Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([CH2:19]Cl)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+].[CH3:24][N:25](C)C=O>O>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([CH2:19][C:24]#[N:25])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: ClCc1cnn(Cc2ccccc2)c1-c1ccccc1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: N#CCc1cnn(Cc2ccccc2)c1-c1ccccc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 44 %

Procedure:
A mixture of 1-benzyl-4-chloromethyl-5-phenyl-1H-pyrazole (8.31 g), potassium cyanide (2.87 g), and N,N-dimethylformamide (100 ml) was stirred for 15 hours at 90° C., and poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and (1-benzyl-5-phenyl-1H-pyrazol-4-yl)acetonitrile (3.50 g, yield: 44%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][CH2:13][CH2:14][CH3:15].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:12]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH3:1])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCBr
Reactant: Cc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCn1c(C)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
A mixture of 2-methylbenzimidazole (1.32 g, 0.01 mol), 1-bromobutane (1.21 g, 0.01 mol), 50% aqueous sodium hydroxide (5 ml), toluene (20 ml) and 0.5 mmol of compound 1 was stirred at 80°-85° C. for 3 hours. After that time, the resulting mixture was allowed to cool to room temperature and the organic layer was separated, extracted with concentrated hydrochloric acid (3×20 ml). The acidic solution was neutralized with 20% sodium hydroxide, extracted with toluene (3×15 ml), dried over magnesium sulphate and evaporated to give a residue which was distilled at reduced pressure (0.4-0.5 mm 162°-6° C.) to give 1-n-butyl-2-methylbenzimidazole. Yield: 65%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[Br:16]Br>C(Cl)(Cl)Cl.CN(C=O)C>[NH2:1][C:2]1[C:11]([Br:16])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1c(N)ccc2ccccc12
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1c(N)c(Br)cc2c1CCCC2
Yield: 101.2 %

Procedure:
Methyl 2-amino-1-naphthoate (0.5 g, 2.4 mmol) in chloroform (5 mL) and DMF (1 mL) was treated with bromine (0.125 mL, 2.4 mmol) for 30 minutes, concentrated, and dissolved in ethyl acetate. The organic layer was washed with NaHCO3 (3×), brine (3×) and water (3×), dried (Na2SO4), filtered, and concentrated to provide the desired product (0.69 g). MS (DCI) m/e 284, 286 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]([O:21]CC)=[O:20])[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.O>[CH:1]1([N:4]([CH2:18][C:19]([OH:21])=[O:20])[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CN(C1CC1)S(=O)(=O)c1c(C)cc(OC)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N(CC(=O)O)C2CC2)c(C)c1
Yield: 83 %

