Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1[C:19]2[N:18]([CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:26]=[C:27]([CH:32]=[C:33]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][N:58]4[C:70]5[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=5[C:64]5[C:59]4=[CH:60][CH:61]=[CH:62][CH:63]=5)[C:34]=3[O:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]3[C:52]4[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=4[C:46]4[C:41]3=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:28](OC)=[O:29])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>C1COCC1>[CH:69]1[C:70]2[N:58]([CH2:57][CH2:56][CH2:55][CH2:54][O:53][C:33]3[CH:32]=[C:27]([CH2:28][OH:29])[CH:26]=[C:25]([O:24][CH2:23][CH2:22][CH2:21][CH2:20][N:18]4[C:19]5[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=5[C:12]5[C:17]4=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:34]=3[O:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]3[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:46]=4[C:47]4[C:52]3=[CH:51][CH:50]=[CH:49][CH:48]=4)[C:59]3[C:64](=[CH:63][CH:62]=[CH:61][CH:60]=3)[C:65]=2[CH:66]=[CH:67][CH:68]=1
Reactant: COC(=O)c1cc(OCCCCn2c3ccccc3c3ccccc32)c(OCCCCn2c3ccccc3c3ccccc32)c(OCCCCn2c3ccccc3c3ccccc32)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(OCCCCn2c3ccccc3c3ccccc32)c(OCCCCn2c3ccccc3c3ccccc32)c(OCCCCn2c3ccccc3c3ccccc32)c1
Temperature: 80 °C
Yield: 70 %

Procedure:
An oven-dried, magnetically stirred, 500 mL RBF was charged with a solution of LiAlH4 (2.2 g, 0.038 mol) in 100 mL freshly distilled THF. Then, THF solution of compound 11 (15.0 g, 0.023 mol) was added dropwise over 0.5 hours. After the reaction was maintained for 2 hours at 80° C., 1 N NaOH was slowly added. The organic phase was separated and extracted with chloroform. The organics were then dried over Na2SO4 and filtered. The solvent was evaporated to give the crude product. The resulting crude product was then purified by silica gel column chromatography (eluent: chloroform:ethyl acetate=1:50 v/v) to yield 13.2 g (92%) of (3,4,5-tris(4-(9H-carbazol-9-yl)butoxy)phenyl)methanol (Compound 12).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1[N:12]=[C:13]([CH:22]2[O:27][CH2:26][CH2:25][NH:24][CH2:23]2)[NH:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl:28][C:29]1[CH:34]=[C:33](Cl)[N:32]=[C:31]([NH2:36])[N:30]=1>C(O)C>[Cl:28][C:29]1[CH:34]=[C:33]([N:24]2[CH2:25][CH2:26][O:27][CH:22]([C:13]3[NH:14][C:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[C:11]([CH3:10])[N:12]=3)[CH2:23]2)[N:32]=[C:31]([NH2:36])[N:30]=1
Reactant: Cc1nc(C2CNCCO2)[nH]c1-c1ccccc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc(C2CN(c3cc(Cl)nc(N)n3)CCO2)[nH]c1-c1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
A suspension of DIPEA (2.39 g, 18.50 mmol), 2-(4-methyl-5-phenyl-1H-imidazol-2-yl)morpholine (1.5 g, 6.17 mmol) and 4,6-dichloro-2-pyrimidinamine (1.011 g, 6.17 mmol) in ethanol (200 mL) was stirred at 100° C. overnight. The solvent was removed under reduced pressure, and the crude product was purified by silica gel chromatography, eluting with CH2Cl2/EtOAc (10:1) to afford the title compound (1.2 g) as a white solid. LC-MS (ES) m/z=371, 373 [M+H]+.
