Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:23][C:24]([NH:26][C:27]1[CH:31]=[C:30]([CH3:32])[O:29][N:28]=1)=[O:25].[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37]>CO>[C:33]([O-:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([O-:38])=[O:37].[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:23][C:24]([NH:26][C:27]1[CH:31]=[C:30]([CH3:32])[O:29][N:28]=1)=[O:25]
Reactant: O=C(O)/C=C\C(=O)O
Agent: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)on4)c(Cl)c3)c2cc1OC
Solvent: CO
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
said process comprising the steps of: adding methanol to N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N′-(5-methyl-3-isoxazolyl)urea, adding a solution of maleic acid in methanol dropwise thereto, stirring the mixture to give a maleate of N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N′-(5-methyl-3-isoxazolyl)urea, and
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)=[O:4].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C1C=CC=CC=1>[N:17]1([CH2:2][C:3]([C:5]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]3[C:6]=2[CH:7]=[CH:8][C:9](=[O:16])[NH:10]3)=[O:4])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCNCC1
Reactant: O=C(CCl)c1ccc(O)c2[nH]c(=O)ccc12
Solvent: c1ccccc1
Product: O=C(CN1CCCCC1)c1ccc(O)c2[nH]c(=O)ccc12
Reaction time: 6 h

Procedure:
10 g of 5-chloroacetyl-8-hydroxycarbostyril (IV) prepared in Example 4 or 8 was suspended in 50 ml of benzene, and 10 ml of piperidine (III) was added to the suspension followed by allowing the mixture to react while heating under refluxing and stirring for 6 hours. The reaction mixture was filtered to recover the reaction product which was then washed with benzene and then with 50 ml of isopropanol. The resulting insoluble material was dissolved in 150 ml of a 2% aqueous hydrochloric acid. The solution was concentrated to dryness under reduced pressure and the resulting residue was recrystallized from ethanol to obtain 7.5 g of white amorphous 5-piperidinoacetyl-8-hydroxycarbostyril (II) hydrochloride 1/2 hydrate having a melting point of 239° - 241° C. (with decomposition).
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:37]1(=[O:43])[NH:41][C:40](=[O:42])[CH2:39][CH2:38]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[F:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:41]4[C:40](=[O:42])[CH2:39][CH2:38][C:37]4=[O:43])=[CH:20][CH:19]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1
Reactant: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(CO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(CN2C(=O)CCC2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
In an atmosphere of argon, N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-4-hydroxymethyl-N-(2-methoxyphenyl)benzamide (54 mg, 0.11 mmol), succinimide (13 mg, 0.132 mmol) and triphenylphosphine (34.6 mg, 0.132 mmol) were dissolved in THF (1 ml) to which was subsequently added dropwise diethyl azodicarboxylate (21 μl, 0.132 mmol) while cooling in an ice bath. After 30 minutes of stirring at room temperature, the reaction solution was diluted with water (10 ml) and extracted with ethyl acetate. The resulting organic layer was washed with water and saturated brine, and dried on anhydrous sodium carbonate. Thereafter, the solvent was removed by evaporation, and the resulting residue was purified by a PTLC (chloroform:methanol=20:1) to obtain 42 mg (66.8%) of the title compound in a light yellow amorphous form.
Reaction SMILES: C(O[CH:5]([CH2:12][CH3:13])[CH:6]([N+]([O-])=O)[CH2:7][CH3:8])(=O)C.[N+:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])#[C-:15].C1CCN2C(=NCCC2)CC1.Cl>C1COCC1>[CH2:12]([C:5]1[C:6]([CH2:7][CH3:8])=[CH:15][NH:14][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:13]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CCC(OC(C)=O)C(CC)[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1[nH]cc(CC)c1CC
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.6 %