Procedure:
A solution of ethyl 2-(N-cyclopropyl-4-methoxy-2,6-dimethylphenyl-sulfonamido)acetate (2.7 mmol, 1 eq.) and LiOH (5 eq.) in THF/H2O (1:1) was stirred at room temperature for 12 h. The solvent was removed completely, in vacuo. The crude product was taken up in water and the mixture was washed with ethyl acetate. The aqueous phase was acidified to pH=4 with 1 M HCl and then extracted with ethyl acetate. The organic phase was dried over Na2SO4. After the solvent had been distilled off completely, the crude product was obtained, and was employed in the next stage without further purification. Yield: 83%
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:19]3[CH2:24][CH2:23][N:22]([CH:25]([CH3:39])[CH2:26][CH2:27][NH:28][C:29]([C:31]4[C:32]([CH3:38])=[N:33][CH:34]=[N:35][C:36]=4[CH3:37])=[O:30])[CH2:21][CH2:20]3)[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[O:41]([NH2:43])[CH3:42].CC([O-])=O.[Na+]>CO>[CH3:42][O:41][N:43]=[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2([CH:19]3[CH2:20][CH2:21][N:22]([CH:25]([CH3:39])[CH2:26][CH2:27][NH:28][C:29]([C:31]4[C:32]([CH3:38])=[N:33][CH:34]=[N:35][C:36]=4[CH3:37])=[O:30])[CH2:23][CH2:24]3)[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[O:14]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CON
Reactant: CC(=O)c1ccc(C2(C3CCN(C(C)CCNC(=O)c4c(C)ncnc4C)CC3)Oc3ccccc3O2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CON=C(C)c1ccc(C2(C3CCN(C(C)CCNC(=O)c4c(C)ncnc4C)CC3)Oc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of COMPOUND 282 (47 mg, 0.089 mmol) in MeOH (4 mL) was added methoxylamine hydrochloride (19 mg, 0.22 mmol) and NaOAc (21 mg, 0.25 mmol) and the mixture was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 283 as a white solid (38 mg, 75%). 1H NMR (CDCl3) δ 0.76-0.81 (m, 1H), 0.94 (d, 3H, J=6.6 Hz), 1.01-1.06 (m, 1H), 1.45-1.75 (m, 4H), 1.88-1.96 (m, 2H), 2.19 (s, 3H), 2.37 (t, 1H, J=10.7 Hz), 2.51 (s, 6H), 2.66-2.82 (m, 3H), 3.22-3.30 (m, 1H), 3.84-3.94 (m, 1H), 3.98 (s, 3H), 6.75-6.78 (m, 2H), 6.84-6.87 (m, 1H), 6.93-6.96 (m, 1H), 7.37 (d, 2H, J=8.4 Hz), 7.61 (d, 2H, J=8.4 Hz), 8.82-8.83 (m, 1H), 9.08 (s, 1H). 13C NMR (CDCl3) δ 12.63, 13.18, 21.54, 21.89, 25.60, 26.25, 30.62, 40.22, 43.57, 45.17, 52.24, 60.78, 61.77, 62.00, 108.53, 108.63, 117.87, 121.39, 125.35, 125.69, 125.79, 127.78, 130.82, 137.07, 140.48, 147.05, 147.16, 154.18, 157.68, 162.88, 166.51. ES-MS m/z 558 (M+H). Anal. Calcd. for C32H39N5O4.0.15CH2Cl2: C, 67.70; H, 6.94; N, 12.28. Found: C, 67.71; H, 7.06; N, 12.16.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)=[N:2]1.CN(C=O)C.Br[CH2:36][CH3:37].O.[OH-].[Cs+]>>[CH2:28]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[N:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]3=[N:21][CH:20]=2)=[O:18])[N:7]([CH2:6][C:3]2[N:2]([CH2:36][CH3:37])[N:1]=[CH:5][CH:4]=2)[N:8]=1)[CH3:29]
Reactant: CCBr
Reactant: CCc1nn(Cc2cc[nH]n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: [Cs+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn(Cc2ccnn2CC)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 1 h
Yield: 4.8 %

