Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]([CH3:18])[CH3:17])[C:6]=2[N:19]=1.[NH2:20][C:21]1[C:36]([O:37][CH3:38])=[CH:35][C:24]([C:25]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:26])=[C:23]([F:39])[CH:22]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[F:14][C:9]1([F:15])[CH2:8][N:7]([CH:16]([CH3:18])[CH3:17])[C:6]2[N:19]=[C:2]([NH:20][C:21]3[C:36]([O:37][CH3:38])=[CH:35][C:24]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[O:26])=[C:23]([F:39])[CH:22]=3)[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1N
Reactant: CC(C)N1CC(F)(F)C(=O)N(C)c2cnc(Cl)nc21
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1Nc1ncc2c(n1)N(C(C)C)CC(F)(F)C(=O)N2C
Temperature: 100 °C
Reaction time: 18 h
Yield: 35.3 %

Procedure:
2-chloro-7,7-difluoro-9-isopropyl-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (100 mg, 0.344 mmol) and 4-amino-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide (100 mg, 0.355 mmol) were suspended in water (2 mL) and sulfuric acid (118 mg, 1.20 mmol) was added. The reaction mixture was stirred in a closed vial at 100° C. for 18 h, cooled, diluted with water (5 mL) and brought to pH=7 using solid sodium carbonate. The resulting mixture was diluted with ethanol (0.5 mL) and stirred for 5 min. The precipitate was filtered, washed with water (5 mL) and dried in air for 20-30 min. It was then suspended in ethanol (˜10 mL), treated with solid sodium bicarbonate (130 mg) and stirred vigorously for 45 min. The insoluble salts were filtered off and filtrate was concentrated in vacuo. The residue was crystallized from ethanol-water (1:7; 8 mL) and dried in vacuum to afford the title compound as a white solid (65 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (d, J=6.82 Hz, 6H) 1.49-1.62 (m, 2H) 1.77 (br. d., 2H) 1.95 (app. t, J=11.2 Hz, 2H) 2.15 (s, 3H) 2.73 (br. d., J=11.12 Hz, 2H) 3.33 (s, 3H) 3.71 (m, J=7.83 Hz, 1H) 3.91 (s, 3H) 4.07 (t, J=13.52 Hz, 2H) 4.90 (m, 1H) 7.19 (d, J=6.57 Hz, 1H) 7.88 (dd, J=7.33, 3.03 Hz, 1H) 7.97 (s, 1H) 8.20-8.32 (m, 2H); [M+H] calc'd for C25H32F3N7O3, 536. found 536.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7](/[CH:8]=[CH:9]/[CH:10]=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7](/[CH:8]=[CH:9]/[CH2:10][OH:11])=[CH:12][CH:13]=1)([O-:3])=[O:2]
Reactant: O=C/C=C/c1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(/C=C/CO)cc1
Reaction time: 0.5 h

Procedure:
(E)-4-Nitrocinnamaldehyde (3,1.0 g, 5.65 mmol) was dissolved in methanol (70 ml ) in a 100 ml flask. Sodium borohydride (106 mg, 2.8 mmol) was added portionwise while stirring. Stirring was continued for 0.5 hr. The solution was evaporated to dryness. The residue was dissolved in a chloroform/water mixture and the organic phase was separated. It was washed twice with distilled water and dried over anhydrous MgSO4. Evaporation of solvent and crystallization from CH2Cl2-hexanes yielded compound 4 (1.0 g, 98%) as a pale yellow solid: mp 129-130° C.; Rf=0.77 (10%CH3OH—CH2Cl2); 1H NMR (300 MHz, CDCl3): δ8.20 (d, aromatic, 2H, J=8.0 Hz), 7.53) (d, aromatic, 2H, J=8.0 Hz), 6.73) (d, 1H, J=16 Hz), 6.57 (m, 1H), 4.20 (d, 2H, J=5.2 Hz), 1.56 (s, 1H); 13C NMR (CDCl3): δ147.16(C), 143.48(C), 133.81(CH), 128.46(CH), 127.13(CH), 124.23(CH), 63.30(CH2).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([O:15]C)=[CH:13][CH:12]=[CH:11][C:10]=2[F:17])[C:5]([Cl:18])=[CH:4][N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]([F:17])=[CH:11][CH:12]=[CH:13][C:14]=2[OH:15])[C:5]([Cl:18])=[CH:4][N:3]=1
Reactant: COc1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(F)c1Nc1nc(Cl)ncc1Cl
Temperature: -78 °C
Reaction time: 6 h