Procedure:
After 4-acetoxy-3-nitrohexane (11.34 g, 60 mmol) had been added to a reaction vessel, air in the vessel was replaced with nitrogen, and dry-THF (150 ml) and ethyl isocyanoacetate (7.28 ml, 66 mmol) were added. Then, DBU (20.76 ml, 144 mmol) was slowly dropwise added while being cooled on an ice bath, and stirred at room temperature for 12 hours. After the completion of the reaction, 1 N hydrochloric acid was added, and extracted with chloroform, and the extract was washed with water and a saturated salt solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After that, the concentrated product was purified by means of silica gel column chromatography to yield ethyl 3,4-diethylpyrrole-2-carboxylate (10.97 g, 94% yield).
Reaction SMILES: [Si]([O:8][C@@H:9]([CH3:42])[C@@H:10]([NH:31][C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([Cl:40])[C:33]=1[CH3:41])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][Si](C(C)(C)C)(C)C)=[C:18]([Cl:30])[CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[Cl:40][C:34]1[C:33]([CH3:41])=[C:32]([NH:31][C@@H:10]([C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:30])[CH:17]=3)=[N:14][N:15]=2)[C@@H:9]([OH:8])[CH3:42])[CH:39]=[CH:38][C:35]=1[C:36]#[N:37]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(O[Si](C)(C)C(C)(C)C)c(Cl)c3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(O)c(Cl)c3)o2)[C@H](C)O)ccc(C#N)c1Cl

Procedure:
4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-(tert-butyldimethylsilyloxy)-3-chloro-phenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (377 mg, 0.58 mmol) was deprotected using tetrabutylammonium fluoride (1.0 M solution in THF, 1.2 mL, 1.2 mmol) in a manner analogous used for the preparation of Example 22. After column chromatography (80% EtOAc/hexanes) the title compound was isolated as an off-white solid (23 mg). 1H NMR (400 MHz, CDCl3, δ in ppm) 7.91 (d, J=2.2 Hz, 1H), 7.77 (dd, J=2.2, 8.4 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 5.68 (d, J=8.4 Hz, 1H), 5.08 (dd, J=3.7, 8.4 Hz, 1H), 4.62 (m, 1H), 2.39 (s, 3H), 1.40 (d, J=6.3 Hz, 3H).
Reaction SMILES: B.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([C:22](O)=[O:23])=[C:11]2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:6][CH:5]=1>O1CCCC1>[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([CH2:22][OH:23])=[C:11]2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:6][CH:5]=1
Reactant: COc1cccc(-c2c(C(=O)O)ccc3ccc(OC)cc23)c1
Agent: B
Solvent: C1CCOC1
Product: COc1cccc(-c2c(CO)ccc3ccc(OC)cc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
A solution of borane in tetrahydrofuran (1M; 10 mL) was added to a solution of crude 7-methoxy-1-(3-methoxyphenyl)-2-naphthalenecarboxylic acid (2 g) in tetrahydrofuran (10 mL) at 0°-5° C. and the mixture was stirred at room temperature for 3 hours. After the solvent was evaporated off, the reaction was diluted with 1N sodium hydroxide and extracted with dichloromethane. The organic layer was washed with brine then was dried (MgSO4) and evaporated to give 1.75 g of crude 7-methoxy-1-(3-methoxyphenyl)-2-naphthalenemethanol.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:8]1([CH2:14][CH2:15][CH2:16]CO)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OC1C=CC(O)=CC=1)C1C=CC=CC=1>[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Ti+4]>[C:1]([O:6][CH2:7][CH2:16][CH2:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC
Reactant: OCCCCc1ccccc1
Agent: [Ti+4]
Agent: CCCC[O-]
Agent: Oc1ccc(OCc2ccccc2)cc1
Product: C=C(C)C(=O)OCCCCc1ccccc1
Temperature: 25 °C
Yield: 74.4 %

