Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]O.C1N2[CH2:15][CH2:16][N:11](CC2)C1.S(Cl)([C:20]1[CH:26]=CC(C)=[CH:22][CH:21]=1)(=O)=O.O>C1COCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:11][C:16]1[CH:15]=[CH:22][CH:21]=[CH:20][CH:26]=1
Reactant: OCCCCCCBr
Reactant: C1CN2CCN1CC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: O
Product: BrCCCCCCNc1ccccc1
Temperature: -20 °C
Reaction time: 24 h
Yield: 89.8 %

Procedure:
To 18.11 g (100 mmoles) of 6-bromo-1-hexanol and 11.22 g (100 mmoles) of DABCO in 100 ml of anhydrous THF at −20° C., there is slowly added 19.06 g (100 mmoles) of tosyl chloride. After 24 hours under stirring at −20° C., the reaction mixture was filtered to remove the precipitate of DABCO hydrochloride. After evaporation of the solvent, a quantitative amount of 6-bromo-1-hexanol tosylate CH3FSO2O(CH2)6Br was recovered. This compound was thereafter dissolved in 20 ml of THF with 40 g of aniline FNH2 (200 mmoles) and this solution was heated to reflux overnight. After cooling, 300 ml of water were added and the organic phase was extracted with ether. After washing with water, the ether phase was dried with magnesium sulfate. After evaporation and drying, 23 g of N-(6-bromohexyl)aniline was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[Br-].[C:17]([Zn+])([CH3:20])([CH3:19])[CH3:18].C1COCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]([C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Reactant: CC(C)(C)[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1nc(C#Cc2ccc(C(C)(C)C)nc2)cs1
Temperature: 150 °C

Procedure:
200 mg (0.85 mmol, 1 eq) 2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine, 50 mg (0.043 mmol, 0.05 eq) tetrakis(triphenylphosphine)palladium(0), and 2 mL of 0.5 M t-butylzinc bromide in THF (1 mmol, 1.1 eq) were combined. The reaction mixture was heated at 150° C. in the microwave for 5 min, quenched with pH 10 PBS, extracted with DCM. Silica gel chromatography (gradient 5% to 50% EtOAc/Hexanes) gave 2-tert-butyl-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (L-001109555). LC-MS calculated for C15H16N2S 256, observed m/e 257.0 (M+H)+. 1H-NMR (500 MHz, CDCl3) δ 8.74 (s, 1H), 7.76 (d, 1H), 7.45 (s, 1H), 7.12 (d, 1H), 2.77 (s, 3H), 2.12 (m, 1H), 0.97 (d, 9H).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25](Br)[CH:26]=4)[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[CH3:31][C:32](N(C)C)=[O:33].[Cl-].[NH4+]>CCCCCC.O1CCCC1.C(OCC)(=O)C>[F:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:32](=[O:33])[CH3:31])[CH:26]=4)[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1
Reactant: Fc1ccc(CCN2CCC(N3CCc4ccc(Br)cc43)CC2)cc1
Reactant: CC(=O)N(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Reaction time: 0.17 h
Yield: 27 %

Procedure:
A 2.5 M solution (1.5 ml) of n-butyllithium in hexane was added dropwise at −78° C. into a solution (30 ml) of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoindoline (1.0 g) in tetrahydrofuran over 5 min. After 10 min, dimethylacetamide (0.34 ml) was added thereto and the resultant mixture was warmed to room temperature. Next, a saturated aqueous solution of ammonium chloride and ethyl acetate were added thereto to and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (250 mg) as a yellow powder (yield: 27%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Li].[O:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.C([Li])CCC.[CH3:17][S:18]([C:21]1[CH:40]=[CH:39][C:24]([CH2:25][N:26]2[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][C:35](OC)=[O:36])[CH2:28][CH2:27]2)=[CH:23][CH:22]=1)(=[O:20])=[O:19].[Cl-].[NH4+]>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:35]([C:8]1[O:7][CH:11]=[CH:10][CH:9]=1)([OH:36])[CH2:34][CH2:33][N:29]1[CH2:30][CH2:31][CH2:32][N:26]([CH2:25][C:24]2[CH:39]=[CH:40][C:21]([S:18]([CH3:17])(=[O:20])=[O:19])=[CH:22][CH:23]=2)[CH2:27][CH2:28]1