Procedure:
To N-(1-((1H-pyrazol-3-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (40 mg, 0.10 mmol) in dry DMF (519 μl, 0.10 mmol) was added bromoethane (11 mg, 0.10 mmol), cesium hydroxide hydrate (17 mg, 0.10 mmol) and 4 angstrom molecular sieves. The reaction mixture was stirred for one hour, filtered through an Acrodisk, rinsed with DCM and MeOH, and concentrated under a nitrogen stream to a residue. Preparative thin layer chromatography eluting with 10% MeOH, 0.5% NH4OH in CHCl3 provided the desired product (2 mg). MS (ES+APCI) m/z=414 (M+H). (The other regioisomer, N-(1-((1H-pyrazol-3-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide, was also isolated and was utilized in Example 40).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[S:9][C:10]([CH2:13][CH2:14][NH2:15])=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].[O:17]1[CH2:22][CH2:21][CH:20]([CH:23]=O)[CH2:19][CH2:18]1.ClC(Cl)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[S:9][C:10]([CH2:13][CH2:14][NH:15][CH2:23][CH:20]2[CH2:21][CH2:22][O:17][CH2:18][CH2:19]2)=[CH:11][N:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CC1CCOCC1
Reactant: CC(C)(C)OC(=O)Nc1ncc(CCN)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1ncc(CCNCC2CCOCC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A flask was charged with compound 14.1 (200 mg, 100 mol %), tetrahydro-pyran-4-carbaldehyde (100 mol %), and dichloroethane. To this was added NaBH(OAc)3 (150 mol %) and the resulting slurry was stirred at room temperature for 2 hours. The solvents were removed in vacuo and the residue was re-suspended in EtOAc and H2O. The organic layer was washed sequentially with saturated sodium bicarbonate, H2O, and brine. The organic layers were combined, dried over Na2SO4, and concentrated to give (5-{2-[(tetrahydro-pyran-4-ylmethyl)-amino]-ethyl}-thiazol-2-yl)-carbamic acid tert-butyl ester (compound 33.1) as an oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C@H:7]([OH:8])[C:5](=[O:6])[O:4][CH2:3]1.[BH4-].[Na+]>CO>[CH3:1][C:2]([CH3:9])([CH2:3][OH:4])[C@H:7]([OH:8])[CH2:5][OH:6]
Reactant: CC1(C)COC(=O)[C@H]1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(CO)[C@H](O)CO
Temperature: 0 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a 0° C. solution of 5.01 g (38.5 mmol) of (S)-(+)-pantolactone in 150 mL of methanol was carefully added 3.72 g (98.5 mmol) of sodium borohydride. After gas evolution had subsided, the ice-bath was removed and the reaction closely monitored, cooling to 0° C. with an ice-water bath as needed when gas evolution became vigorous. The ice-water bath was removed and the reaction mixture was stirred at room temperature for 4 h. Dowex 50W×4-400 (H+) resin was added to the solution until a pH of 7 was achieved, as indicated by wet pH paper. The resin was filtered off, and the filtrate was evaporated under reduced pressure. Portions of methanol and toluene were distilled from the resulting oil, which was further dried under high vacuum to afford 5.16 g (quantitative yield) of (2S)-3,3-dimethyl-1,2,4-butanetriol. 1H NMR (300 MHz, CDCl3) δ 3.49-3.82 (m, 5H), 3.11 (d, J=4 Hz, 1H), 2.62 (m, 1H), 2.42 (m, 1H), 0.98 (d, J=6 Hz, 6H).
Reaction SMILES: C([O:4][C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[CH2:10][CH2:11][O:12]C)(=O)C.B(Br)(Br)Br.O>C(Cl)Cl>[OH:12][CH2:11][CH2:10][C:6]1[C:5](=[O:4])[CH2:9][CH2:8][CH:7]=1
Reactant: COCCC1=C(OC(C)=O)CCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C1CCC=C1CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The enol acetate of Example 896 is brominated and dehydrobrominated by the method described in Example 13. The crude product is then dissolved in methylene chloride and is added at -78° C. to a methylene chloride solution containing about seven molar equivalents of boron tribromide. After one hour at -78° C. the solution is allowed to warm to room temperature and is then kept at ambient temperatures for a total of 18 hours. The mixture is poured into water and extracted with ether. The organic phase is washed with saturated saline solution, then water and is dried. Evaporation of solvents leaves subject product, which is purified by distillation. The combined organic phases are washed with ice cold 5% sodium hydroxide solution, ice cold 5% hydrochloric acid, and saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation gives a pale yellow oil; λ max 5.85 μ (carbonyl group).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(OC(=O)C[N:19]1[C:23]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[N:22][C:21]([C:30]2[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=2)=[N:20]1)C>O>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][N:20]1[C:21]([C:30]2[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=2)=[N:22][C:23]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[N:19]1)[CH3:13]
Reactant: CCOC(=O)Cn1nc(-c2cc(Cl)cc(Cl)c2)nc1-c1ccncc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)Cn1nc(-c2ccncc2)nc1-c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iso-nicotinic hydrazide (1.0 g, 7.3 mmol), 3,5-dichlorobenzonitrile (1.5 g, 8.8 mmol), and sodium ethoxide (1.5 g, 22 mmol) were transferred to a pressure tube. Ethanol (4 mL) was added and the reaction was stirred at 120° C. overnight. The reaction was monitored by LCMS. Upon completion, the ethanol was removed in vacuo to afford the triazole as a solid and carried on to the next step without purification. This material was dissolved in DMF (10 mL), and potassium carbonate (1.5 g, 11 mmol) and ethyl bromoacetate (1.2 mL, 11 mmol) were added. The reaction was stirred at room temperature overnight. The reaction was monitored by LCMS. Upon completion, the reaction mixture was diluted with water. The precipitate was collected via vacuum filtration and the filtrate was discarded. The crude product was purified by silica gel chromatography (3:2 hexanes/ethyl acetate) to afford two regioisomers as solids. 1H NMR (400 MHz, d6-DMSO): δ 8.7 (d, 21, 7.95 (s, 2H), 7.9 (d, 1H), 7.8 (d, 2H), 5.5 (s, 2H), 4.1 (q, 2H), 1.1 (t, 3H). MS (EI) for C17H14N4O2Cl2: 377 (MH+). Ethyl[3-(3,5-dichlorophenyl)-5-pyridin-4-yl-1H-1,2,4-triazol-1-yl]acetate: 1H NMR (400 MHz, d6-DMSO): δ 8.8 (d, 2H), 8.0 (s, 2H), 7.8 (m, 3H), 5.5 (s, 2H), 4.1 (q, 2H), 1.2 (t, 3H). MS (EI) for C17H14N4O2Cl2: 377 (MH+).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:9]=[N:8][C:7]([NH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)=[N:6][CH:5]=1)[CH3:3].C(N(CC)CC)C.[C:30]([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36])#[N:31]>ClCCl>[C:30]([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([NH:1][CH:2]([C:4]1[N:9]=[N:8][C:7]([NH:10][C:11]2[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=2)=[N:6][CH:5]=1)[CH3:3])=[O:36])#[N:31]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(C#N)c3)nn2)cc(OC)c1OC
Yield: 83.7 %