Procedure:
A three neck round bottom flask containing a teflon coated magnetic stirring bar was successively charged with 120 mL (1.09 mol) of methyl methacrylate (2), 5.35 g (0.015 mol) of titanium tetrabutoxide (Ti(OC4H9)4), 60 mL (0.39 mol) of 4-phenyl-1-butanol (1), and 14.6 g (0.073 mol) of 4-benzyloxyphenol (4-BOP). An addition funnel, thermometer, and a short path still head with thermometer and receiver flask were placed in the flask necks. The flask was placed in an oil bath and the temperature was increased until distillation began. Methyl methacrylate (2) was placed in the addition funnel and was added dropwise at the same rate as the distillate. The reaction mixture was heated for 4 hours and then cooled to room temperature. The crude product was vacuum distilled to isolate 62.8 g (0.29 mol, 74%) of 4-phenylbutyl methacrylate (3) as a clear, colorless liquid. Example 2: Synthesis of 3-benzyloxypropyl methacrylate.
Reaction SMILES: [N+:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:30])[C@@H:18]([NH:19]C(=O)COC4C=CC=CC=4)[C@H:15]3[S:14][C@:13]2([CH2:32][O:33][C:34](=[O:39])[NH:35]C(=O)C)[CH3:31])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C)C1C=CC=CC=1.CO>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:30])[C@@H:18]([NH2:19])[C@H:15]3[S:14][C@:13]2([CH2:32][O:33][C:34](=[O:39])[NH2:35])[CH3:31])=[O:11])=[CH:40][CH:41]=1)([O-:3])=[O:2]
Reactant: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Solvent: CO
Product: C[C@@]1(COC(N)=O)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
A solution of (2R,3S,5R,6R) 2-(N-acetyl)carbamoyloxymethyl-2-methyl-6-phenoxyacetamidopenam-3-carboxylic acid p-nitrobenzyl ester (1.17 g, 2.0 mmol) in methylene chloride (10 ml) at -40° was charged with dimethylaniline (1.03 ml, 8.0 mmol) and phoshorous pentachloride (0.92 g, 4.4 mmol). The solution was stirred at -35° to -40° for 30 minutes and cold (~-35°) methanol (4.1 ml, 100 mmol) was added dropwise. The pale green solution was stirred at -35° to -40° for 2 hours and then quenched into ice-water (10 ml). The pH was adjusted to 1.7 with conc. ammonia and the layers were separated. The aqueous was washed with CH2Cl2 (5 ml), combined with a water back-extract (5 ml), and stirred with CH2Cl2 (10 ml) during pH adjustment to 6.5 with ammonia. The organic phase was withdrawn, washed (5 ml, H2O), combined with a back-extract (CH2Cl2, 10 ml), dried (4 A sieves), filtered, concentrated to 4 ml and diluted with heptane (10 ml). The suspension was concentrated to 8 ml and the liquids were decanted. The solids were treated with CH2Cl2 (4 ml) and heptane (10 ml) in the same fashion, and the product was washed with heptane and dried to an off-white solid (0.28 g) 34%; nmr 100 MHz CDCl3 --D2O δ8.24 (2, d, J=8.5 Hz, 1/2pNB AB), 7.56 (2, d, J=8.5, pNB AB), 5.68 (1, brd J=4, C5 --H), 5.32 (2 s, benzyl CH2), 4.76 (1, s, C3 --H) 4.55 (HOD overlapping C6 --H d), 4.16 and 3.97 (2, ABq J=11.5 C2 --CH2 --O), 1.43 (3, s, C3 --C3), with 2.36 ##STR79##
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd]>[C:2]1([C:1]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Agent: [Pd]
Product: c1ccc(-c2ccccc2)cc1

