Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([OH:30])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.O[CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][C:36]1=[O:42].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][C:36]3=[O:42])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: CN1CCN(CCCO)C(=O)C1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1=O
Reaction time: 1 h
Yield: 50.2 %

Procedure:
Di-tert-butylazodicarboxylate (393 mg, 1.71 mmol) was added portionwise, at room temperature, to a stirred suspension of 4-chloro-6-methoxyquinazolin-7-ol, (300 mg, 1.42 mmol), 1-(3-hydroxypropyl)-4-methylpiperazin-2-one (270 mg, 1.57 mmol) and triphenylphosphine (522 mg, 1.99 mmol) in dichloromethane (10 ml). The reaction was stirred 1 hr before adding further di-tert-butylazodicarboxylate (393 mg) and triphenylphosphine (522 mg) and stirring for a further 1 hr. The resulting reaction solution was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent to give 1-{3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]propyl}-4-methylpiperazin-2-one (260 mg, 50%) as a pale yellow solid; NMR Spectrum:(DMSOd6) 2.06 (quintet, 2H), 2.20 (s, 3H), 2.60 (t, 2H), 2.91 (s, 2H), 3.33 (t, 2H), 3.48 (t, 2H), 4.00 (s, 3H), 4.22 (t, 2H), 7.40 (s, 1H), 7.41 (s, 1H), 8.87 (s, 1H); Mass Spectrum: M+H+ 365/367.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12](O)[CH3:13])=[CH:8][CH:7]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].P(Cl)(Cl)[Cl:16]>CC(C)=O.N1C=CC=CC=1>[Cl:16][CH:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:1][CH:2]=[C:3]([CH3:5])[CH3:4])=[CH:7][CH:8]=1)[CH3:13]
Reactant: ClP(Cl)Cl
Reactant: CC(C)=CCc1ccc(C(C)O)cc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)=CCc1ccc(C(C)Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
166 g of 1-(p-prenylphenyl)ethanol was dissolved in a mixture of 870 ml of acetone and 34.5 g of pyridine. While the solution was maintained at 0° C., 60.1 of phosphorus trichloride was added over the course of about 2 hours. The mixture was stirred at room temperature for 2 hours. Acetone was distilled off, and n-hexane and cold water were added to the mixture. The n-hexane layer was washed successively with a 1.6% aqueous solution of sodium hydroxide and water, dried and concentrated to give 174.6 g of 1-chloro-1-(p-prenylphenyl)ethane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH2:13][C:14]([O:16]C)=[O:15].[C:18]([O-])(=O)C.[Na+]>CO>[CH3:18][N:1]([C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=1)[CH2:13][C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1cccc(N)c1
Reactant: COC(=O)CBr
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(N(C)CC(=O)O)c1
Yield: 45 %