Procedure:
In a similar manner as described for Intermediate 18 (below), 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (0.10 g, 0.33 mmol), triethylamine (0.10 mL, 0.73 mmol) and 3-cyanobenzoyl chloride (0.059 g, 0.36 mmol) in dichloromethane (10 mL) gave 3-cyano-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (0.12 g) as a white solid. MS m/z 435 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[N:11][CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)(=O)C.O>[C:1]1([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cnccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: c1ccc(C2CNCCN2)cc1
Reaction time: 4 h
Yield: 59.5 %

Procedure:
To a solution of 2-phenylpyrazine (11.64 g, 74.53 mmol) in acetic acid (58.2 mL) was added palladium acetate Pd(OAc)2 (2.33 g, 9.94 mmol). The mixture was hydrogenated at 50 psi for 4 h. After the reaction was complete, the catalyst was filtered off and rinsed with a small portion of acetic acid. The filtrate was concentrated under house vacuum to give a brown-black solid which was suspended in deionized water (300 mL) and adjusted to pH 13 with 20% NaOH solution. The product was extracted from aqueous solution with EtOAc (200 mL, 3×), dried over MgSO4, filtered and evaporated to dryness to give 2-phenylpiperazine (7.2 g). An additional 1.6 g of 2-phenylpiperazine was obtained by evaporating the aqueous fraction to a solid and triturating the solid with CH2Cl2. Total yield of 2-phenyl-piperazine was 73%. The crude material was crystallized from EtOAc and hexane for characterization, m.p. 86°-88° C.; FAB MS [M+1]+ 163;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12]/[CH:13]=[CH:14]/[C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[CH:9](O)[CH3:10])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:44](C(OCC)=O)=NC(OCC)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12]/[CH:13]=[CH:14]/[C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[CH:9]([NH2:44])[CH3:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: CC(O)C(C/C=C/c1ccc2ccccc2c1)c1ccc(Cl)cc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(N)C(C/C=C/c1ccc2ccccc2c1)c1ccc(Cl)cc1

Procedure:
4.06 g of (2RS,3SR,5E)-3-(4-chlorophenyl)-6-(2-naphthyl)-5-hexen-2-ol was dissolved in 30 ml of tetrahydrofuran, and 4.77 g of triphenylphosphine, 2.89 ml of diethyl azodicarboxylate and 4.77 g of diphenylphosphoryl azide were added under cooling with ice with stirring, followed by stirring at room temperature for 30 minutes. The reaction solution was evaporated to dryness under reduced pressure. Then, the residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/1→30/1). The obtained azide product was heated and refluxed together with 3.2 g of triphenylphosphine in 100 ml of 10% water-containing tetrahydrofuran. The reaction solution was evaporated to dryness under reduced pressure. Then, the residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1→20/1) to obtain 2.30 g of the above-identified compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[S:13]([OH:16])(=[O:15])=[O:14]>>[CH3:1][C:2]1[C:10]2[O:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[S:13]([OH:16])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1cccc2[nH]c(=O)oc12
Product: Cc1c(S(=O)(=O)O)ccc2[nH]c(=O)oc12
Yield: 60 %