Procedure:
In step 1 of Scheme A, nitrobenzoic acid a is subject to iodination under sulfuric acid conditions to afford iodo-nitrobenzoic acid b. Benzoic acid compound b is reacted with arylboronic acid compound c in the presence of tetrakis-triphenylphosphine)palladium catalyst to afford biphenyl acid compound d. The acid group of biphenyl acid d is protected by esterification in step 3 to form biphenyl acid methyl ester e. Biphenyl ester e is then subject to reduction to form biphenylamine f in step 4. An iodination reaction is carried out in step 5 by treating biphenylamine f with methylene iodide or like iodination reagent to afford iodo compound g. In step 6 iodo compound g is treated with thiadiazole h in the presence of palladium catalyst to give thiadiazole ester compound i. Compound i then undergoes base-catalyzed hydrolysis in step 7 to give the corresponding carboxylic acid compound j. Compound j is then reacted with amine k to provide thiazole amide compound m, which is a compound of formula I in accordance with the invention.
Reaction SMILES: C(N(CC)[CH2:4][CH2:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)C.COC1C=C(CCCC(=O)C=C)C=CC=1.C(C(C=C)=O)=C.[CH2:42]([CH:44]1[C:48](=[O:49])[CH2:47][CH2:46][C:45]1=[O:50])[CH3:43]>[OH-].[K+]>[CH2:42]([C:44]1([CH2:4][CH2:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:48](=[O:49])[CH2:47][CH2:46][C:45]1=[O:50])[CH3:43]
Reactant: CCC1C(=O)CCC1=O
Reactant: CCN(CC)CCC(=O)CCCc1cccc(OC)c1
Agent: C=CC(=O)C=C
Agent: C=CC(=O)CCCc1cccc(OC)c1
Agent: [K+]
Product: CCC1(CCC(=O)CCCc2cccc(OC)c2)C(=O)CCC1=O

Procedure:
Referring now to FIG. 1, wherein the compounds are assigned Roman numerals for identification schematically, the sequence of reactions involved in the synthesis of a specific embodiment, namely, 13β,17α-diethyl-17β-hydroxygon-4-en-3-one, is illustrated. 3-(m-Methoxyphenyl)propanol (I) is heated with phosphorus tribromide in benzene after dropwise addition in the cold to form 3-(m-methoxyphenyl)propyl bromide (II). This halogen compound (II) dissolved in tetrahydrofuran is condensed with sodium acetylide in liquid ammonia to obtain 5-(m-methoxyphenyl)-1-pentyne (III). Compound III is allowed to stand under nitrogen with water, 30% formalin, acetic acid, diethylamine, dioxan, and cuprous chloride at 70° C for about 12 hours, whereby there is obtained 1-diethylamino-6-(m-methoxyphenyl)-2-hexyne (IV), which is in turn hydrated in the presence of a mercury salt and sulfuric acid to form 1-diethylamino-6-(m-methoxyphenyl)-3-hexanone (V). The ketamine (V) may eliminate diethylamine on distillation to give the vinyl ketone 6-(m-methoxyphenyl)-1-hexen-3-one (VI). Either the ketamine (V) or the ketone (VI), or mixtures thereof, is then reacted with 2-ethyl-1,3-cyclopentanedione (VII) under Michael condensation conditions, e.g. refluxing in methanolic potassium hydroxide to form 2-ethyl-2-[6-(m-methoxyphenyl)-3-oxohexyl]-1,3-cyclopentanedione (VIII).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[CH3:27][NH:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=1>>[C:25]([C:22]1[CH:21]=[CH:20][C:19]([S:16]([NH:15][C:10]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:28]([CH3:27])[C:29]4[CH:34]=[CH:33][C:32]([O:35][C:36]([F:37])([F:38])[F:39])=[CH:31][CH:30]=4)=[CH:4][CH:5]=3)=[N:14][CH:13]=[CH:12][N:11]=2)(=[O:17])=[O:18])=[CH:24][CH:23]=1)#[N:26]
Reactant: CNc1ccc(OC(F)(F)F)cc1
Reactant: N#Cc1ccc(S(=O)(=O)Nc2nccnc2-c2ccc(CCl)cc2)cc1
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccc(C#N)cc2)cc1)c1ccc(OC(F)(F)F)cc1
Yield: 70 %

