Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(=O)(=O)(O)O.[CH2:16](O)[CH3:17].C(=O)([O-])O.[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:16][CH3:17])=[O:9])=[N:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)c1ccc(Br)cn1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(Br)cn1
Temperature: 75 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
A mixture of 5-bromopyridine-2-carboxylic acid (35.0 g, 173 mmol), sulfuric acid (12.0 mL) and ethanol (300 mL) was stirred at 75° C. for 2 hr. After cooling to 0° C., the mixture was neutralized with sodium hydrogen carbonate and diluted with water (150 mL). Ethanol was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (300 mL). The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained solid was collected by filtration, washed with hexane, and dried to give the title compound (34.5 g, 86%) as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]([CH2:17][OH:18])([OH:16])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.O>CN(C)C=O>[CH2:3]([N:10]1[CH2:11][CH2:12][C:13]([CH2:17][O:18][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)([OH:16])[CH2:14][CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: OCC1(O)CCN(Cc2ccccc2)CC1
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(OCC2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
60% sodium hydride (0.30 g) was added to a solution of the compound (1.66 g) obtained in Step 2 in anhydrous dimethylformamide (8 mL) under cooling with ice-water, and stirred at room temperature for thirty minutes under nitrogen atmosphere. 4-fluorobenzonitrile (0.91 g) was added to the mixture and stirred at room temperature for two days. The resulting mixture was poured into water (30 mL) and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (Chromatorex NH™)(eluent; ethyl acetate:hexane=1:1) to obtain the titled compound (2.2 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:9][N:8]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:7]1)=[O:5])[CH3:2].[Sn](Cl)(Cl)(Cl)Cl.O>C(OCC)(=O)C.C(O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:9][N:8]([C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)c2ccccc2)CC1c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CN(C(=O)c2ccccc2)CC1c1ccc(N)cc1
Temperature: 80 °C
Yield: 59.7 %

Procedure:
A stirred solution of 1-benzoyl-4-(4-nitro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (10 g, Reference Example 9) in a mixture of ethyl acetate (324 ml) and ethanol (78 ml), at 24° C., was treated portionwise with tin chloride (30.65 g) then heated at 80° C. for 4 hours. After cooling to 24° C. the mixture was treated with water (400 ml), then with aqueous sodium bicarbonate solution (125 ml, 5%) and then filtered through a pad of celite washing twice with ethyl acetate (300 ml). The aqueous layer from the filtrate was separated and extracted twice with ethyl acetate (300 ml). The combined organic phases were dried over magnesium sulphate and evaporated (40° C. and 2.7 kPa). The residue was triturated with diethyl ether (100 ml) affording the title compound (5.48 g) as a white powder. 1H-NMR [250 MHz, (CD3)2SO at 373° K.]: δ 1.14 (t, J=7 Hz, 3H); 3.24 (m, 1H); 3.40 to 3.60 (m, 2H); 3.73 (dd, J=11 and 8.5 Hz, 1H); 3.80 to 4.00 (m, 2H); 4.08 (q, J=7 Hz, 2H); 6.58 (d, J=8 Hz, 2H); 6.98 (d, J=8 Hz, 2H); 7.40 to 7.60 (m, 5H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[C:5]([CH3:16])[CH:4]=1)#[N:2].S(Cl)([Cl:20])(=O)=O.Cl>C(Cl)(Cl)(Cl)Cl>[Cl:20][CH2:16][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][C:6]=1[NH:9][C:10](=[O:15])[C:11]([F:13])([F:12])[F:14]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1cc(C#N)ccc1NC(=O)C(F)(F)F
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(NC(=O)C(F)(F)F)c(CCl)c1
Temperature: 25 °C

Procedure:
In a round-bottomed flask N-(4-cyano-2-methylphenyl)-2,2,2-trifluoroacetamide (Intermediate 1, 19.37 g, 85 mmol), sulfuryl dichloride (27.6 mL, 340 mmol) and diphenylperoxyanhydride (1.028 g, 4.24 mmol) were heated in carbon tetrachloride (210 mL) at 100° C. for 3 h. The mixture was cooled to room temperature and then the reaction mixture was poured into 2M HCl (350 mL). The organic layer was then collected and the solvent was removed to give N-[2-(chloromethyl)-4-cyanophenyl]-2,2,2-trifluoroacetamide as an orange oil, (25.54 g) which was used in the next step without further purification. This oil was added to triphenylphosphine (26.2 g, 100 mmol) and the mixture was heated in toluene (300 mL) at 110° C. for 3 h. The mixture was cooled to room temperature overnight and the precipitate was filtered and washed with small amounts of toluene and diethyl ether to give the title compound as an off-white solid (29.91 g);
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][NH:14][C:13]2=[O:17])[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH:24]1([CH2:27]Br)[CH2:26][CH2:25]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[CH:24]1([CH2:27][N:14]2[CH2:15][CH2:16][N:12]([C:4]3[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=3)[C:13]2=[O:17])[CH2:26][CH2:25]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: CCOC(=O)c1sc(N2CCN(CC3CC3)C2=O)nc1C
Yield: 96 %