Procedure:
A solution of methyl 3-aminobenzoate (4.00 g, 26.5 mmol), methyl bromoacetate (4.05 g, 26.5 mmol) and sodium acetate (1.1 eq.) in methanol (30 mL) was stirred at ambient temperature for 48 h. The resulting white precipitate was collected by filtration, washed with a small amount of methanol, and dried under vacuum to afford methyl-N-(3-carbomethoxyphenyl)glycine (2.69 g, 12.1 mmol, 45%). 1H NMR (CDCl3, 300 MHz): δ 7.41 (1H, d, J=8 Hz), 7.28-7.20 (2H, m), 6.79 (1H, d, J=8 Hz), 4.43 (1H, br), 3.97 (2H, s), 3.90 (3H, s), 3.80 (3H, s).
Reaction SMILES: [CH2:1]=[O:2].[N+:3]([CH:6]([CH2:8][CH3:9])[CH3:7])([O-:5])=[O:4]>C(N(CC)CC)C>[CH3:7][C:6]([N+:3]([O-:5])=[O:4])([CH2:8][CH3:9])[CH2:1][OH:2]
Reactant: CCC(C)[N+](=O)[O-]
Reactant: C=O
Solvent: CCN(CC)CC
Product: CCC(C)(CO)[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A 2-liter 3-neck flask is equipped with a mechanical stirrer, a reflux condenser with a nitrogen bubbler, an addition funnel and a temperature controller with heating mantle and thermocouple. The flask is charged with aqueous formaldehyde solution (420 mL, 37% active, 5.64 mol) and 4 mL triethylamine catalyst. The addition funnel is charged with 2-nitrobutane (554.1 g, 5.37 mol). The 2-nitrobutane is added dropwise, over a period of 7 hours to the formaldehyde solution, which is being stirred under nitrogen. The reaction is maintained at 40° C. during the addition. After all the 2-nitrobutane is added, the turbid mixture is warmed to 45° C. for 30 min, and then heating and stirring are discontinued overnight. If a GC analysis indicates the reaction is not yet complete; an additional 10.9 g aqueous formaldehyde is added and the mixture stirred at 45° C. for 2.5 hours. Upon cooling to room temperature, the reaction mass separates into an oil layer with a smaller, separate water layer. The oil layer is collected (1022.8 g, 97.9% of theory) and GC indicates 94.8% purity. The oil is used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:25][CH:24]([CH:26]=[CH2:27])[O:23][C:10]2([CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:29]([O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=O)=[CH:35][C:34]=1[CH3:42])([CH3:31])[CH3:30].F[P-](F)(F)(F)(F)F.C[NH2+]C.C(N(CC)CC)C>C(O)C.CN(C=O)C>[CH2:1]([N:8]1[CH2:25][CH:24]([CH:26]=[CH2:27])[O:23][C:10]2([CH2:11][CH2:12][N:13]([C:37]([C:36]3[CH:40]=[CH:41][C:33]([O:32][CH:29]([CH3:30])[CH3:31])=[C:34]([CH3:42])[CH:35]=3)=[O:39])[CH2:14][CH2:15]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Reactant: C=CC1CN(Cc2ccccc2)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Agent: C[NH2+]C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC1CN(Cc2ccccc2)CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)O1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To tert-butyl 8-benzyl-10-vinyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (600 mg, 1.61 mmol) in ethanol (1 mL) was added HCl (4 mL of 4 M in dioxane, 16.11 mmol) and the mixture was stirred for 30 minutes. The reaction mixture was concentrated in vacuo, then DMF (4 mL), 4-isopropoxy-3-methyl-benzoic acid (313 mg, 1.61 mmol) and dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium hexafluorophosphate (613 mg, 1.61 mmol) were added and the reaction mixture was stirred for 10 minutes. Triethylamine (898 μL, 6.44 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, diluted with DCM (5 mL), washed with 1 N aq. NaOH (2 mL) and brine (2 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography using 0-100% EtOAc/hexane as eluent to give (8-benzyl-10-vinyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone as a pale yellow oil (715 mg, 99%). 1H NMR (400 MHz, CDCl3) δ 7.35-7.22 (m, 5H), 7.20-7.14 (m, 2H), 6.79 (d, J=8.2 Hz, 1H), 5.83-5.74 (m, 1H), 5.34-5.26 (m, 1H), 5.15 (d, J=10.6 Hz, 1H), 4.59-4.50 (m, 1H), 4.33-4.14 (m, 2H), 3.59-3.14 (m, 7H), 2.79 (d, J=11.0 Hz, 1H), 2.56 (d, J=11.1 Hz, 1H), 2.19 (s, 3H), 1.91-1.80 (m, 2H), 1.69-1.39 (m, 2H), 1.34 (d, J=6.0 Hz, 6H); ESI-MS m/z calc. 448.6. found 449.5 (M+1)+; Retention time: 1.54 minutes (3 min run).
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].[Li]CCCC.CN(P(N(C)C)(N(C)C)=O)C.[CH2:24]([O:26][C:27]([CH:29]1[CH2:38][CH2:37][C:32]2([O:36][CH2:35][CH2:34][O:33]2)[CH2:31][CH2:30]1)=[O:28])[CH3:25].BrCC#N>C1COCC1.O>[CH2:24]([O:26][C:27]([C:29]1([CH2:2][C:1]#[N:4])[CH2:38][CH2:37][C:32]2([O:33][CH2:34][CH2:35][O:36]2)[CH2:31][CH2:30]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Reactant: CC(C)NC(C)C
Agent: N#CCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C1(CC#N)CCC2(CC1)OCCO2
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
To a stirred solution of diisopropylamine (10.09 ml, 69.76 mmol) in THF (150 ml) was added nBuLi (1.9 M solution in hexane, 26.09 ml, 51.1 mmol) drop wise at −40° C. followed by HMPA (31.0 ml, 178.0 mmol) under nitrogen atmosphere, and the reaction mixture was stirred for 30 minutes at −40° C. It was then cooled further to −78° C., and a solution of 1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (10 g, 46.5 mmol) in THF (20 ml) was added keeping the temperature below −70° C. throughout the addition. After stirring for 25 min at −78° C., bromoacetonitrile (3.8 ml, 55.8 mmol) was added slowly, and the reaction mixture was then allowed to warm to 25° C. The mixture was poured into cold water (100 ml) and the aqueous layer was extracted with EtOAc (5×70 ml). The combined organic layer was washed successively with saturated aqueous solution of NH4Cl (3×50 ml), H2O (2×50 ml) and then with brine (1×40 ml), dried (Na2SO4), filtered and evaporated in vacuo. The crude compound obtained was purified by column chromatography over silica gel (22-25% EtOAc/hexane) to give the title compound (6 g) as a pale yellow liquid. MS (m/e): 254.2 [MH+].
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:25].O1CCOCC1>C(Cl)Cl>[ClH:25].[C:1]1([C:7]2[N:8]=[C:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccccc3)cs2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1ccc(-c2csc(C3CCNCC3)n2)cc1
Reaction time: 3 h

