Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.C(=O)([O-])O.[Na+].[H][H]>CO.[Pd]>[F:14][C:3]1[CH:2]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([O:12][CH3:13])=[N:10]2)=[N:5][CH:4]=1
Reactant: COc1ccc2ncc(F)c(Br)c2n1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ncc(F)cc2n1
Yield: 87 %

Procedure:
8-Bromo-7-fluoro-2-(methoxy)-1,5-naphthyridine (for a synthesis see WO2004058144, Example 53(g)) (5.040 g, 19.61 mmol) was stirred in MeOH (200 ml) with sodium hydrogen carbonate (3.29 g, 39.22 mmol) and 10% palladium on carbon (2.5 g), and the resulting suspension was hydrogenated at 1 atmosphere of hydrogen pressure under for 4 h. The mixture was filtered with suction through celite and the solids were washed with MeOH (500 ml). The combined filtrate plus washings were concentrated to about 50 ml under reduced pressure and then treated with water (200 ml) and DCM (300 ml). The aqueous phase was separated and extracted twice more with DCM (300 ml). The combined organic phases were separated, dried over anhydrous magnesium sulphate, filtered and evaporated to give the desired compound as an off-white solid (3.044 g, 87%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:14][C:13]([NH2:15])=[N:12][C:11]2[C:7]=1[N:8]=[CH:9][N:10]=2.O[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CN(C=O)C.C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:14]=[C:13]([NH2:15])[N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: Nc1nc2ncnc-2c(-c2ccco2)[nH]1
Reactant: OCCc1ccccn1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1nc(-c2ccco2)c2ncn(CCc3ccccn3)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
A mixture of 6-(2-furyl)-1H-purine-2-amine (50 mg, 0.25 mmol) and triphenylphosphine polystyrene (0.21 g, 0.62 mmol) in anhydrous DMF (0.5 mL) and anhydrous THF (2 mL) was treated with 2-(2-hydroxyethyl)pyridine (61 mg, 0.50 mmol), shaken at room temperature for 10 min, treated with di-tert-butyl azodicarboxylate (0.115 g, 0.50 mmol), shaken for 16 h, filtered and the filtrate concentrated in vacuo and purified by chromatography [SiO2; CH2Cl2-MeOH (100:5)] to give the title compound (36 mg, 47%) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:14])[CH3:13].Br.C(Cl)Cl.CS(C)=[O:22]>>[CH3:15][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:14])[CH:13]=[O:22]
Reactant: CC(=O)c1ccccc1OCCN(C)C
Reactant: CS(C)=O
Agent: Br
Solvent: ClCCl
Product: CN(C)CCOc1ccccc1C(=O)C=O
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 1-[2-(2-dimethylamino-ethoxy)-phenyl]-ethanone (4.35 g) in dimethylsulfoxide (8.8 ml) was added with 48% HBr (1.8 ml). The mixture was stirred at 80° C. for 6 hours under nitrogen stream. Then it was poured into methylene chloride (50 ml) and dried over magnesium sulfate. The mixture was neutralized to pH 7 with solid sodium bicarbonate, then filtered and evaporated under high vacuum at low temperature. The title compound was used without further purification.
Reaction SMILES: [CH2:1]([C@H:8]([CH2:20][C@@H:21]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:22]([OH:24])=[O:23])[C:9]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.O.[Rh]>[CH:2]1([CH2:1][C@@H:8]([CH2:20][C@H:21]([CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[C:22]([OH:24])=[O:23])[C:9]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)O)C(=O)O
Agent: [Rh]
Solvent: CCO
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@@H](CC1CCCCC1)C[C@H](CC1CCCCC1)C(=O)O)C(=O)O
Reaction time: 36 h

