aldrich, 500 mg, 0.71 mmol) and CuI (Aldrich, 400 mg, 1.52 mmol) in THF (20 mL) was treated with TEA (5 mL) at room temperature for 20 min. The reaction was heated at 60 for 4 hours. The solid was filtered off through a pad of celite and the filtrate was concentrated to give yellow solid, which was then purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as yellow oil.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[C:15]([O:19][C:20](=[O:29])[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](Br)[N:23]=1)([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:24]2[N:23]=[C:22]([NH:21][C:20](=[O:29])[O:19][C:15]([CH3:17])([CH3:16])[CH3:18])[CH:27]=[CH:26][CH:25]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc(-c2cccc(NC(=O)OC(C)(C)C)n2)cc1
Temperature: 80 °C
Yield: 72.2 %

Procedure:
To a solution of 4-(N-methylsulfamoyl)phenylboronic acid (17.2 g, 0.08 mol) and (6-bromo-pyridin-2-yl)carbamic acid tert-butyl ester (21.9 g, 0.08 mol) in DMF (125 mL) and H2O (125 mL) were added Pd(PPh3)4 (9.2 g, 0.008 mol) and K2CO3 (16.6 g, 0.12 mol). The resulting mixture was degassed by gently bubbling argon through the solution for 5 minutes at 20° C. The reaction mixture was then heated at 80° C. for 16 h. The mixture was evaporated under reduced pressure, then poured into H2O, and extracted with EtOAc. The organic phase was dried over Na2SO4, and was evaporated under reduced pressure to give tert-butyl 6-(4-(N-methylsulfamoyl)phenyl)pyridin-2-ylcarbamate (21 g, 58%), which was used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][CH:3]1[NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].[CH2:30]([O:32][CH:33]([O:36][CH2:37][CH3:38])[CH2:34]Br)[CH3:31]>>[CH2:30]([O:32][CH:33]([O:36][CH2:37][CH3:38])[CH2:34][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13](=[O:18])[C:14]([CH3:17])([CH3:15])[CH3:16])[CH2:4][CH:3]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[C:2]1=[O:1])[CH3:31]
Reactant: CCOC(CBr)OCC
Reactant: CC(C)(C)C(=O)N1CC(NC(=O)OCc2ccccc2)C(=O)Nc2ccccc21
Product: CCOC(CN1C(=O)C(NC(=O)OCc2ccccc2)CN(C(=O)C(C)(C)C)c2ccccc21)OCC

Procedure:
Step 2 of Example 1 was repeated except that 2-oxo-3-benzyloxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine was used instead of 2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine, and that bromoacetaldehyde diethylacetal was used instead of 2-bromo-2′-methylacetophenone, to thereby obtain the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:24])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:26])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:25])[CH:6]=[CH:5]1.[CH3:27][O:28][CH2:29][CH2:30][C:31](Cl)=[O:32]>>[OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:24])[C:17](=[O:20])[CH2:18][O:19][C:31](=[O:32])[CH2:30][CH2:29][O:28][CH3:27])[C@H:12]2[C@H:3]1[C@:4]1([CH3:26])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:25])[CH:6]=[CH:5]1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reactant: COCCC(=O)Cl
Product: COCCC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
Under the conditions of Example 3(a), 10.0 g of 11β,17,21-trihydroxy-1,4-pregnadiene-3,20-dione is reacted with 3-methoxypropionic acid chloride, worked up, and purified, thus isolating 7.3 g of 11β,17-dihydroxy-21-(3-methoxypropionyloxy)-1,4-pregnadiene-3,20-dione.
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:30])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.Br[CH2:32][CH:33]1[O:37][CH2:36][CH2:35][O:34]1>CN(C=O)C>[O:34]1[CH2:35][CH2:36][O:37][CH:33]1[CH2:32][N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][O:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:5]([OH:30])=[O:4])[CH2:16][CH2:17]2)=[CH:22]1
Reactant: BrCC1OCCO1
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(CC3OCCO3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
0.02 g (0.42 mmol) of a dispersion of 60% NaH in mineral oil were added to a solution of 0.06 g (0.16 mmol) of 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester prepared in step D in 1 mL of anhydrous DMF under an inert atmosphere. After stirring 30 minutes at room temperature, 0.04 mg (0.24 mmol) of 2-bromomethyl-[1,3]dioxolane were added and the mixture was stirred for 18 hours. The solvent was removed under reduced pressure and the crude mixture was dissolved in 1 mL of ethanol. 0.1 mL of 2N NaOH were added and the mixture was stirred at 60° C. for 3 hours. 0.1 mL of 2N HCl were added and the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the crude mixture was purified using a 500 mg Varian C18 chromatography column, affording 0.040 g (56% yield) of 2-{2-[4-(1-[1,3]dioxolan-2-ylmethyl-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][N:5]=[C:4]([Cl:8])[C:3]=1Cl.[NH3:10].[OH-].[Na+]>>[NH2:10][C:3]1[C:2]([Cl:1])=[N:7][N:6]=[N:5][C:4]=1[Cl:8]
Reactant: N
Reactant: Clc1nnnc(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1c(Cl)nnnc1Cl

Procedure:
45 parts of a trichlorotriazine melt at 160° C. are sprayed through a pressure nozzle, below the surface, into a dispersion column which is supplied with 21 parts of a 30% aqueous ammonia solution. The reaction mixture is pumped continuously into a vessel where, at about 25° C. with maintenance of the pH value at 8.5 to 9.0 with sodium hydroxide solution, the substitution is completed. The amino-dichlorotriazine obtained in practically quantitative amounts can be used directly to produce a reactive dye.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:26])[C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[CH2:27]([OH:29])[CH3:28].[H-].[Na+]>O1CCOCC1>[CH2:27]([O:29][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:26])[C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1)[CH3:28]
Reactant: CCNC(=O)C(C)c1ccc(C2CCN(c3ccnc(Cl)n3)CC2)cc1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCNC(=O)C(C)c1ccc(C2CCN(c3ccnc(OCC)n3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 80 mg (0.22 mmol) 2-{4-[1-(2-chloro-pyrimidin-4-yl)-piperidin-4-yl]-phenyl}-N-ethyl-propionamide (XII.1) and 25 μL (0.43 mmol) ethanol in 1 mL 1,4-dioxane are added 26 mg (0.64 mmol) sodium hydride (60%) at 0° C. The mixture is stirred for 12 h at rt. After that time, the mixture is directly purified by HPLC (XBridge 10 μM; water, 0.3% NH4OH/MeOH) to yield the desired product.