Procedure:
Under ice-cooling, to a mixture of tert-butyl 4-(4-phenyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (5.79 g) and DCM (30 mL) was added 4 M hydrogen chloride/dioxane (30 mL), followed by stirring for 3 hours. The resulting solid was collected by filtration, washed with diisopropyl ether, and then dried under reduced pressure to obtain 4-(4-phenyl-1,3-thiazol-2-yl)piperidine hydrochloride (4.51 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:7][C:6]=1[C:22]1[CH:23]=[N:24][CH:25]=[N:26][CH:27]=1)=[O:4].[OH-].[Li+].Cl.O>C1COCC1.CO>[CH3:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[C:6]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[CH:9]=1
Reactant: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)cc1-c1cncnc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)cc(-c2cncnc2)c1C(=O)O
Temperature: 50 °C
Reaction time: 40 h
Yield: 95.4 %

Procedure:
To a solution of 0.43 g (1.20 mmol) of 5-methyl-3-pyrimidin-5-yl-3′-trifluoromethyl-biphenyl-4-carboxylic acid methyl ester in 12 ml of THF/MeOH (1:1) was added 2.89 ml (2.90 mmol) of lithium hydroxide solution (1 molar in water) drop by drop and the reaction mixture was then heated up to 50° C. After 40 hours, the reaction mixture was poured into crashed ice and acidified with HCl/H2O (1N) to pH 3.0 and then extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 3:2) to give 0.410 g (99%) of the title compound as colorless solid. MS: 357.0 (M−H−).
Reaction SMILES: [CH2:1]([C:3]1[S:21][C:6]2[NH:7][C:8](=[O:20])[N:9]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[N:40]=[C:39](C(Cl)(Cl)Cl)[O:38][N:37]=2)=[CH:26][CH:25]=1.C(=O)([O-])[O-:46].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:3]1[S:21][C:6]2[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]4[NH:40][C:39](=[O:46])[O:38][N:37]=4)=[CH:26][CH:25]=3)[C:8](=[O:20])[N:9]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)n(CCc3ccccn3)c(=O)[nH]c2s1
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CCc3ccccn3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.9 %

Procedure:
A mixture of 6-ethyl-3-(2-pyridin-2-ylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.4 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.58 g), potassium carbonate (0.18 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (5 mL) and methanol (5 mL). 1N Aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was adjusted to pH 7 with water and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.1 g, 14%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].C[O:8][C:9]([C:11]1[C:15]([NH:16][C:17]([C:19]2[C:24]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:23][CH:22]=[C:21]([CH:32]3[CH2:34][CH2:33]3)[N:20]=2)=[O:18])=[CH:14][N:13]([CH3:35])[N:12]=1)=O>>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:9]([C:11]1[C:15]([NH:16][C:17]([C:19]2[C:24]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:23][CH:22]=[C:21]([CH:32]3[CH2:34][CH2:33]3)[N:20]=2)=[O:18])=[CH:14][N:13]([CH3:35])[N:12]=1)=[O:8]
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: NCC(O)CO
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)NCC(O)CO)n1
Yield: 15 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 3-amino-propane-1,2-diol with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (15%) as sticky solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][NH:11][CH2:10][C:9]=3[C:14](=[O:16])[O:15][C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl[CH2:25][CH2:26][N:27]1[CH2:34][CH:33]2[CH2:35][CH:29]([CH2:30][CH2:31][CH2:32]2)[CH2:28]1>>[CH:33]12[CH2:35][CH:29]([CH2:30][CH2:31][CH2:32]1)[CH2:28][N:27]([CH2:26][CH2:25][N:11]1[CH2:12][CH2:13][C:8]3[C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=4[O:15][C:14](=[O:16])[C:9]=3[CH2:10]1)[CH2:34]2
Reactant: ClCCN1CC2CCCC(C2)C1
Reactant: Cc1ccc2c3c(c(=O)oc2c1)CNCC3
Solvent: CCN(CC)CC
Product: Cc1ccc2c3c(c(=O)oc2c1)CN(CCN1CC2CCCC(C2)C1)CC3
Reaction time: 72 h
Yield: 70.2 %