Procedure:
A suspension of 0.5 g of N-[(S,S)-2,4-dibenzyl-4-carboxybutyryl]-(L)-leucine and 0.5 g of 5% Rh/C in 10 ml of ethanol and 10 ml of water is hydrogenated for 36 hours at 3 atmospheres pressure (50 psi). The mixture is filtered through celite and concentrated. The colorless oil is treated with 1.0N sodium hydroxide in methanol and concentrated to yield N-[(S,S)-2,4-di-(cyclohexylmethyl)-4-carboxybutyryl]-(L)-leucine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1([F:15])[CH2:14][O:13][CH2:12]1.[CH:16]1([CH2:19][OH:20])[CH2:18][CH2:17]1.CC([O-])(C)C.[Na+]>CN(C=O)C.C1COCC1>[CH:16]1([CH2:19][O:20][C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=2[C:11]2([F:15])[CH2:14][O:13][CH2:12]2)[CH2:18][CH2:17]1
Reactant: O=C(O)c1ccc(C2(F)COC2)c(Cl)n1
Reactant: OCC1CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(C2(F)COC2)c(OCC2CC2)n1
Temperature: 50 °C
Yield: 21.7 %

Procedure:
6-Chloro-5-(3-fluorooxetan-3-yl)pyridine-2-carboxylic acid (Example 134 e, 44 mg, 190 μmol) and cyclopropylmethanol (CAN 2516-33-8, 17.8 mg, 20.0 μL, 247 μmol) were dissolved in DMF (1.32 mL). A solution of sodium 2-methylpropan-2-olate (42.0 mg, 437 μmol) in THF (800 μL) was added and the mixture was heated to 50° C. for 3 h and for additional 3 h to 70° C. After cooling to ambient temperature, the reaction mixture was poured onto ice/0.1 N HCl (25 mL) and extracted with EtOAc (2×25 mL). The combined extracts were washed with ice/brine (20 mL), dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by thin layer chromatography (2 mm SiO2, dichloromethane/MeOH 19:1, elution with EtOAc) to give the title compound (11 mg, 22 mg) as colorless oil, MS (ESI) m/e=268.2 [MH+].
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:20](=[CH:21][CH:22]=1)[C@@H:19]1[C@H:10]([C@H:11]3[C@@:15]([CH2:17][CH2:18]1)([CH3:16])[C:14](=[O:23])[CH2:13][C@H:12]3[CH2:24][CH2:25][C:26]([NH:28][C:29]1[S:30][C:31]([CH3:34])=[CH:32][N:33]=1)=[O:27])[CH2:9][CH2:8]2)=[O:4].[Li+].[OH-].CO>O>[CH3:34][C:31]1[S:30][C:29]([NH:28][C:26](=[O:27])[CH2:25][CH2:24][C@H:12]2[C@H:11]3[C@H:10]4[C@H:19]([CH2:18][CH2:17][C@:15]3([CH3:16])[C:14](=[O:23])[CH2:13]2)[C:20]2[C:7](=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:22][CH:21]=2)[CH2:8][CH2:9]4)=[N:33][CH:32]=1
Reactant: COC(=O)c1ccc2c(c1)CC[C@H]1[C@@H]3[C@H](CCC(=O)Nc4ncc(C)s4)CC(=O)[C@@]3(C)CC[C@H]21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cnc(NC(=O)CC[C@@H]2CC(=O)[C@@]3(C)CC[C@@H]4c5ccc(C(=O)O)cc5CC[C@H]4[C@H]23)s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
350 mg 15β-{3-[(5-methyl-1,3-thiazol-2-yl)amino]-3-oxopropyl}-17-oxoestra-1(10),2,4-triene-3-carboxylic acid methyl ester and 5 eq LiOH are mixed with 30 ml MeOH and 10 ml H2O and stirred at 50° C. (water bath) for about 4 h. Then a few mg LiOH, 30 ml MeOH and 10 ml H2O were added and the reaction mixture was stirred for another 2 h at 50° C. After reducing the solvents, H2O is added, the reaction mixture is extracted with EtOAc. The combined aquatic layers are acidified with KHSO4aq to pH 2-3, and extracted twice with EtOAc. The latter organic layers are combined, washed with brine, dried (Na2SO4) and the solvent removed. Purifying by column chromatography (CH2Cl2: MeOH:AcOH 37:3:0.1) give 150 mg pure 15β-{3-[(5-methyl-1,3-thiazol-2-yl)amino]-3-oxopropyl}-17-oxoestra-1(10),2,4-triene-3-carboxylic acid (=EXAMPLE 4, NMR data see below). 15β-{3-[(5-methyl-1,3-thiazol-2-yl)amino]-3-oxopropyl}-17-oxoestra-1(10),2,4-triene-3-carboxamide
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[C:19](=O)([O-])[O-:20].[Na+].[Na+]>CN(C)C=O>[CH3:1][C:2]1([CH3:18])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:19]=[O:20])[CH:8]=2)[N:3]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C([O-])[O-]
Reactant: CCCCCCCN1c2ccccc2CC1(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCN1c2ccc(C=O)cc2CC1(C)C
Temperature: 80 °C
Yield: 36.1 %