Reaction SMILES: COC(=O)[NH:4][C:5]1[N:6]=[C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[O:22])[NH:20][CH3:21])[CH:14]=3)[CH:10]=[N:9][N:8]2[C:23]=1Br.[Cl:26][C:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[CH:29][N:28]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[NH2:4][C:5]1[N:6]=[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=3)[C:19]([NH:20][CH3:21])=[O:22])[CH:10]=[N:9][N:8]2[C:23]=1[C:31]1[CH:30]=[CH:29][N:28]=[C:27]([Cl:26])[CH:32]=1
Reactant: CNC(=O)c1cccc(-c2cnn3c(Br)c(NC(=O)OC)nc3c2)c1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CNC(=O)c1cccc(-c2cnn3c(-c4ccnc(Cl)c4)c(N)nc3c2)c1

Procedure:
[3-Bromo-7-(3-Methylcarbamoyl-phenyl)-imidazo-[1,2-b]-pyridazin-2-yl]-carbamic acid methyl ester (1 eq, 0.159 mmol, 65 mg) and 2-chloropyridine-4-boronic acid (1.2 eq, 0.191 mmol, 30.1 mg) are dissolved in DME (3 ml) and water (0.75 ml) and Na2CO3 (3 eq, 0.478 mmol, 50.6 mg) is added. PdCl2(PPh3)2 (0.05 eq, 0.008 mmol, 5.59 mg) is then added and the reaction mixture is heated using microwave radiation at 120° C. for 50 min. At the completion of this time the solvent is evaporated and the reaction mixture is dissolved in MeOH, filtered and the solvent is removed in vacuo to yield 3-[2-Amino-3-(2-Chloro-pyridin-4-yl)-imidazo -[1,2-b]-pyridazin-7-yl]-N-methyl benzamide as a yellow solid; [M+H]+=379
Reaction SMILES: [N:1]([C:4]1[C:9](Cl)=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:12]/[C:13]1[C:20]([Cl:21])=[CH:19][C:16](C#N)=[CH:15][C:14]=1[Cl:22])=[N+:2]=[N-:3].N(C1C([Br:32])=CN=CC=1C=O)=[N+]=[N-].ClC1C=CC=C(Cl)C=1N>>[N:1]([C:4]1[C:9]([Br:32])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:12]/[C:13]1[C:20]([Cl:21])=[CH:19][CH:16]=[CH:15][C:14]=1[Cl:22])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1c(Br)cncc1C=O
Reactant: N#Cc1cc(Cl)c(/N=C/c2cncc(Cl)c2N=[N+]=[N-])c(Cl)c1
Agent: Nc1c(Cl)cccc1Cl
Product: [N-]=[N+]=Nc1c(Br)cncc1/C=N/c1c(Cl)cccc1Cl

Procedure:
Following the procedure described for 4-{[1-(4-azido-5-chloropyridin-3-yl)meth-(E)-ylidene]amino}-3,5-dichlorobenzonitrile, 4-azido-5-bromopyridine-3-carbaldehyde and 2,6-dichloroaniline were reacted to afford the title compound as a beige solid that was used without purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH:20]([C:26]([CH3:28])=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CO.C(OCC)(=O)C>[CH3:28][C:26]1[N:1]=[C:2]2[C:7]([O:8][CH2:9][C:10]3([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:12][CH2:11]3)=[CH:6][CH:5]=[CH:4][N:3]2[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: Nc1ncccc1OCC1(c2ccccc2)CC1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1c(C)nc2c(OCC3(c4ccccc4)CC3)cccn12
Yield: 8.6 %

Procedure:
A stirred mixture of 2-amino-3-[(1-phenylcyclopropyl)methoxy]pyridine (2.82 g, 11.7 mmol, see example 23), ethyl 2-chloroacetoacetate (6.5 mL, 47 mmol) and molecular sieves (15.1 g, type 4 Å, beads, 8–12 mesh) in anhydrous methanol (55 mL) was refluxed for 39 h under argon. The molecular sieves were filtered off and the filtrate was concentrated in vacuo to give an oil which was dissolved in ethyl acetate (200 mL) and then washed successively with a 1:1 (v/v) mixture of saturated aq sodium bicarbonate and water (2×25 mL), and water (20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the crude product. Purification by dry column (600 mL funnel with 450 mL of silica gel 10–40μ, Sigma cat. S-6628) eluted with a mixture of ethyl acetate-hexanes (1:3 v/v, containing 0.5% v/v isopropylarnine) afforded 0.352 g (8.6% yield) of ethyl 2-methyl-8-[(1-phenylcyclopropyl)methoxy]imidazo[1,2-α]pyridine-3-carboxylate (Rf=0.30 in ethyl acetate-hexanes, 1:3 v/v, containing 0.5% v/v isopropylamine). A stirred solution of ethyl 2-methyl-8-[(1-phenylcyclopropyl)methoxy]imidazo[1,2-α]pyridine-3-carboxylate (0.190 g, 0.542 mmol) in a mixture of dichloromethane (3.5 mL) and anhydrous diethyl ether (3 mL) was treated with ethereal hydrogen chloride to form the hydrochloride salt. Concentration of the solution in vacuo gave a residue which was triturated in anhydrous diethyl ether to afford the title compound as an off-white solid (0.168 g, 80% yield). 1H-NMR (300 MHz, CDCl3) δ 16.91 (br s, 1H, +NH), 9.05 (d, 1H, Ar), 7.65 (d, 2H, Ar), 7.18 (m, 4H, Ar), 6.92 (d, 1H, Ar), 4.45 (q, 2H, CH3CH2), 4.32 (s, 2H, CH2O), 3.03 (s, 3H, CH3), 1.42 (t, 3H, CH3CH2), 1.15 (m, 4H, CH2CH2); 13C-NMR (75 MHz, CDCl3, APT) δ 159.49 (+), 145.10 (+), 143.90 (+), 142.24 (+), 133.68 (+), 130.21 (−), 128.26 (−), 126.78 (−), 120.27 (−), 118.13 (−), 113.77 (+), 112.02 (−), 78.61 (+), 62.09 (+), 25.48 (+), 14.14 (−), 12.56 (−), 11.51 (+); LRMS-FAB m/z: MH+ 351 (100%); Anal. calcd for C21H22N2O3.HCl: C, 65.20; H, 5.99; N, 7.24%. found: C, 64.87; H, 5.96; N, 7.20%.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([NH:15][C:16]([C@H:18]1[CH2:23][CH2:22][C@H:21]2[C@H:24]3[C@H:34]([CH2:35][CH2:36][C@:19]12[CH3:20])[C@:32]1([CH3:33])[C:27]([CH:28]=[C:29]([C:37]#N)[CH2:30][CH2:31]1)=[CH:26][CH2:25]3)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(O)(=O)C(C(C(O)=O)O)[OH:41]>C1(C)C=CC=CC=1>[C:11]([NH:15][C:16]([C@H:18]1[CH2:23][CH2:22][C@H:21]2[C@H:24]3[C@H:34]([CH2:35][CH2:36][C@:19]12[CH3:20])[C@:32]1([CH3:33])[C:27]([CH:28]=[C:29]([CH:37]=[O:41])[CH2:30][CH2:31]1)=[CH:26][CH2:25]3)=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2 ml of a 1M solution of diisobutyl aluminum hydride in toluene were added at 0° C. to 10 ml of a dry solution of toluene containing 380 mg of N-t-butyl-3-cyanoandrosta-3,5-diene-17β-carboxamide (prepared as described in Preparation 2). The reaction mixture was then stirred at 0° C. for 30 minutes, after which 30 ml of an aqueous solution of 1.5 g of tartaric acid were added to the mixture. The reaction mixture was then stirred at room temperature for 2 hours, and rhea extracted with methylene chloride three times. The combined organic extracts were washed with water and with a saturated aqueous solution of sodium chloride, in that order. They were then dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 50 g of silica gel and using a gradient elution method, with mixtures of acetone and methylene chloride in ratios ranging from 1:99 to 4:96 by volume as the eluent, to give 325 mg of the title compound.