Procedure:
Prepared by the method described for Example 13 from 1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (3.0 g, 0.014 moles), triethylamine (4.2 ml, 0.030 moles), and 3-(2-chloroethyl)-3-azabicyclo[3.3.1]nonane (3.3 g, 0.015 moles). The reflux time is 72 hours. Recrystallization from ethanol gave the product (3.6 g), mp 150°-152° C.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([NH2:25])=[O:24])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(N([CH2:31][CH3:32])CC)C.CS(Cl)(=O)=O.[Br-:38].[Li+]>O1CCCC1>[Br:38][CH2:5][C:4]1[CH:3]=[C:2]([NH:25][C:23](=[O:24])[CH2:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:17][CH:18]=2)[CH:1]=[CH:31][CH:32]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(N)=O)cc1
Reactant: [Br-]
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(CBr)c2)cc1
Reaction time: 24 h

Procedure:
To a stirred solution of 4.0 g of N-[3-hydroxymethyl)phenyl]-4-(tetradecyloxy)-benzeneacetamide in 100 ml of tetrahydrofuran is added 1.19 g of triethylamine followed by 1.34 g of methanesulfonyl chloride. Also added is 7.66 g of lithium bromide and continued stirring for 24 hours. The solvent is removed under vacuum and the residue is partitioned between chloroform and water followed by an additional wash of the organic layer with saturated sodium bicarbonate. The organic layer is dried and filtered through a pad of silica gel. The filtrate is evaporated to a residue which is crystallized from hexane:carbon tetrachloride to give 4.1 g of the desired product as a white powder, m.p. 116°-118° C.
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[C:10]([C:12]2[CH:35]=[CH:34][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH2:29][C:30]([F:33])([F:32])[F:31])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH:9]=[N:8]1)([CH3:6])[C:3](O)=[O:4].[Cl-].[NH4+:37]>>[F:33][C:30]([F:31])([F:32])[CH2:29][N:25]1[C:24]([C:18]2[S:19][C:20]3[CH2:21][CH2:22][O:23][C:14]4[CH:13]=[C:12]([C:10]5[CH:9]=[N:8][N:7]([C:2]([CH3:1])([CH3:6])[C:3]([NH2:37])=[O:4])[CH:11]=5)[CH:35]=[CH:34][C:15]=4[C:16]=3[N:17]=2)=[N:28][CH:27]=[N:26]1
Reactant: CC(C)(C(=O)O)n1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Reactant: [NH4+]
Agent: [Cl-]
Product: CC(C)(C(N)=O)n1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1

Procedure:
Following the procedure for 240, 2-Methyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-propionic acid was reacted with ammonium chloride to give 288. MS (ESI+) 504.1. 1H NMR (400 MHz, DMSO) δ 8.44 (s, 1H), 8.3-8.25 (m, 2H), 8.04 (s, 1H), 7.51 (dd, J=8.3, 1.5, 1H), 7.40 (d, J=1.4, 1H), 7.16 (br, 1H), 6.77 (br, 1H), 5.86 (q, J=8.7, 2H), 4.40 (t, J=4.9, 2H), 3.47 (t, J=4.9, 2H), 1.74 (s, 6H)
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)(=O)=O.O>CS(C)=O>[C:1]([C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](C#N)C1
Reaction time: 18 h
Yield: 61.8 %

Procedure:
Potassium cyanide (5.80 g, 89.0 mmol) was added to a solution of tert-butyl (3S)-3-[(methylsulphonyl)oxy]-1-pyrrolidinecarboxylate (preparation 78) (9.35 g, 35.3 mmol) in dimethylsulphoxide (100 ml), and the reaction stired at room temperature for 18 hrs, and then at 100° C. for a further 24 hrs. The cooled mixture was poured into water and extracted well with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate:pentane (20:80) as eluant to give the title compound as an oil, (4.28 g, 62%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][CH2:11][CH:12]1[CH2:14][O:13]1>>[CH2:1]([NH:8][CH2:14][CH:12]([OH:13])[CH2:11][O:10][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC1CO1
Reactant: NCc1ccccc1
Product: COCC(O)CNCc1ccccc1