Procedure:
To 2,2-dimethyl-N-n-heptylindoline (12.5 g) in dimethylformamide (100 cm3) phosphorus oxychloride (15.3 g) was added at 5° C. before heating the mixture at 80° C. for 2-5 hours. The reaction mixture was cooled, poured onto ice, neutralised with solid sodium carbonate and extracted into toluene. The toluene was washed with water, separated, dried over magnesium sulphate, filtered and evaporated to leave an oil. The oil was eluted from silica using dichloromethane as eluent, evaporation of the solvent gave 2,2-dimethyl-5-formyl-N-n-heptylindoline (4.9 g, 36.1%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:18]=[CH:17][C:10]([CH2:11][CH:12]([CH2:15][OH:16])[CH2:13][OH:14])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[CH:22](OCC)[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:29])[CH3:28])C>>[CH:1]1([O:6][C:7]2[CH:18]=[CH:17][C:10]([CH2:11][CH:12]3[CH2:13][O:14][CH:22]([CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:16][CH2:15]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OCC(CO)Cc1ccc(OC2CCCC2)cc1
Reactant: CCOC(CCCNC(C)=O)OCC
Product: CC(=O)NCCCC1OCC(Cc2ccc(OC3CCCC3)cc2)CO1

Procedure:
2-(4-Cyclopentyloxybenzyl)propane-1,3-diol (92 mg, 337 μmol) was reacted with N-(4,4-diethoxybutyl)acetamide in analogy to example 3d. Yield: 81 mg (60%), M+H+: 362.27.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)=[CH:14][C:12]=2[CH:13]=1.[I:26]N1C(=O)CCC1=O>>[I:26][C:13]1[C:12]2[CH:14]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[CH:24][CH:25]=3)[CH:16]=[CH:17][C:11]=2[O:10][C:9]=1[CH2:8][CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C@H:2]1[CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: C[C@@H]1CCCN1CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Product: C[C@@H]1CCCN1CCc1oc2ccc(-c3ccc(C#N)cc3)cc2c1I
Yield: 18 %