Procedure:
To a suspension of ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate (1.02 g, 4.00 mmol), tetra-n-butylammonium iodide (0.10 g) and potassium carbonate (0.90 g, 6.50 mmol) in acetone (80 mL) was added cyclopropylmethyl bromide (0.6 mL, 6.18 mmol). The reaction mixture was heated to reflux for 72 hours. The solvent was removed in vacuo, and the residue was washed with water (100 mL) and hexanes (30 mL) to afford the title compound in 96% yield (1.20 g): 1H NMR (300 MHz, CDCl3) δ 4.23 (q, J=7.2 Hz, 2H), 4.07 (t, J=7.8 Hz, 2H), 3.67 (t, J=7.8 Hz, 2H), 3.16 (d, J=6.9 Hz, 2H), 2.58 (s, 3H), 1.28 (t, J=7.2 Hz, 3H), 0.97-0.88 (m, 1H), 0.59-0.42 (m, 2H), 0.25-0.12 (m, 2H); MS (ES+) m/z 310.3 (M+1).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:23]=[C:22]2[C:11]([CH2:12][C:13]3[CH:17]=[CH:16][N:15]([CH2:18][C@H:19](O)[CH3:20])[C:14]=32)=[CH:10][CH:9]=1.C(N(CC)CC)C.[N-:31]=[N+:32]=[N-:33].[Na+]>ClCCl.C(OCC)C.CN(C)C=O.O>[N:31]([C@@H:19]([CH3:20])[CH2:18][N:15]1[CH:16]=[CH:17][C:13]2[CH2:12][C:11]3[C:22]([C:14]1=2)=[CH:23][C:8]([O:7][CH3:6])=[CH:9][CH:10]=3)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(c1)-c1c(ccn1C[C@H](C)N=[N+]=[N-])C2
Yield: 60.5 %

Procedure:
0.96 ml of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.5 g of (R)-1-(7-methoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 3.45 ml of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 200 ml of diethyl ether, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of diethyl ether. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 60 ml of anhydrous dimethylformamide, treated with 0.77 g of sodium azide and the reaction mixture was heated to 60° for 15 hours while stirring. After cooling, the solution was poured into 140 ml of water and extracted twice with 140 ml of diethyl ether each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 1.0 g (60%) of (S)-1-(2-azido-propyl)-7-methoxy-1,4-dihydro-indeno[1,2-b]pyrrole was obtained as a colorless oil.
Reaction SMILES: O1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(O)[CH3:7].C(O)=O.O.[NH2:19][NH2:20]>C(O)C>[C:9]1([CH:6]([C:2]2[N:19]=[N:20][CH:5]=[CH:4][CH:3]=2)[CH3:7])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NN
Reactant: CC(O)(c1ccccc1)c1ccco1
Solvent: O
Solvent: CCO
Solvent: O=CO
Product: CC(c1ccccc1)c1cccnn1
Reaction time: 1 h

Procedure:
(±) 1-(2-Furyl)-1-phenylethanol (43 g.) was dissolved in a solution of hydrazine hydrate (25 ml.) in ethanol (100 ml.). Formic acid (23 ml.) was added to the solution cautiously in portions and the heterogeneous mixture was heated at reflux on a steam bath for 4 hours. After 1 hour the mixture became homogeneous. The solution was evaporated to low volume and the residue was digested with a mixture of diethyl ether (100 ml.) and water (200 ml.). Dilute sodium hydroxide solution was added to adjust the pH to 9 and the ether layer was separated. The aqueous layer was extracted with diethyl ether (2 × 150 ml.) and the combined ethereal extracts were washed with water (3 × 150 ml.) and filtered. The filtrate was extracted with 2N hydrochloric acid (5 × 100 ml.). The combined acidic extracts were washed with diethyl ether (2 × 200 ml.) and basified by the addition of 50% aqueous sodium hydroxide solution. The oil which was deposited was extracted with diethyl ether (2 × 200 ml.) and the combined extracts were washed with water (2 × 200 ml.), dried over sodium sulphate, filtered and evaporated to give a brown oil, which was distilled to give 3-(1-phenylethyl)pyridazine (5.4 g.), m.p. 43°-48° C. (b.p. 120° C./0.05 mm.Hg), as an off-white solid.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1ccc(Sc2ccc(Cl)cc2)c([N+](=O)[O-])c1
Yield: 47.4 %