Reactant: [Li]c1ccco1
Reactant: c1ccoc1
Reactant: COC(=O)CCN1CCCN(Cc2ccc(S(C)(=O)=O)cc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(CN2CCCN(CCC(O)(c3ccco3)c3ccco3)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-furyl lithium prepared in 50 mL of THF using 3 mL of furan and 2 mL of 1.63 M n-butyllithium was added dropwise at 0° C., a 10 ml solution in THF of 99 mg of methyl 3-[4-{4-(methylsulfonyl)benzyl}homopiperazinyl]propionate. After stirring at 0° C. for 1 hour, the mixture was mixed with 50 mL of an aqueous saturated ammonium chloride, and extracted with 50 mL×2 of ethyl acetate. The extracts were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, ethyl acetate) to give 62 mg of the titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].CC([O-])=O.[Na+].[Br:17]Br>CC(O)=O>[Br:17][C:10]1[C:2]([CH3:1])=[C:3]([C:7]([CH3:11])=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(Br)c(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6-dimethylbenzoic acid (25.00 g, 166 mmol) in HOAc (432 mL) was added NaOAc (16.39 g, 200 mmol) followed by bromine (11.2 mL, 216 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was poured onto ice water (800 mL) and stirred for 20 minutes. The solid was filtered off, washed with H2O and dried at 50° C. under vacuum to give INT 34.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10](C(=O)C(F)(F)F)[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].Cl[S:24]([OH:27])(=O)=[O:25].C(N(CC)C(C)C)(C)C.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>C(Cl)Cl.O>[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([S:24]([C:14]2[CH:15]=[C:16]3[C:6]4([CH2:7][CH2:8][N:4]([C:1](=[O:3])[CH3:2])[CH2:5]4)[CH2:9][NH:10][C:11]3=[CH:12][CH:13]=2)(=[O:27])=[O:25])[CH2:40][CH2:39]1
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)C(F)(F)F)c1ccccc12
Reactant: CN1CCNCC1
Reactant: O=S(=O)(O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCC2(CNc3ccc(S(=O)(=O)N4CCN(C)CC4)cc32)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
1-(1′-Acetylspiro[indoline-3,3′-pyrrolidin]-1-yl)-2,2,2-trifluoroethanone (1.19 g, 3.81 mmol) was dissolved in methylene chloride (10 mL). Thereafter, chlorosulfonic acid (1.27 mL, 19 mmol) was added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred for 30 minutes. Thereafter, while stirring, the reaction solution was added dropwise to ice water, and was then extracted with chloroform. The obtained organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was dissolved in methylene chloride (20 mL). Thereafter, N,N-diisopropylethylamine (0.7 mL, 4 mmol) and 1-methylpiperazine (0.22 mL, 2 mmol) were added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred at room temperature for 15 hours. Thereafter, the reaction solution was diluted with water, and was then extracted with chloroform. The obtained organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was dissolved in methanol (3 mL), and a saturated solution of ammonium-methanol (3 mL) was then added to the above obtained solution, followed by stirring the mixture at room temperature for 30 minutes. Thereafter, the reaction solution was concentrated in vacuo, and the obtained residue was then purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain 1-(5-((4-methylpiperazin-1-yl)sulfonyl)spiro[indoline-3,3′-pyrrolidin]-1′-yl)ethanone (559 mg, 82%) in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][C:14](O)=O.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[O:38]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[O:41][CH2:40][CH:39]1[CH2:48][NH2:49]>CN(C=O)C>[O:38]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[O:41][CH2:40][CH:39]1[CH2:48][NH:49][CH2:14][CH2:13][CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][CH:6]=1