Procedure:
The mono-(L)-tartaric acid salt of the product of Example 1D and N-iodosuccinimide were processed as in Example 156, except that a large excess of N-iodosuccinimide (2.4 molar equivalents) was utilized, to provide the title compound as a tan gum (18% yield). MS (ESI) m/z 457 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 1.49 (d, 3H), 1.67-1.84 (m, 1H), 2.00-2.25 (m, 2H), 2.29-2.44 (m, 1H), 3.22-3.63 (m, 5H), 3.72-3.91 (m, 2H), 7.59-7.64 (m, 2H), 7.72 (dd, 1H), 7.80-7.89 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si](C)(C)C)=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][CH:8]=1
Reactant: C[Si](C)(C)C#Cc1ccc(OCc2cccc(F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(OCc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2.06 g (6.9 mmol) of [4-(3-fluoro-benzyloxy)-phenylethynyl]-trimethyl-silane in 35 ml methanol is treated with 95 mg (0.69 mmol) of solid potassium carbonate. The mixture is stirred at RT for 3 h, concentrated and treated with saturated aqueous sodium hydrogencarbonate. The compound is extracted three times with dichloromethane, dried over magnesium sulfate and concentrated to yield 1.53 g (98%) of a slightly brown oil. MS (neg.ions): m/e=225.4 (M−H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([F:9])[C:5]([F:8])=[N:6][CH:7]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH3:44][C:45]1[CH:49]=[C:48]([Sn](C)(C)C)[S:47][N:46]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:8][C:5]1[C:4]([F:9])=[CH:3][C:2]([C:48]2[S:47][N:46]=[C:45]([CH3:44])[CH:49]=2)=[CH:7][N:6]=1
Reactant: Cc1cc([Sn](C)(C)C)sn1
Reactant: Fc1cc(Cl)cnc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: Cc1cc(-c2cnc(F)c(F)c2)sn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
5-chloro-2,3-difluoropyridine (0.069 ml, 0.67 mmol), X-Phos (0.045 g, 0.094 mmol) and palladium (II) acetate (0.011 g, 0.047 mmol) were combined in 1,4-dioxane (0.2 M, 3.4 mL). To the reaction vessel was added 3-methyl-5-(trimethylstannyl)isothiazole (0.53 g, 2.0 mmol) and, after purging with argon, the reaction was stirred at 100° C. for 2 h and then concentrated in vacuo. The crude material was dissolved in minimal DCM and purified via MPLC (eluting first with 100% EtOAc followed by 20% EtOAc in hexanes-isocratic) to yield 2,3-difluoro-5-(3-methylisothiazol-5-yl)pyridine (0.139 g, 98% yield) as a yellow solid. 2,3-difluoro-5-(3-methylisothiazol-5-yl)pyridine was converted to the title compound using a procedure similar to 1-(4-methyl-6-phenylpyridazin-3-yl)hydrazine.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[N:13]3[N:14]=[C:15]([O:22][CH2:23]C4N=CN(C)N=4)[C:16]4[C:21]([C:12]3=[N:11][N:10]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:5]=1.[CH3:30][N:31]1[C:35](CO)=[N:34][CH:33]=[N:32]1>>[CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[N:13]3[N:14]=[C:15]([O:22][CH2:23][C:35]4[N:31]([CH3:30])[N:32]=[CH:33][N:34]=4)[C:16]4[C:21]([C:12]3=[N:11][N:10]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:5]=1
Reactant: Cn1ncnc1CO
Reactant: COCc1cc(-c2nnc3c4ccccc4c(OCc4ncn(C)n4)nn23)no1
Product: COCc1cc(-c2nnc3c4ccccc4c(OCc4ncnn4C)nn23)no1

Procedure:
The title-compound was prepared from the product of Example 116 part a and 1-methyl-1,2,4-triazole-5-methanol (prepared using the conditions of Itoh and Okongi, EP-A-421210) in a similar manner to Example 98, mp 206-207.56° C.; 1H NMR (360 MHz, CDCl3) δ 3.53 (3H, s, CH3), 4.12 (3H, s, CH3), 4.73 (2H, s, CH2), 5.87 (2H, s, CH2), 7.20 (1H, s, ArH), 7.42 (1H, s, ArH), 7.93 (1H, m, ArH), 8.06 (1H, m, ArH), 8.30 (1H, d, J=7.7 Hz, ArH), 8.70 (1H, d, J=7.2 Hz, ArH); MS (ES+) m/e 393 [MH]+.
Reaction SMILES: [CH3:1][C:2]([OH:11])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH3:4].N1C=CC=CC=1.[C:18](Cl)(=[O:25])[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CCCCCC>[CH3:1][C:2]([O:11][C:18](=[O:25])[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH3:4]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCCCCCC(C)(O)CC
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CCCCCCC(C)(CC)OC(=O)C1CCCCC1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
36 G. (0.25 mole) of 3-methylnonan-3-ol, 20 g. of pyridine and 60 ml. of hexane are combined and cooled to 5° C. under agitation. To the resulting solution is added, under agitation over a period of 1 to 2 hours while maintaining the reaction temperature between 5°-15° C. a solution of 37 g. (0.25 mole) hexahydrobenzoyl-chloride dissolved in 60 ml. of hexane. The source of cooling is removed and the reaction mixture is agitated overnight, permitting the temperature of the reaction mixture to rise to room temperature (25°-30° C.). After completion of the reaction, the formed pyridine hydrochloride is removed by successive washings with 100 ml. portions of warm water. The solvent is removed by distillation and the desired ester is rectified by fractional distillation in a vacuum, preferably at 1 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:4]([N:11]1[CH2:10][CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([OH:14])[CH2:13][CH2:12]1)[CH2:3][C:2]#[CH:7]
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Yield: 145.3 %