Procedure:
In ethanol (15 mL) were suspended ethyl 4-chloro-3-nitrobenzoate (1.10 g, 4.79 mmol), 4-chlorothiophenol (0.72 g, 4.98 mmol) and potassium carbonate (0.95 g, 6.78 mmol), and the suspension was heated under refluxing for 3 hours. The mixture was then placed under reduced pressure to distill the solvent off. After addition of water (100 mL), the mixture was subjected to extraction with ethyl acetate (100 mL×2) and dried over anhydrous sodium sulfate. The dry extract was placed under reduced pressure to distill the solvent off. The residue was purified-by silica gel column chromatography (ethyl acetate/hexane), to obtain 767 mg (yield 47%) of the titled compound as a yellow crystalline product.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([C:14]1([C:20]([N:22]2[CH2:27][C:26]3[CH:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=[CH:31][C:25]=3[O:24][CH2:23]2)=[O:21])[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15]1)[CH3:13].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:12]([C:14]1([C:20]([N:22]2[CH2:27][C:26]3[CH:28]=[C:29]([C:32]([F:34])([F:35])[F:33])[CH:30]=[CH:31][C:25]=3[O:24][CH2:23]2)=[O:21])[CH2:18][CH2:17][C:16](=[O:19])[CH2:15]1)(=[O:11])[CH3:13]
Reactant: CC(O)C1(C(=O)N2COc3ccc(C(F)(F)F)cc3C2)CCC(O)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(=O)C1(C(=O)N2COc3ccc(C(F)(F)F)cc3C2)CCC(=O)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A precooled (−78° C.) solution of oxalyl chloride (2.82 mL, 32.4 mmol) in 150 mL of DCM was treated dropwise with a solution of DMSO (4.60 mL, 64.8 mmol) in 25 mL of DCM. After an additional 5 min, a solution of 3-(1-hydroxyethyl)-3-{[6-(trifluoromethyl)-2H-1,3-benzoxazin-3(4H)-yl]carbonyl}cyclopentanol (4.33 g, 10.8 mmol) in 25 mL of DCM was added dropwise. The reaction mixture was stirred for an additional 30 min, then neat triethylamine (18.1 mL, 130 mmol) was added dropwise. The mixture was stirred for an additional 10 min, then was warmed to rt and stirred for 1.5 h. The reaction mixture was poured into 1N HCl solution and the resulting mixture was extracted with DCM. The organic layer was washed again with 1N HCl solution, then with saturated NaHCO3 solution, and finally with brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. Purification by MPLC (silica, 75% ethyl acetate/hexanes) gave 3-acetyl-3-{[6-(trifluoromethyl)-2H-1,3-benzoxazin-3(4H)-yl]carbonyl}cyclopentanone as a mixture of two enantiomers. ESI-MS calc. for C17H16F3NO4: 355; Found: 356 (M+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]([OH:10])[CH3:9])[N:2]=1.N1C=CC=CC=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>ClCCl.C(OCC)(=O)C>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:10][CH:8]([CH3:9])[CH2:7][C:3]2[N:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CC(O)Cc1cccnn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(C)Cc2cccnn2)cc1
Reaction time: 19 h
Yield: 55.7 %