Reaction SMILES: [S].[H-].[Na+].C([N-][CH:8]([CH3:10])[CH3:9])(C)C.[Li+].C=[C:13]([P:20](=[O:59])([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>[P].C1COCC1>[CH2:13]([P:20](=[O:59])([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:14][CH:15]([P:20](=[O:59])([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:10][CH2:8][CH3:9])[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C=C(CCCCCC)P(=O)(OCCCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCCCC
Reactant: CC(C)[N-]C(C)C
Agent: [H-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOP(=O)(CCC(CCCC)P(=O)(OCCCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCCCC

Procedure:
Dioctadecyl hydrogen phosphonate may be reacted with dioctadecyl oct-1-en-2-ylphosphonate to produce tetra-octadecyl heptane-1,3-diyldiphosphonate, J, using substantially the conditions found in Phosphorus, Sulfur and Silicon and the Related Elements, 83 (1-4), 77-98:1993. (See FIG. 9) Thus, dioctadecyl hydrogen phosphonate (MW 586.95, 1.56 g, 2.66 mmol), dissolved in THF (6 mL) and sodium hydride (95%, FW 24.0, 2.66 mmol, 0.064 g) are allowed to react under inert atmosphere at RT with stirring. Alternatively, sodium hydride may be replaced by molar equivalence of strong bases such as lithium di-isoproylamide or sodium alkoxide or the like. Then dioctadecyl oct-1-en-2-ylphosphonate, A, (MW 697.15, 1.88 g, 2.69 mmol) is added and allowed to react under an inert atmosphere until the reaction is complete. The reaction progress may be followed by TLC, hplc or 31P nmr. At the completion of reaction the solvent may be removed by evaporation and the crude product purified by normal phase flash chromatography using a suitable solvent system (e.g., hexanes-ethyl acetate gradient (ELSD detection) to yield substantially pure tetraoctadecyl heptane-1,3-diyldiphosphonate. The crude product may also be purified using rphplc (C4, 300 A, and suitable a solvent gradient. The mass of the desired product is 1270.1.
Reaction SMILES: [NH:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9]3.[CH3:20]C(C)([O-])C.[K+].IC>O1CCCC1>[CH3:20][N:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9]3
Reactant: O=C1COc2cccc3nc4c(c(c23)N1)CCCC4
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)COc2cccc3nc4c(c1c23)CCCC4
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
To a suspension of 1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.0 g) in dry tetrahydrofuran (120 ml) was added potassium tert-butoxide (1.94 g). The mixture was stirred at room temperature for 15 mins, iodomethane (1.08 ml) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, saturated potassium carbonate solution (150 ml) was added, and mixture was extracted twice with 150 ml portions of ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, concentrated. Trituration with diethyl ether/pentane gave 3.47 g (82%) of product. Recrystallization from methanol gave the analytical sample, mp 176.5°-177.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[N:9]1.C(N(CC)CC)C.C(NC1C=CC(S([N:41]=[N+:42]=[N-])(=O)=O)=CC=1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C(#N)C>[N+:41](=[C:11]1[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[N:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:12]1=[O:13])=[N-:42]
Reactant: O=C1CC(c2ccccc2F)=NN1c1ccccc1F
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: [N-]=[N+]=C1C(=O)N(c2ccccc2F)N=C1c1ccccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2,5-Bis(2-fluorophenyl)-2,4-dihydro-3H-pyrazol-3-one (0.63 g, 2.3 mmol) was suspended in acetonitrile (10 mL), treated with triethylamine (0.27 mL, 2.7 mmol, 1.15 equiv) and cooled to 0° C. To the mixture was added 4-acetamidobenzenesulfonyl azide (0.61 g, 2.5 mmol, 1.1 equiv) and after 30 minutes at 0° C., the mixture was warmed to ambient temperature. After stirring for 30 minutes, the mixture was poured into sodium carbonate (25 mL, aqueous saturated) and sodium hydroxide (10 mL, 1 N aqueous) and extracted with dichloromethane (2×125 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([C:14]#[N:15])[S:12][CH:13]=2)[C:4]1=[O:16].[C:17]([NH:27][C:28]1[C:29]([Cl:42])=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([S:38](Cl)(=[O:40])=[O:39])[CH:32]=[CH:31]2)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>>[C:14]([C:11]1[S:12][CH:13]=[C:9]([CH2:8][N:5]2[CH2:6][CH2:7][C@H:3]([NH:2][S:38]([C:33]3[CH:32]=[CH:31][C:30]4[C:35](=[CH:36][CH:37]=[C:28]([NH:27][C:17]([O:19][CH2:20][C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)=[O:18])[C:29]=4[Cl:42])[CH:34]=3)(=[O:39])=[O:40])[C:4]2=[O:16])[CH:10]=1)#[N:15]