Reactant: O=C(O)CCCc1c[nH]c2ccc(F)cc12
Reactant: NCC1COc2ccccc2O1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc2[nH]cc(CCCCNCC3COc4ccccc4O3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
5-Fluoroindole-3-butyric acid (1.5 g, 6.8 mmole), 1-hydroxybenzotriazole hydrate (1.1 g, 8.2 mmole) and 1,3-diisopropylcarbodiimide (2.6 ml, 16.3 mmole) were combined in 150 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.4 g, 6.8 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions of the products were concentrated and washed with a minimum amount of THF to remove a by-product and to give 1.5 g (60%) of the desired product, (2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-4-(5-fluoro-1H-indole-3yl)-butanamide, as an oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]2[CH:13]=[CH:12][NH:11][C:6]=2[N:7]=[C:8]([NH2:10])[N:9]=1.Br[CH2:15][CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].O>CN(C=O)C>[Si:18]([O:17][CH2:16][CH2:15][N:11]1[C:6]2[N:7]=[C:8]([NH2:10])[N:9]=[C:4]([Cl:3])[C:5]=2[CH:13]=[CH:12]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Nc1nc(Cl)c2cc[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc2c(Cl)nc(N)nc21
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (0.618 g, 15.45 mmol) in anhydrous DMF (15 mL) at 0° C. is added slowly a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-amine (2 g, 11.86 mmol) in 5 mL of anhydrous DMF. The mixture is stirred at this temperature under N2 for 15 min, then (2-bromoethoxy)-t-butyldimethylsilane (4.0 mL, 18.64 mmol) is added at 0° C. The mixture is stirred at RT overnight. The reaction mixture is poured into water and extracted with ethyl acetate (EtOAc; 4×). The organic layer is dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated in vacuo. The crude product is purified by flash cromatography using EtOAc/cyclohexane (1/1) as eluent to yield 7-[2-(t-butyldimethylsilanyloxy)ethyl]-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-amine as white needles: LC/MS (M+1=327). 1H NMR (CDCl3, 400 MHz) δ −0.08 (s, 6H), 0.84 (s, 9H), 3.88 (t, 2H, J=5.2 Hz), 4.17 (t, 2H, J=5.2 Hz), 4.89 (s, 2H, NH2), 6.35 (d, 1H, J=3.6 Hz), 6.90 (d, 11, J=16 Hz).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:6][N:5]([C:17]2([CH2:21][C:22]#[N:23])[CH2:20][NH:19][CH2:18]2)[N:4]=1.Cl[C:25]1[N:26]=[CH:27][C:28]([C:31]([NH:33][CH:34]([CH3:36])[CH3:35])=[O:32])=[N:29][CH:30]=1.C(N(CC)C(C)C)(C)C.C(O)(C)(C)C>>[C:22]([CH2:21][C:17]1([N:5]2[CH:6]=[C:7]([B:8]3[O:9][C:10]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:14])[O:12]3)[C:3]([CH3:2])=[N:4]2)[CH2:18][N:19]([C:25]2[N:26]=[CH:27][C:28]([C:31]([NH:33][CH:34]([CH3:36])[CH3:35])=[O:32])=[N:29][CH:30]=2)[CH2:20]1)#[N:23]
Reactant: Cc1nn(C2(CC#N)CNC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)NC(=O)c1cnc(Cl)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: Cc1nn(C2(CC#N)CN(c3cnc(C(=O)NC(C)C)cn3)C2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 100 °C

Procedure:
A mixture of {3-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile HCl salt (0.43 g, 1.3 mmol), 5-chloro-N-isopropylpyrazine-2-carboxamide (0.24 g, 1.2 mmol) and N,N-diisopropylethylamine (0.63 mL, 3.6 mmol) in tert-butyl alcohol (12 mL, 120 mmol) was heated at 100° C. for 4 h. After cooling, the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexanes (0-60%) to afford the desired product. LCMS cacld. for C23H33BN7O3 (M+1)+: m/z=466.3. Found: 466.2.