Procedure:
1-(3-Pyridazinyl)-2-propanol (1.40 g) was dissolved in dichloromethane (10 ml). To the solution were added, at 0° C., pyridine (1.63 ml) and 4-toluenesulfonyl chloride (2.89 g), successively. The mixture was stirred for 19 hours at the same temperature, to which was added water (10 ml). The mixture was stirred for 2 hours, to which was added ethyl acetate (80 ml). The organic layer was separated and washed with a saturated aqueous saline solution and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The concentrate was purified by means of a silica gel column chromatography (developing solvent: ethyl acetate) to afford the title compound (1.65 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH2:16][C:17]3[CH:18]=[C:19]([C:23]4[N:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][N:24]=4)[CH:20]=[CH:21][CH:22]=3)[N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[N:24]=[CH:25][C:26]([CH2:29][N:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)=[CH:27][N:28]=4)[CH:18]=3)[N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CN1CCNCC1
Reactant: O=Cc1cnc(-c2cccc(Cn3nc(-c4cc(F)cc(F)c4)ccc3=O)c2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCN(Cc2cnc(-c3cccc(Cn4nc(-c5cc(F)cc(F)c5)ccc4=O)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
7.2 A suspension of 472 mg (1.17 mmol) of 2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidine-5-carbaldehyde in 5 ml of dichloromethane is given successively with 166 μl of 1-methylpiperazine, 495 mg (2.34 mmol) of sodium triacetoxyborohydride and 67 μl of acetic acid, and the reaction mixture is stirred at room temperature for 42 hours. The reaction mixture is partitioned between dichloromethane and 1 N NaOH. The organic phase is separated off, dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with dichloromethane/methanol as eluent: 6-(3,5-difluorophenyl)-2-{3-[5-(4-methylpiperazin-1-ylmethyl)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one (“A14”) as colourless crystals; ESI 489;
Reaction SMILES: [CH3:1][C:2]1(C(OCC)=O)[C:16](=[O:17])[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]1.[OH-].[K+]>C(O)C>[CH3:1][CH:2]1[CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][C:16]1=[O:17]
Reactant: CCOC(=O)C1(C)CC=CCCCCCCC=CCCC1=O
Agent: CC1C/C=C/CCCCCC/C=C/CCC1=O
Agent: CCOC(=O)C1(C)C/C=C/CCCCCC/C=C/CCC1=O
Agent: [K+]
Solvent: CCO
Product: CC1CC=CCCCCCCC=CCCC1=O

Procedure:
A solution of ethyl 1-methyl-15-oxocyclopentadeca-3E,11E-dienecarboxylate (0.180 g, 0.59 mmole) and potassium hydroxide (0.15 g, 2.68 mmole) in 50% aqueous ethanol (3 ml) was heated to 65° C. for 5 hours. The solvents were removed by reduced pressure distillation and to the residue was added 5% aqueous hydrochloric acid and methylene chloride. The mixture was shaken, the layers separated, and the organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to give the crude product. The crude product was purified by flash chromatography to give 2-methylcyclopentadeca-4E,12E-diene-1-one (0.060 g, 44% yield). C16H26O (234 g/mol): 1HNMR (500 MHz, CDCl3): 1.05 (d, 3H), 1.17 (m, 3H), 1.25-1.41 (m, 3H), 1.97 (m, 4H), 2.08 (m, 2H), 2.27 (m, 1H), 2.36 (m, 1H), 2.46 (m, 1H), 2.52 (m, 1H), 2.59 (m, 1H), 5.32 (m, 3H), 5.46 (m, 1H) ppm. 13CNMR (125 MHz, CDCl3): 17.59, 26.07, 26.72, 27.19, 27.65, 28.74, 30.76, 30.98, 36.59, 42.32, 46.34, 127.81, 129.61, 131.06, 132.12, 213.70 ppm. IR (νmax(cm−1)): 3030(w), 2920(s), 2852(s), 1714(s), 1456(m), 1436(m), 970(s). MS (m/z): 234(M), 219, 191, 177, 163, 149, 135, 121, 109, 95, 81, 67, 55, 41.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[CH2:7][CH:8]([CH2:10]OS(C3C=CC(C)=CC=3)(=O)=O)[O:9][C:5]=2[CH:4]=1.[CH3:24][C:25]1[CH:38]=[CH:37][C:28]([CH2:29][C:30]2([OH:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:27][CH:26]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[CH2:7][CH:8]([CH2:10][N:33]3[CH2:34][CH2:35][C:30]([CH2:29][C:28]4[CH:27]=[CH:26][C:25]([CH3:24])=[CH:38][CH:37]=4)([OH:36])[CH2:31][CH2:32]3)[O:9][C:5]=2[CH:4]=1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Reactant: COc1ccc2c(c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC(CN1CCC(O)(Cc3ccc(C)cc3)CC1)C2
Temperature: 130 °C
Yield: 66 %