Reactant: O=C(Nc1ccc2cc(S(=O)(=O)Cl)ccc2c1Cl)OCc1ccccc1
Reactant: N#Cc1cc(CN2CC[C@H](N)C2=O)cs1
Agent: Cl
Product: N#Cc1cc(CN2CC[C@H](NS(=O)(=O)c3ccc4c(Cl)c(NC(=O)OCc5ccccc5)ccc4c3)C2=O)cs1

Procedure:
The title compound is prepared from 4-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)thiophene-2-carbonitrile hydrochloride as described in EXAMPLE 125, Part C using N-Cbz-6-amino-5-chloro-naphthalene-2-sulfonyl chloride in place of 7-methoxynaphthalene-2-sulfonyl chloride. The crude product is concentrated from EtOAc to afford the title compound as a white solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[F:17][C:18]1[CH:19]=[C:20]([CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[OH:26])[CH:21]=[C:22]([F:24])[CH:23]=1>>[F:17][C:18]1[CH:19]=[C:20]([CH:25]([O:26][C:10](=[O:11])[O:9][C@@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH:21]=[C:22]([F:24])[CH:23]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Reactant: OC(c1cccc(F)c1)c1cc(F)cc(F)c1
Product: O=C(OC(c1cccc(F)c1)c1cc(F)cc(F)c1)O[C@H]1CN2CCC1CC2

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with (3,5-difluoro-phenyl)-(3-fluoro-phenyl)-methanol.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:17]([O:24][C:25]([C@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[S:32]([C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]2)=[CH:37][CH:36]=1)(=[O:34])=[O:33])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]([C@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[S:32]([C:35]1[CH:36]=[CH:37][C:38]([N:41]2[CH2:46][CH2:45][CH:44]([NH:1][CH2:2][C@H:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:43][CH2:42]2)=[CH:39][CH:40]=1)(=[O:33])=[O:34])=[O:26])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(S(=O)(=O)N3CCC[C@@H]3C(=O)OCc3ccccc3)cc2)CC1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(S(=O)(=O)N4CCC[C@@H]4C(=O)OCc4ccccc4)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from N-[5-((1R)-2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide and Reference Example 23, (2R)-1-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid benzyl ester, according to the procedure of Example 1 as a white solid; mp 62-69° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.40-1.90 (m, 6H), 2.50-3.20 (m, 5H), 3.75-3.85 (m, 2H), 4.15 (dd, 1H), 4.40-4.50 (m, 1H), 5.19 (s, 2H), 6.80 (d, 1H), 6.92 (d, 3H), 7.15 (d, 1H), 7.40-7.50(m, 5H), 7.52 (d, 2H); MS (ES) m/z: 673.1.1 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][CH2:16]4)[C@H:13]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:44][C:45]([F:60])([C:56]([F:59])([F:58])[F:57])[CH2:46][CH2:47][CH2:48][S:49][CH2:50][C@@H:51]1[CH2:55][CH2:54][CH2:53][NH:52]1>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][CH2:16]4)[C@H:13]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:52]3[CH2:53][CH2:54][CH2:55][C@H:51]3[CH2:50][S:49][CH2:48][CH2:47][CH2:46][C:45]([F:44])([F:60])[C:56]([F:57])([F:58])[F:59])[CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCC[C@@H]2Cc3cc(OCc4ccccc4)ccc3[C@H]3CC[C@]4(C)C(=O)CC[C@H]4[C@H]23)cc1
Reactant: FC(F)(F)C(F)(F)CCCSC[C@@H]1CCCN1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCN4CCC[C@H]4CSCCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CCC2=O
Yield: 72.5 %

Procedure:
Under the conditions of Example 23h, 4.58 g of 3-benzyloxy-7α-(5-tosyloxypentyl)-estra-1,3,5(10)-trien-17-one is reacted with 3.17 g of (2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidine, worked up, and the crude product is chromato-graphed on silica gel with hexane/ethyl acetate. 3.9 g of 3-benzyloxy-7α-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentyl-thiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-trien-17-one is obtained as oil. [α]D22 =+32.5° (c=0.117 in chloroform).