Procedure:
Starting materials: benzyl amine and 2-(methoxymethyl)oxirane
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7](Br)[CH:8]=[CH2:9].[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([S:31][CH3:32])=[C:18]([S:20]([C:23]2[CH:28]=[C:27]([OH:29])[CH:26]=[C:25]([Br:30])[CH:24]=2)(=[O:22])=[O:21])[CH:19]=1)=[O:14].O>CN(C=O)C.CCOC(C)=O>[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([S:31][CH3:32])=[C:18]([S:20]([C:23]2[CH:24]=[C:25]([Br:30])[CH:26]=[C:27]([O:29][CH2:9][CH:8]=[CH2:7])[CH:28]=2)(=[O:21])=[O:22])[CH:19]=1)=[O:14]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cc(O)cc(Br)c2)c(SC)s1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOc1cc(Br)cc(S(=O)(=O)c2cc(C(=O)OC)sc2SC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Cesium carbonate (33 mg, 0.1 mmol) and allylbromide (30 μL, 0.35 mmol) were added to a solution of 4-(3-bromo-5-hydroxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 12: step d) 30 mg, 0.71 mmol) dissolved in dry DMF (3 mL). After stirring for 16 h at rt, the solution was poured into a mixture of water (20 mL) and EtOAc (30 mL). The layers were separated and the organic layer was extracted with water (5×5 mL), brine (20 mL), and was dried over sodium sulfate. The solvent was removed in vacuo to yield the title compound, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2.Cl.[CH2:23]([O:25][NH2:26])[CH3:24].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:23]([O:25][NH:26][C:19]([C:18]1[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2)=[O:20])[CH3:24]
Reactant: CCON
Reactant: O=C(O)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCONC(=O)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a solution of 4-(2-fluoro-4-iodophenylamino)-1H-indazole-5-carboxylic acid (100 mg, 0.252 mmol) in DMF (3 mL) was added O-ethyl hydroxylamine hydrochloride (37 mg, 0.378 mmol), HOBt (37 mg, 0.277 mmol) and EDCI (53 mg, 0.277 mmol). The reaction mixture was stirred at room temperature for 1 hour then DIPEA (91 μl, 0.529 mmol) was added and the reaction stirred at room temperature for 18 hours. Additional quantities, as at the start of the reaction, of O-ethyl hydroxylamine hydrochloride, HOBt, EDCI and DIPEA were added to the reaction and stirring was continued for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate, the solid precipitate in the mixture was filtered off, washed with water to give the title compound (41 mg, 37%). LCMS (Method A): RT=9.65 min, [M+H]+=441. 1H NMR (DMSO-d6, 400 MHz): 13.19 (1 H, s), 11.51 (1 H, s), 9.97 (1 H, s), 7.66 (1 H, dd, J=10.35, 1.95 Hz), 7.46 (1 H, d, J=8.78 Hz), 7.42 (1 H, dd, J=8.47, 1.84 Hz), 7.25 (1 H, s), 7.02 (1 H, d, J=8.76 Hz), 6.91 (1 H, t, J=8.66 Hz), 3.86 (2 H, q, J=7.04 Hz), 1.15 (3 H, t, J=7.03 Hz).
Reaction SMILES: C(C1C=C(B(O)O)C=CC=1)(=O)C.Br[C:14]1[CH:15]=[CH:16][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[N:18][CH:19]=1.C(NC(C1C(=O)C2C(=NC=CC=2)[N:32]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43](Br)[CH:42]=2)C=1)=O)(C)C>>[NH2:32][C:41]1[CH:42]=[C:43]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[N:18][CH:19]=2)[CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)(O)c1ccc(Br)cn1
Reactant: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Agent: CC(=O)c1cccc(B(O)O)c1
Product: CC(C)(O)c1ccc(-c2cccc(N)c2)cn1

Procedure:
Following the procedure of Step 5 of Example 1, but substituting 3-aminophenylboronic acid for 3-acetyl phenylboronic acid and 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine from Step 1 of Example 30 for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, the 5-(3-Aminophenyl)-2-(1-hydroxy-1-methylethyl)pyridine compound was obtained as a solid.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=1[C:22]([F:25])([F:24])[F:23]>>[N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=3[C:22]([F:23])([F:25])[F:24])[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Reactant: C1CCN(CC2CCNCC2)C1
Product: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)c(C(F)(F)F)c1

Procedure:
Prepared from the product of Example 4 and 4-fluoro-3-trifluoromethyl-benzaldehyde.