Procedure:
(RS)-toluene-4-sulfonic acid 6-methoxy-2,3-dihydro-benzofuran-2-ylmethyl ester (110 mg, 0.33 mmol) and 4-(4-methyl-benzyl)-piperidin-4-ol (148 mg, 0.72 mmol) were dissolved in DMF (3 ml) and heated at 130° C. for 1 h. DMF was then evaporated, the residue was dissolved in CH2Cl2 (5 ml) and washed with H2O (5 ml). Organic phase was dried over Na2SO4, and concentrated. The residue was chromatographed over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2-MeOH(19:1) to provide (RS)-1-(6-methoxy-2,3-dihydro-benzofuran-2-ylmethyl)-4-(4-methyl-benzyl)-piperidin-4-ol (80 mg, 66%) as a yellow oil, MS:m/e=368.4 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([CH2:14][C:15](=[O:23])[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[O:25]=[C:26]1[CH:35]=[N:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]1[CH2:36][CH:37]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[C:1]([O:5][C:6](=[O:24])[N:7]([CH2:14][C:15](=[O:23])[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH:8]1[CH2:9][CH2:10][N:11]([CH2:37][CH2:36][N:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:34]=[CH:35][C:26]2=[O:25])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CCn1c(=O)cnc2ccccc21
Reactant: CC(C)(C)OC(=O)N(CC(=O)Nc1ccccn1)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(CC(=O)Nc1ccccn1)C1CCN(CCn2c(=O)cnc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To 3 mL of dichloromethane solution containing 0.18 g of tert-butyl(2-oxo-2-(pyridin-2-ylamino)ethyl)(piperidin-4-yl)carbamate, 0.10 g of (2-oxoquinoxalin-1(2H)-yl)acetaldehyde and 30 μl of acetic acid were added and stirred at room temperature for 2 hours. To the reaction mixture, 0.17 g of sodium triacetoxyborohydride was added and stirred at the same temperature for 30 min. Chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=10:1] to give 0.26 g of tert-butyl(2-oxo-2-(pyridin-2-ylamino)ethyl)(1-(2-(2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a pale yellow foam.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:8][CH:7]([N:9]2[C:13]3[N:14]=[C:15]([S:28][CH3:29])[N:16]=[C:17]([NH:18][CH:19]4[CH2:21][CH:20]4[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:12]=3[N:11]=[N:10]2)[CH:6]([OH:30])[CH:5]1[OH:31].[CH2:32](S)[CH2:33][CH2:34]C>>[CH2:29]([S:28][C:15]1[N:16]=[C:17]([NH:18][CH:19]2[CH2:21][CH:20]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:12]2[N:11]=[N:10][N:9]([CH:7]3[CH2:8][CH:4]([CH2:3][CH2:2][OH:1])[CH:5]([OH:31])[CH:6]3[OH:30])[C:13]=2[N:14]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(CCO)C(O)C3O)c2n1
Reactant: CCCCS
Product: CCCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(CCO)C(O)C3O)c2n1

Procedure:
Prepared by the method of Example 4, step (b) using the product of Example 110, step a) and butanethiol then deprotected using the method of Example 1, step (b). Purification (HPLC, Novapak® C18 column, 0.1% aqueous ammonium acetate:acetonitrile, isocratic elution 45% MeCN over 30 minutes) afforded the title compound (210 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](C1CCCCO1)[N:13]=[C:12]2[C:24]1[N:29]=[C:28]([O:30][C@H:31]2[CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35][C:32]32[CH2:34][CH2:33]3)[CH:27]=[N:26][CH:25]=1.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>C(Cl)Cl>[CH2:34]1[C:32]2([CH2:35][CH2:36][NH:37][CH2:38][C@@H:31]2[O:30][C:28]2[N:29]=[C:24]([C:12]3[C:11]4[C:15](=[CH:16][CH:17]=[C:9]([C:3]5[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[CH:10]=4)[NH:14][N:13]=3)[CH:25]=[N:26][CH:27]=2)[CH2:33]1.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cccc(F)c1-c1ccc2[nH]nc(-c3cncc(O[C@H]4CNCCC45CC5)n3)c2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (4R)-tert-butyl 4-(6-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (0.983 g, 1.591 mmol) in 8 mL DCM was added TFA (3.68 mL, 47.7 mmol). After 6 h at RT, the orange reaction was placed in the freezer overnight, and in the morning was warmed and stirred at RT for 3 h. The reaction was concentrated in vacuo, then taken up in DMSO (6 mL total), filtered, and purified by RPHPLC, 20-70% ACN/H2O with 0.1% TFA; product-containing fractions were combined and concentrated in vacuo to give (R)-3-(6-(6-azaspiro[2.5]octan-4-yloxy)pyrazin-2-yl)-5-(2,6-difluorophenyl)-1H-indazole*1.5 TFA (0.530 g, 0.88 mmol, 55% yield) yellow solid: MS (ESI, pos. ion) m/z: 434 (M+1).