Procedure:
Into a 1-Neck round-bottom flask was added (2,5-Dichloro-pyrimidin-4-yl)-(2-fluoro-6-methoxy-phenyl)-amine (3.676 g, 0.013 mol) and CH2Cl2 (54 mL, 0.85 mol). The reaction mixture was cooled to −78° C. and 1.00 M of BBr3 in CH2Cl2 (51.0 mL) was added dropwise. The reaction mixture was allowed to warm to rt, was stirred for 6 hrs and was quenched with H2O. Title compound obtained as off-white solid. (3.497 g, 81%). HPLC purity 99%, LCMS 274.08 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 10.37 (s, 1H), 9.13 (s, 1H), 8.33 (s, 1H), 7.22-7.16 (m, 1H), 6.79-6.72 (m, 2H).
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5](=O)[CH2:6][CH3:7].O.[NH2:17]N>CCO>[CH2:6]([C:5]1[NH:17][N:2]=[CH:3][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:7]
Reactant: NN
Reactant: CCC(=O)C(=CN(C)C)c1ccccc1
Solvent: O
Solvent: CCO
Product: CCc1[nH]ncc1-c1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a mixture of 1-(dimethylamino)-2-phenylpent-1-en-3-one (3.32 g, 16.33 mmol) in EtOH (80.0 mL) was added hydrazine hydrate (1.58 mL, 32.66 mmol). The resulting mixture was stirred at 80° C. for 3 h. The reaction mixture was cooled to room temperature and concentrated to give a solid. The solid was re-crystallized, using 20% ethanol in water to give the title compound as a white solid (2.81 g). LCMS m/z=173 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.31 (t, J=7.58 Hz, 3H), 2.88 (q, J=7.58 Hz, 2H), 7.22-7.30 (m, 1H), 7.35-7.42 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=1)([O-])=O>C(OCC)(=O)C>[NH2:1][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)[nH]c1ccccc12
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)[nH]c1ccccc12

Procedure:
2-Nitrocarbazole [Mendenhall, G. D.; Smith, P. A. S. Org. Syn. Coll. Vol. 5 1973, 829, the disclosure of which is herein incorporated by reference ] (structure 14 of Scheme IV, where R1-6 =H, X=NH) (1.0 g, 4.7 mmol), in 50 mL of ethyl acetate was hydrogenated over 10% pd/C (50 mg) under an atmosphere of hydrogen for 1.5 h at rt giving, after filtration through Celite™, 840 mg (100%) of 2-aminocarbazole. Data for 2-aminocarbazole: 1H NMR (400 MHz, CDCl3) 7.94 (d, J=9.0, 1H), 7.83 (d, J=8.0, 1H), 7.80 (br s, 1H), 7.35 (m, 2H), 7.15 (dd, J=8.2, 1H), 6.67 (d, J=1.8, 1H), 6.58 (dd, J=9.0, 1.8, 1H), 3.73 (br s, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH:10]([CH3:21])[N:11]([C:16](OCC)=O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[K+]>O1CCCC1>[CH2:1]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH:10]([CH3:21])[N:11]([CH3:16])[CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CC2CCN(Cc3ccccc3)C2C1C
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC1C2C(CCN2Cc2ccccc2)CN1C