Procedure:
Following the general method as outlined in Example 1 (Method D), N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-4-cyanobenzenesulfonamide, and N-methyl-4-(trifluoromethoxy)aniline, the title compounds were isolated as a yellow solid in 70% yield (92% purity by HPLC).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]([C:13]3[S:20][C:19]([CH3:21])=[C:18]4[C:14]=3[CH2:15][C@H:16]3[C:22]([CH3:24])([CH3:23])[C@H:17]34)=[N:11][N:12]=2)[CH:5]=[C:4]([CH3:25])[N:3]=1.[CH3:26]N1C(=O)CCC1.C[Mg]I>C1COCC1>[CH3:26][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]([C:13]3[S:20][C:19]([CH3:21])=[C:18]4[C:14]=3[CH2:15][C@H:16]3[C:22]([CH3:24])([CH3:23])[C@H:17]34)=[N:11][N:12]=2)[CH:5]=[C:4]([CH3:25])[N:3]=1
Reactant: Cc1cc(-c2nnc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)o2)cc(Cl)n1
Reactant: CN1CCCC1=O
Agent: C[Mg]I
Solvent: C1CCOC1
Product: Cc1cc(-c2nnc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)o2)cc(C)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46.9 %

Procedure:
To a solution of 2-chloro-6-methyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine (62.9 mg, 0.17 mmol), Fe(acac)3 (6 mg) and NMP (20 mg) in THF (5 mL) is added a solution of methylmagnesiumiodide in THF (3M, 0.51 mmol) and the mixture is stirred at rt for 15 h. The mixture is quenched with water (30 mL) and extracted with Et2O (2×50 mL). The organic extracts are dried (MgSO4), filtered and evaporated. The residue is purified by TLC (SiO2, EA-hexane) to give 2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine (28 mg); LC-MS: tR=0.88 min, [M+1]=352.54.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([C@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][OH:17])[CH2:10]2)[C:7]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:6]=2[N:5]=1)[CH3:3].[NH2:23][C:24]1[C:29]([C:30]#[N:31])=[C:28](Cl)[N:27]=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:23][C:24]1[C:29]([C:30]#[N:31])=[C:28]([NH:1][C@H:2]([C:4]2[N:8]([C@H:9]3[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][OH:17])[CH2:10]3)[C:7]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:6]=3[N:5]=2)[CH3:3])[N:27]=[CH:26][N:25]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1[C@H]1CCCN(CCO)C1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1[C@H]1CCCN(CCO)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 33.4 %

Procedure:
A mixture of 2-{(S)-3-[2-((S)-1-aminoethyl)-6-fluorobenzoimidazol-1-yl]piperidin-1-yl}ethanol (35.6 mg, 0.12 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (18 mg, 0.12 mmol), and DIPEA (40 μL, 0.23 mmol) in IPA (1 mL) was stirred at 90° C. for 3 h. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue purified by column chromatography (Si—PCC, gradient 2-10% 2M NH3/MeOH in DCM) affording 285 as a colourless solid (17 mg, 35%). LCMS (Method K): RT 2.24 min [M+H]+ 425.1. 1H NMR (CD3OD, 400 MHz): δ 8.06 (1H, s), 7.58 (1H, dd, J=8.9, 5.0 Hz), 7.49 (1H, dd, J=9.6, 2.4 Hz), 7.01 (1H, dt, J=9.2, 2.4 Hz), 5.84 (1H, q, J=6.9 Hz), 4.70-4.61 (1H, m), 3.63 (2H, t, J=6.0 Hz), 3.17-3.12 (1H, m), 3.01-2.96 (1H, m), 2.83 (1H, t, J=11.0 Hz), 2.66-2.54 (2H, m), 2.39-2.24 (2H, m), 1.99-1.88 (2H, m), 1.86-1.77 (1H, m), 1.70 (3H, d, J=6.9 Hz)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:31]>C(OCC)(=O)C.O1CCOCC1>[ClH:31].[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2nn(-c3ccccc3F)c3ccccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Fc1ccccc1-n1nc(OC2CCNCC2)c2ccccc21
Reaction time: 0.67 h
Yield: 55 %