Reaction SMILES: [OH:1][C@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:3]1.C1(C)C=CC=CC=1.C1CCCCC1.CC([O-])C.CC([O-])C.CC([O-])C.[Al+3]>CCOCC>[CH3:18][CH:16]([CH2:15][CH2:14][CH2:13][C@H:12]([C@@H:11]1[C@:20]2([CH3:28])[C@H:8]([C@H:7]3[C@H:23]([CH2:22][CH2:21]2)[C@:24]2([CH3:27])[C:4](=[CH:3][C:2](=[O:1])[CH2:26][CH2:25]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1)[CH3:19])[CH3:17]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
111 g. of 3β-hydroxy-5-cholestene is heated in 2.2 l. of toluene and 111 ml. of cyclohexane to boiling. A solution of 55.5 g. of aluminum isopropylate in 666 ml. of toluene is added dropwise thereto. The mixture is then further heated for 90 minutes with gradual distillation. The cooled reaction solution is diluted with ether, washed with dilute sulfuric acid and water, and concentrated. The residue is distilled with steam and the crude product, obtained after extraction with methylene chloride, is chromatographed on silica gel. After recrystallization from methanol, 70 g. of 4-cholesten-3-one is obtained, m.p. 79° - 80.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH3:11])=[CH:4][C:3]=1[F:12].CN(C)[CH:15]=[O:16].C(O)(=O)C.O>O1CCCC1.C(NC(C)C)(C)C.[Li]>[F:12][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[C:5]([O:8][CH2:9][CH2:10][CH3:11])[C:4]=1[CH:15]=[O:16]
Reactant: CN(C)C=O
Reactant: CCCOc1ccc(F)c(F)c1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Product: CCCOc1ccc(F)c(F)c1C=O
Yield: 41.5 %

Procedure:
In a manner similar to the method described in example 52a, 1,2-difluoro-4-propoxy-benzene (17 g, 98.8 mmol) prepared in example 104a was reacted with lithium diisopropyl amine (59.2 mL, 2.0 M in THF, 0.118 mmol), N,N-dimethyl-formamide (9.17 mL, 0.118 mol) and quenched with acetic acid (23.7 g, 0.395 mol) and water (41.2 mL) in tetrahydrofuran to give 2,3-difluoro-6-propoxy-benzaldehyde as a yellow solid (Yield: 8.2 g, 42%).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:29])[C:16]3[CH:21]=[C:20]([Cl:22])[C:19]([NH:23][C:24](=[O:26])[CH3:25])=[CH:18][C:17]=3[O:27][CH3:28])[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:30]O>C(O)(=O)C>[CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH+:14]([O-:30])[C:15](=[O:29])[C:16]3[CH:21]=[C:20]([Cl:22])[C:19]([NH:23][C:24](=[O:26])[CH3:25])=[CH:18][C:17]=3[O:27][CH3:28])[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NC1CCN(CC2CCCCC2)CC1
Reactant: OO
Solvent: CC(=O)O
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)[NH+]([O-])C1CCN(CC2CCCCC2)CC1

Procedure:
To a solution of N-(1-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-acetamido-5-chlorobenzamide (10 g; 0.023 moles) in glacial acetic acid (50 ml) a 30% hydrogen peroxide solution (6 ml) was added. The mixture was heated for 8 hours at a temperature between 70° and 80° C. Afterwards the solvent was evaporated in vacuo, and N-(1-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-acetamido-5-chlorobenzamide N-oxide was obtained as a viscous liquid. After recrystallisation from a mixture of acetone and diethyl ether, there was obtained 7.3 g of the N-oxide, melting at 206°-208° C.