Procedure:
14.4 g (50 mol) of ethyl 2-benzyl-8-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate in 20 ml of absolute tetrahydrofuran are added dropwise to 3.8 g (0.1 mol) of lithium aluminum hydride in 100 ml of absolute tetrahydrofuran and the mixture is then heated under reflux overnight. It is decomposed successively using 4 ml each of water, 15% strength potassium hydroxide solution and water, and the inorganic salts are filtered off with suction and boiled three times with 50 ml of tetrahydrofuran each time. The organic solutions are concentrated and the residue is distilled.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[C:30]([C:39]([F:42])([F:41])[F:40])[CH:29]=1>C(#N)C>[CH:34]1([C:31]2[CH:32]=[CH:33][C:28]([CH2:27][O:1][C:2]3[CH:10]=[CH:9][C:8]4[NH:7][C:6]5[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=5[C:4]=4[CH:3]=3)=[CH:29][C:30]=2[C:39]([F:40])([F:41])[F:42])[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: FC(F)(F)c1cc(CCl)ccc1C1CCCC1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Temperature: 78 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
Ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (24.0 g, 1.0 eq) was charged into a 1 L, 3-neck round bottom flask set in a heating mantel with a J-KEM controller. Cesium carbonate (39.2 g, 1.3 eq) was charged into the flask. Acetonitrile (250 mL) was charged into the flask and the reaction mixture was stirred with a magnetic stir bar. 4-(Chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (26.7 g, 1.1 eq) was charged slowly over 20 minutes while heating the reaction mixture. The internal temperature at the beginning of the charge was about 21° C. and the internal temperature at the end of the charge was about 82° C. Reaction temperature was maintained at 78° C. 1PC taken after 2.0 hours indicated 95% conversion to product by HPLC. After 2.5 hours the reaction temperature was reduced from about 78° C. to about 54° C. over 33 minutes. 125 mL of acetonitrile (5 vol) was heated to 50° C. in a 250 mL Ehrlenmeyer flask. Celite® was placed in a glass sintered filter funnel and acetonitrile used to wash and pack the filter aid. The acetonitrile wash was discarded to waste. The packed Celite® was approximately 0.5 inches. The reaction mixture was cooled to about 54° C. and filtered through the Celite® filter aid in the glass sintered filter funnel and washed with the 125 mL acetonitrile heated to about 50° C. The acetonitrile filtrate was stirred under nitrogen at ambient temperature for 1.0 hour. The filtrate was concentrated under reduced pressure at about 24° C. forming a thick slurry; 260 mL of distillate was collected. 375 mL of methanol was used to transfer the slurry into a 1 L round bottom flask. The slurry was stirred under nitrogen at ambient temperature for 15.0 hours. The slurry was placed in an ice/salt bath and stirred under nitrogen for 1.2 hours. 150 mL of methanol was placed in an ice/salt bath. The solids were filtered in a Whatman disposable filter cup at about −11° C. and washed with chilled methanol (125 mL). The off-white solids were placed in a vacuum oven set at about 29° C. for 22.5 hours to afford 35.7 g of ethyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (Compound of Formula (IIk), wherein R3 is ethyl), 79% yield with 99.57 Area % by HPLC.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:12][CH2:11][CH2:10][O:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:2]1[C:3]2[CH2:12][CH2:11][CH2:10][O:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: Nc1nc(Cl)c2c(n1)OCCC2
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc2c1CCCO2

Procedure:
6,7-Dihydro-4-hydroxy-5H-pyrano[2,3-d]pyrimidin-2-amine can be prepared from diethyl 3-chloropropylmalonate, guanidine carbonate and sodium ethoxide in ethanol. Treatment of the product ##STR39## with phosphorus oxychloride gives 4-chloro-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-amine and subsequent reaction with sodium methoxide in refluxing methanol affords 6,7-dihydro-4-methoxy-5H-pyrano[2,3-d]pyrimidin-2-amine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[C:14]([C:18](=O)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:15]([NH2:17])[S:16][C:10]=2[CH2:9]1)=O)(C)(C)C.[CH:26]1([C:29](=[O:34])[CH2:30][C:31](=O)[CH3:32])[CH2:28][CH2:27]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH:26]1([C:29]([C:30]2[C:31]([CH3:32])=[N:17][C:15]3[S:16][C:10]4[CH2:9][NH:8][CH2:13][CH2:12][C:11]=4[C:14]=3[C:18]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:34])[CH2:28][CH2:27]1
Reactant: CC(=O)CC(=O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc(N)c2C(=O)c2ccccc2)C1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2ccccc2)c1C(=O)C1CC1)CCNC3
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
To a stirred solution of 1.0 g (2.79 mmol) 2-amino-3-benzoyl-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (the preparation of which is described in example 23) in 15 ml acetic acid was added 0.70 g (5.55 mmol) of 1-cyclopropyl-butane-1,3-dione and three drops of sulfuric acid. The mixture was then stirred at 100° C. for 30 minutes and then concentrated in vacuo. Flash chromatography (dichloromethane/methanol 95:5) afforded 0.47 g (48%) cyclopropyl-(2-methyl-4-phenyl-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl)-methanone as a brown oil. ES-MS m/e (%): 349 (M+H+, 100).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[N:20]([CH3:21])[NH:19][C:18]([O:23][CH3:24])(O)[C:17]=1[C:25]1[CH:33]=[CH:32][C:28]2[O:29][CH2:30][O:31][C:27]=2[CH:26]=1.CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[O:29]1[C:28]2[CH:32]=[CH:33][C:25]([C:17]3[C:18]([O:23][CH3:24])=[N:19][N:20]([CH3:21])[C:16]=3[NH:15][S:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)(=[O:13])=[O:12])=[CH:26][C:27]=2[O:31][CH2:30]1
Reactant: COC1(O)NN(C)C(N)=C1c1ccc2c(c1)OCO2
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: COc1nn(C)c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1-c1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 6 %