Procedure:
A mixutre of 3-butyn-1-methanesulfate (1.48 g, 0.01 mol), 4-(p-chlorophenyl)-4-hydroxypiperidine (2.54 g, 0.012 mol) and potassium carbonate (4.14 g, 0.03 mol) in 25 mL of acetonitrile was refluxed for 12 hrs. The mixture was filtered and washed with ethyl acetate (3×30 mL). The filtrate was evaporated in vacuo and was purified by flash chromatography to give 2.30 g (87%) of the product as a white solid. mp 98-100° C. 1H NMR (CHCl3) 1.550 (s, 1 H), 1.749 (m, 2 H), 1.997 (m, 1 H), 2.109 (m, 2 H), 2.423 (m, 4 H), 2.655 (m, 2 H), 2.798 (m, 2 H), 7.329 (d, J=7.2 Hz, 2 H), 7.429 (d, J=7.2 Hz, 2 H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])(C)[CH3:9]>C(Cl)Cl>[C:11]([SiH:8]([CH3:9])[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Product: CN1CCN([SiH](C)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 91.8 %

Procedure:
10 g (0.1 mol) of 1-methylpiperazine and 11.1 g (0.11 mol) of triethylamineare dissolved in 500 ml of methylene chloride and then the reaction mixtureis cooled to 0° C. A solution of 16.6 g (0.11 mol) of t-butyldimethylsilyl chloride in 20 ml of methylene chloride is slowly added to the reaction mixture and stirred at room temperature for 18 hours. The reaction mixture is passed through a silica gel column and the solvent is stripped off under reduced pressure. The residue is distilled under reduced pressure (115° C. to 120° C./0.5 mmHg) to afford 18.4 g of a colorless liquid compound.
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=3[OH:20])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[CH3:21]I.O>C1COCC1>[C:3]12([C:13]3[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=3[O:20][CH3:21])[CH2:4][CH:5]3[CH2:11][CH:9]([CH2:8][CH:7]([CH2:6]3)[CH2:12]1)[CH2:10]2
Reactant: CI
Reactant: Oc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (80% in oil, 4.32 g, 144 mmol) in 50 ml of THF, there are slowly added, while maintaining the temperature at 20° C., 36.8 g (120 mmol) of 2-(1-adamantyl)-4-bromophenol. The mixture is stirred for 1 hour at ambient temperature at which point 9 ml (144 mmol) of methyl iodide are added. The mixture is then stirred for 2 hours at 20° C., poured into water, extracted with ether, dried and evaporated. The product is purified by passage through a silica column (10×30 cm), eluting with a mixture of hexane (90%) and dichloromethane (10%). On evaporation, 26.2 g of a white solid are obtained. Yield--68%. Melting point: 138°-139° C.
Reaction SMILES: C(O[C:4]([CH:6]1[N:13]2[CH:9]([CH2:10][CH2:11][C:12]2=[O:14])[CH2:8][CH2:7]1)=[O:5])C.[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@H:18]([CH3:22])[N:17]1[CH2:23][CH2:24][CH2:25][NH2:26]>>[CH3:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH:18]([CH3:22])[N:17]1[CH2:23][CH2:24][CH2:25][NH:26][C:4]([CH:6]1[N:13]2[CH:9]([CH2:10][CH2:11][C:12]2=[O:14])[CH2:8][CH2:7]1)=[O:5]
Reactant: C[C@H]1CCC[C@H](C)N1CCCN
Reactant: CCOC(=O)C1CCC2CCC(=O)N21
Product: CC1CCCC(C)N1CCCNC(=O)C1CCC2CCC(=O)N21