Procedure:
7-Methyl-3H-benzooxazol-2-one [5.0 g, 33 mmol, prepared according to the procedure described in J. Org. Chem. (1982), 47(14), 2804–6) was treated with chlorosulphonic acid as described in Example 15 (i) to give the title compound as an off-white solid (4.5 g, 60%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[O:10][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[N:32][NH:33]3)O1.C([O-])(=O)C.[K+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:33]1[C:34]2[C:30](=[C:29]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[O:10][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[CH:8][C:6]=4[N:7]=3)[CH:37]=[CH:36][CH:35]=2)[CH:31]=[N:32]1
Reactant: CC(C)(O)c1cc2nc(Cl)nc(N3CCOCC3)c2o1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2o1
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
2-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)propan-2-ol (60 mg, 1.0 eq) was dissolved in acetonitrile (2.0 ml) and treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 (123 mg, 2.5 eq), PdCl2(PPh3)2 (14.1 mg, 0.10 eq) and 1M potassium acetate (0.6 ml). The vial was sealed and heated with stirring in the microwave to 140° C. for 30 minutes. The crude reaction mixture was concentrated and purified by reverse phase HPLC to afford 2-(2-(1H-indazol-4-yl)-4-morpholinofuro[3,2-d]pyrimidin-6-yl)propan-2-ol 107. MS (Q1) 380 (M)+.
Reaction SMILES: [CH3:1][C:2]1([CH2:14][CH3:15])[CH2:11][CH:10]([CH2:12][CH3:13])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.[CH2:16]1[O:18][CH2:17]1>C(O)CO>[OH:18][CH2:17][CH2:16][N:3]1[CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:10]([CH2:12][CH3:13])[CH2:11][C:2]1([CH3:1])[CH2:14][CH3:15]
Reactant: C1CO1
Reactant: CCC1CC(C)(CC)NC2CCCCC12
Solvent: OCCO
Product: CCC1CC(C)(CC)N(CCO)C2CCCCC12

Procedure:
Following the procedure given in E above, 75 grams of 2-methyl-2,4-diethyl decahydroquinoline were reacted with ethylene oxide in the presence of 50 milliliters of ethylene glycol at 200° C. for 10 hours to yield 1-(2'-hydroxyethyl)-2-methyl-2,4-diethyl decahydroquinoline, which had a boiling point of 140° C. at 0.8 mm Hg. The NMR and infrared spectra were consistent with the desired product. For formula of C16H31NO, the calculated carbon, hydrogen, nitrogen contents are 75.83% carbon, 12.33% hydrogen, and 5.53% nitrogen and the analyzed contents were 74.69% carbon, 12.24% hydrogen, and 5.14% nitrogen.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][C@@H:12]1[NH:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:13]1=[O:27].CN1CCOCC1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:17]2[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)[C:13](=[O:27])[C@@H:12]2[CH3:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: C[C@@H]1NCCN(CCCN2CCCCC2)C1=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@H]1C(=O)N(CCCN2CCCCC2)CCN1C(=O)Nc1cccc(Cl)c1
Yield: 82.4 %

Procedure:
3-Chlorophenyl isocyanate (36 mg, 0.23 mmol) was added to a solution of (S)-3-methyl-1-(3-piperidin-1-yl-propyl)-piperazin-2-one (intermediate 20; 52 mg, 0.21 mmol) and 4-methylmorpholine (21 mg, 0.21 mmol) in N,N-dimethylformamide (1 ml), then after 16 h the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; dichloro-methane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (68 mg, 84%). Colorless gum, MS (ISP)=393.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13](#[N:17])[CH2:14][C:15]#[N:16]>C1C=CC=CC=1.C(O)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[C:14]([C:13]#[N:17])[C:15]#[N:16])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: N#CCC#N
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(=C(C#N)C#N)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 28.8 %

Procedure:
A mixture of 1-(4-Nitro-phenyl)ethanone (10 g, 60.5 mmol), malononitrile (4 g, 60.5 mmol), NH4OAc (4.66 g, 121 mmol) in benzene (100 mL) and acetic acid (6.4 mL) was refluxed overnight using a Dean Stark to collect water. The reaction was allowed to cool to r.t., partitioned between water and EtOAc (3×). the combined organic were washed with brine, dried (Na2SO4), concentrated and purified via silica gel chromatography eluting with 3 to 1 hexanes:EtOAc to give 3.71 g (29%) of the title compound. Rf=0.22 (4:1 hexanes: EtOAc).