Procedure:
4-(tert-butyl)benzenesulfonyl chloride (190 mg) was added at room temperature under an atmosphere of nitrogen to a solution of 5-amino-4-(1,3-benzodioxol-5-yl)-3-methoxy-1-methyl-1H-pyrazol-3-ol (Preparation 43) (100 mg) and dimethylaminopyridine (50 mg) in anhydrous pyridine (4 ml). The reaction was stirred overnight. The mixture was concentrated under reduced pressure, then a saturated solution of ammonium chloride (6 ml), ethyl acetate (6 ml), and brine (6 ml) were sequentially added. The aqueous phase was extracted with ethyl acetate (2×8 ml) and the combined organic fractions were washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified to yield the title compound (10 mg).
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].BrCCC1C=CC=C([Cl:41])C=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[Cl:41][C:21]1[CH:20]=[C:19]([CH2:18][CH2:17][N:16]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]([CH3:1])([CH3:6])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Clc1cccc(CCBr)c1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCc2cccc(Cl)c2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 1-(2-bromo-ethyl)-3-chloro-benzene and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:17]=[O:18]>>[CH2:13]([C:12]1[CH:11]=[C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:15]=[CH:14][C:17]=1[OH:18])[C:14]1[CH:15]=[C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:11]=[CH:12][C:13]=1[OH:16]
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: C=O
Product: CCCCCCCCCc1ccc(O)c(Cc2cc(CCCCCCCCC)ccc2O)c1

Procedure:
2,2'methylenebis(4-nonylphenol) was prepared in a similar manner by replacement of the 1,1,3,3,-Tetramethylbutylphenol by 4-nonylphenol in the same mole ratio to formaldehyde.
Reaction SMILES: C(OC([NH:8][C:9]1[N:10]=[C:11]2[C:16]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[N:15][CH:14]=[C:13]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[N:12]2[CH:35]=1)=O)(C)(C)C.C(OC(N1CCN(C2C3N(C=C(C(OCC)=O)N=3)C(C3SC=CC=3)=CN=2)CC1)=O)(C)(C)C>>[N:17]1([C:16]2[C:11]3[N:12]([CH:35]=[C:9]([NH2:8])[N:10]=3)[C:13]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)=[CH:14][N:15]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)Nc1cn2c(-c3cccs3)cnc(N3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Agent: CCOC(=O)c1cn2c(-c3cccs3)cnc(N3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Product: Nc1cn2c(-c3cccs3)cnc(N3CCNCC3)c2n1

Procedure:
The title compound was prepared as described as in Example 61 step 6, except that tert-butyl 4-(2-((tert-butoxycarbonyl)amino)-5-(thiophen-2-yl)imidazo[1,2-a]pyrazin-8-yl)piperazine-1-carboxylate was substituted for ethyl 8-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-(thiophen-2-yl)imidazo[1,2-a]pyrazine-2-carboxylate. 1H NMR (300 MHz, DMSO-d6) δ: 7.71 (dd, J=5.1, 1.2 Hz, 1H), 7.46 (dd, J=3.6, 1.2 Hz, 1H), 7.40 (s, 1H), 7.22 (dd, J=5.1, 3.6 Hz, 1H), 7.08 (s, 1H), 5.23 (br, 2H), 4.01 (t, J=5.0 Hz, 4H), 2.79 (t, J=5.0 Hz, 4H). MS m/z: 301 (M+H+).
Reaction SMILES: S(=O)(=O)(O)O.Cl.[C:7]1([CH3:15])[CH:12]=[CH:11][C:10]([NH:13]N)=[CH:9][CH:8]=1.[CH3:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=O>O1CCOCC1>[CH3:16][N:17]1[CH2:22][CH2:21][C:20]2[NH:13][C:10]3[CH:9]=[CH:8][C:7]([CH3:15])=[CH:12][C:11]=3[C:19]=2[CH2:18]1
Reactant: Cc1ccc(NN)cc1
Reactant: CN1CCCCC1=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54 %