Procedure:
A solution of hexahydro-5-oxo-1H-pyrrolizine-3-carboxylic acid ethyl ester (5.0 g, 0.0254 mol) in trans-3-[2,6-dimethylpiperidinyl]propylamine (34 g, 0.2 mol) is stirred at room temperature 24 hours. The solution is concentrated at reduced pressure and distilled to yield N-[3-[2,6-dimethyl-1-piperidinyl]propyl]-hexahydro-5-oxo-1H-pyrrolizine-3-carboxamide, trans-isomer.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:12]2[CH:11]3[CH2:15][CH2:16][N:7]([CH2:8][CH2:9][CH2:10]3)[C:6]=2[CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:23](I)[CH3:24]>CC(C)=O>[CH2:16]([N:7]1[CH2:6][CH:12]2[CH2:11][CH2:10][CH:9]([C:23]3[CH:24]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][C:13]=32)[CH2:8]1)[CH3:15]
Reactant: CCI
Reactant: O=[N+]([O-])c1ccc2c(c1)N1CCCC2CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1CC2CCC(C1)c1cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.4 %

Procedure:
4-Nitro-1-aza-tricyclo[6.3.2.0*2,7*]trideca-2(7),3,5-triene (82 mg, 0.376 mmol) was dissolved in acetone (5 mL) and K2CO3 (104 mg, 0.752 mmol, 2.0 eq) and ethyl iodide (64.2 mg, 0.414 mmol, 32.9 μL, 1.1 eq) were added. The reaction was stirred at room temperature for 48 hours. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (10 mL) and washed with water (10 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-20% MeOH/CH2Cl2 as the eluting solvent to obtain 10-ethyl-4-nitro-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2(7),3,5-triene as a pale orange oil (68 mg, 73%). LCMS (m/e) 247 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.03 (dd, 1H, J=2.3 and 8.1 Hz), 7.94 (d, 1H, J=2.3 Hz), 7.20 (d, 1H, J=8.1 Hz), 3.17-3.08 (m, 2H), 2.95-2.86 (m, 2H), 2.43 (q, 2H, J=7.1 Hz), 2.30-2.19 (m, 4H), 1.66-1.57 (m, 2H), 0.99 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[N+](N[C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH3:33])[CH3:32])=[CH:26][CH:25]=2)=[CH:18][N:17]=1)([O-])=O>C(O)C>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH3:32])[CH3:33])=[CH:26][CH:25]=2)=[CH:18][N:17]=1
Reactant: CN(C)Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc1
Reactant: Cc1[nH]cnc1CSCCN
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2ccc(CN(C)C)cc2)c(=O)[nH]1

Procedure:
A mixture of 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.37 g) and 2-nitroamino-5-(4-dimethylaminomethylbenzyl)-4-pyrimidone (2.27 g) in ethanol (12 ml) was heated under reflux for 24 hr. The ethanol was evaporated at reduced pressure giving 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-dimethylaminomethylbenzyl)-4-pyrimidone which was washed by mixing it with water, warming the mixture, allowing it to cool over about 16 hr. and decanting the water. The residue was reacted with ethanolic hydrochloric acid (7 ml) and ethanol removed at reduced pressure. The residue was recrystallised from methanol/ethanol to give the trihydrochloride (2.14 g) as a white solid m.p. 213.5°-216° C.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C@@H:14]3[CH2:16][C@H:15]3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]1>C(O)(CC)C>[Br:1][C:2]1[C:3]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:25]2)=[C:4]2[C:10]([NH:11][C:12]([C@@H:14]3[CH2:16][C@H:15]3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)[C@@H]1C[C@H]1c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCC(C)O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)[C@@H]4C[C@H]4c4ccccc4)c23)C1
Yield: 48.3 %

Procedure:
trans-N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylcyclopropanecarboxamide (500 mg, 1.34 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (1338 mg, 6.68 mmol) in s-BuOH (5 mL) were heated to 135° C. in a sealed tube for 24 hours. After cooling down, the residue was concentrated and purified by reverse phase chromatography (SP4, 25M, water/ACN 80/20→0/100, 30 CV) to yield tert-butyl (R)-1-(5-bromo-3-(trans-2-phenyl cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (359 mg, 48.5% yield) as a solid.