Procedure:
To a stirred solution of 187 g (0.456 mole) of 4-[1-(2-fluoro-phenyl)-1H-indazol-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester in 600 mL of ethyl acetate was added 300 mL of 4M hydrogen chloride in dioxane dropwise over a 30 minute period. The temperature rose to 24° C. from 21° C. during the addition. When the addition was complete, gas evolution was observed and the temperature rose to 28° C. A cold water bath was used to lower the temperature to 18° C. After stirring for approximately 40 min, a solid began separating. Stirring was continued at 18-20° C. for 3 hours and then at −10° C. (ice-acetone bath) for 1 hour. The solid was collected by filtration, rinsed with 60 mL of ethyl acetate and pressed dry under suction. Further drying in vacuo at 30° C. for 16 hours afforded 87.3 g (55%) of product. The combined filtrate and washing was concentrated in vacuo to near dryness. The residue was taken up in 250 mL of ethyl acetate and the suspension was stirred at −10° C. for 2 hours. The solid was collected by filtration, rinsed with 30 mL of ethyl acetate and pressed dry under suction. Further drying in vacuo at 30° C. for 16 hours provided an additional 23.2 g (15%) of product. Total yield=110.5 g (70%). 1H NMR (CD3OD) δ ppm: 7.7 (d, 1H), 7.6 (t, 1H), 7.5-7.6 (m, 2H), 7.3-7.5 (m, 2H), 7.25 (m, 1H), 7.2 (t, 1H), 5.2 (m, 1H), 3.4-3.5 (m, 2H), 3.2-3.3 (m, 2H), 2.3-2.4 (m, 2H), 2.2-2.3 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[B:16]1[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]1)([O-])=O>C(OCC)(=O)C.[C].[Pd]>[N:10]1([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[C:5]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)[CH:6]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CC1(C)OB(c2cc(N3CCCCC3)ccc2[N+](=O)[O-])OC1(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cc(N3CCCCC3)ccc2N)OC1(C)C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 1-(4-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (600.0 mg, 1.81 mmol, 1.00 equiv) in ethyl acetate (30.0 mL), then Palladium carbon (10%) (150 mg) was added next. The gas of H2 was introduced in. The resulting solution was stirred for 1 h at 0˜5° C. The Pd/C was filtered out and the filtrate was collected and concentrated under vacuum. This resulted in 545.8 mg (99%) of 4-(piperidin-1-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine as a green to yellow solid. The target product was unstable, it was used to the next reaction step rapidly
Reaction SMILES: CN1CCCC1=O.[CH:8]1[C:20]2[N:19]([NH2:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1.[Cl:22][C:23]1[CH:28]=[C:27](Cl)[N:26]=[CH:25][N:24]=1>O>[Cl:22][C:23]1[N:24]=[CH:25][N:26]=[C:27]([NH:21][N:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3[C:20]2=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:28]=1
Reactant: Nn1c2ccccc2c2ccccc21
Reactant: Clc1cc(Cl)ncn1
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1cc(Nn2c3ccccc3c3ccccc32)ncn1
Temperature: 100 °C

Procedure:
To 150 ml of 1-methyl-2-pyrrolidinone was added 10.0 g of 9H-carbazol-9-amine, and 8.2 g of 4,6-dichloropyrimidine, and the mixture was heated to 100° C. and stirred for eleven hours. The mixture was then poured into water and extracted with toluene. The organic layer was washed with water and dried (sat. NaCl, anhydrous MgSO4).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[C:13]1([C:19]#[CH:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1.[Cu]I>[C:13]1([C:19]#[C:20][C:2]2[C:6]3[CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=[CH:10][C:5]=3[O:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C#Cc1ccccc1
Reactant: O=Cc1ccc2occ(Br)c2c1
Agent: [Cu]I
Solvent: C1CCOC1
Product: O=Cc1ccc2occ(C#Cc3ccccc3)c2c1
Temperature: 55 °C
Yield: 56 %

Procedure:
In a dry flask 3-Bromo-1-benzofuran-5-carbaldehyde (1 g, 4.4 mmol) were dissolved in anhydrous THF (50 ml). To this was added under Argon Bis (triphenylphosphine) palladium(II) chloride (160 mg, 0.2 mmol), TEA (2.81 mL, 5 eq.), CuI (40 mg, 0.2 mmol) and Phenylacetylene (897 mg, 8.8 mmol). The reaction was heated at 55° C. for 2 days. The crude was filtered through celite and purified on silicagel using as eluent cyclohexan-ethyl acetate (7-3) affording 680 mg (yield: 56%)