Procedure:
Sulfuric acid (2 mL) was added to a solution of p-tolyl hydrazine hydrochloride (6.0 g, 37 mmol) in dioxane (60 mL), and stirred for 5 min. at RT. N-Methyl piperidone (5.03 g, 41 mmol) was added and the mixture was heated at 80° C. for 2 h. After reaction completion as determined by TLC), the reaction mixture was concentrated to approximately 20 mL under reduced pressure and basified to pH 10 using 10% aqueous KOH solution. The reaction mixture was extracted with EtOAc (3×300 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure using a rotary evaporator to provide the desired compound as a brown colored solid (4.0 g, 52% yield). 1H NMR (DMSO-d6, di-HCl salt) δ (ppm): 7.30 (s, 1H), 7.20-7.10 (d, 1H), 7.10-7.00 (d, 1H), 3.80 (s, 2H), 2.90 (s, 4H), 2.60 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH:6]([OH:26])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH2:20][CH2:19][CH2:18][C:17]3([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:16]=2)=[CH:9][CH:8]=1)[CH3:2].[CH:28](N(CC)C(C)C)(C)[CH3:29].ClCCl.F[B-](F)(F)F.C([O+](CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH:6]([O:26][CH2:28][CH3:29])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH2:20][CH2:19][CH2:18][C:17]3([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)[CH:16]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)CC(O)c1ccc(OCC2=CC3(CCCCC3)CCC2)cc1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)CC(OCC)c1ccc(OCC2=CC3(CCCCC3)CCC2)cc1
Reaction time: 2.5 h

Procedure:
To a solution of 3-hydroxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionic acid ethyl ester (4.98 g) obtained in Step 7 and N,N-diisopropylethylamine (6.97 mL) in chloroform (100 mL) was added dropwise a 1M dichloromethane solution of triethyloxonium tetrafluoroborate (20 mL) under ice-cooling over 5 minutes, followed by stirring the reaction mixture under ice-cooling for 10 minutes and then at room temperature for 2.5 hours. Then, the reaction mixture was concentrated and the residue was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio) 1:5) to give 3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-pr opionic acid ethyl ester (2.175 g).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57][C:58]#[C:59][C:60]([CH2:71][CH3:72])([O:63][Si:64]([CH2:69][CH3:70])([CH2:67][CH3:68])[CH2:65][CH3:66])[CH2:61][CH3:62]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:57][C:58]#[C:59][C:60]([CH2:71][CH3:72])([O:63][Si:64]([CH2:69][CH3:70])([CH2:65][CH3:66])[CH2:67][CH3:68])[CH2:61][CH3:62])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H](O)C1=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
Reactant: CCC(C#CCBr)(CC)O[Si](CC)(CC)CC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C#CCO[C@H](C)C1=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)(CC)O[Si](CC)(CC)CC
Yield: 71.9 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (58.9 mg, 0.105 mmol), sodium hydride (60%, 21.0 mg, 0.525 mmol), 15-crown-5 (10 μl) and 1-bromo-4-ethyl-4-triethylsilyloxy-2-hexyne (134 mg, 0.420 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=19:1, developed once) to give the title compound as a colorless oil (60.2 mg, 72%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)([O:13][CH3:14])[CH2:9]1)C1C=CC=CC=1.ClCCCl.ClC(OC(Cl)C)=O>CO>[F:22][C:17]1[CH:16]=[C:15]([C:10]2([O:13][CH3:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: COC1(c2ccc(F)c(F)c2)CCN(Cc2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: ClCCCl
Product: COC1(c2ccc(F)c(F)c2)CCNC1
Yield: 97.6 %

Procedure:
Preparation according to Example 1. (−)-1-benzyl-3-(3,4-difluorophenyl)-3-methoxypyrrolidine (0.264 g, 0.87 mmol), 1,2-dichloroethane (20 ml), 1-chloroethyl chloroformate (0.49 g, 3.48 mmol) refluxed for 1 h, and methanol (20 ml) reflux 1 h Purification by HPLC on waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 50:50) gave the title compound (0.181 g, 97%). [a]D=−6.1° (methanol). MS m/z (rel. intensity, 70 eV) 213 (M+, 1), 198 (51), 183 (88), 171 (bp), 141 (53).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:29](O)=[O:30])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:28])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1.[NH:36]1[CH2:41][CH2:40][CH:39]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH2:38][CH2:37]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:21]=[C:22]([CH3:28])[C:23]([OH:27])=[C:24]([CH3:26])[CH:25]=3)[C:29]([N:36]3[CH2:41][CH2:40][CH:39]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[CH2:38][CH2:37]3)=[O:30])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Reactant: C1CC(N2CCOCC2)CCN1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCOCC3)CC2)cc(C)c1O

Procedure:
Prepared analogously to Example 1i from 70 mg (0.15 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 25 mg (0.15 mmol) 4-piperidin-4-yl-morpholine.