Reaction SMILES: [CH2:1]([C:8]1[CH:15]=[C:12]([CH:13]=O)[C:11]([OH:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:24](C(OCC)=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26].O>CC(=O)CC>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:16][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13][C:12]=2[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: O=Cc1cc(Cc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCOC(=O)c1cc2cc(Cc3ccccc3)ccc2o1

Procedure:
6.9 g of 1A was dissolved in 130 ml of 2-butanone. The solution was heated to reflux and 8.1 g of potassium carbonate was added. Then 7.8 g of diethyl bromomalonate was added, drop-by-drop over a 10-minute period. The mixture was stirred at reflux for 58 hours, then was cooled and filtered. The filtrate was concentrated under reduced pressure to leave an oil, which was poured into water. The mixture was extracted with ether. The extract was washed with 5% sodium hydroxide solution, then with water, dried (MgSO4), and concentrated under reduced pressure. The residue was recrystallized from methanol and dried over P2O5 to give 1, mp: 78°-79° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20](=[O:21])[N:19]([CH2:22][CH3:23])[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[C:4]([Cl:24])[CH:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20](=[O:21])[N:19]([CH2:22][CH3:23])[C:11]3[N:12]=[C:13]([NH:36][C:35]4[CH:34]=[CH:33][C:32]([N:29]5[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]5)=[CH:38][CH:37]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[C:4]([Cl:24])[CH:3]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCn1c(=O)c(-c2ccc(Br)cc2Cl)cc2cnc(S(C)=O)nc21
Solvent: ClCCl
Product: CCn1c(=O)c(-c2ccc(Br)cc2Cl)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Yield: 41.1 %

Procedure:
6-(4-Bromo-2-chlorophenyl)-8-ethyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one (11, 0.60 g, 1.41 mmol) and 4-(4-methylpiperazino)aniline (0.27 g, 1.41 mmol) were stirred at 150° C. for 4 h. The cooled reaction mixture was taken up in dichloromethane (50 mL) and washed with 10% NaOH (1×25 mL) then with water (1×20 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography using chloroform:methanol (100:3) as eluent to give the title compound as a yellow solid (0.32 g, 0.58 mmol, 41%). ESMS m/z 553 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.53 (s, 1H), 7.65 (d, J=1.8 Hz, 1H), 7.52-7.59 (m, 3H), 7.45 (dd, J=8.2, 1.9 Hz, 1H), 7.28 (d, J=8.2 Hz, 1H), 6.97 (d, J=8.8 Hz, 2H), 4.48 (q, J=7.0 Hz, 2H), 3.17-3.26 (m, 4H), 2.55-2.70 (m, 4H), 2.37 (s, 3H), 1.37 (t, J=7.0 Hz, 3H).
Reaction SMILES: N1C2NCCCC=2C=CC=1CC(N)[OH:13].CCOC(/N=N/C(OCC)=O)=O.CC1(C)[C@H](C2C=CC(O)=CC=2)[C@@H]1CC(OCC)=O.[C:45]1([P:51]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C=O)C>[C:58]1([P:51](=[O:13])([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: NC(O)Cc1ccc2c(n1)NCCC2
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: CCOC(=O)C[C@H]1[C@@H](c2ccc(O)cc2)C1(C)C
Solvent: CN(C)C=O
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2-(5,6,7,8-tetrahydro-1,8-naphthyridyl)-aminoethanol (0.832 g, 4.8 mmol) and DEAD (0.835 g, 4.8 mmol) in DMF (10 mL) was added to a solution of ethyl (cis)2,2-dimethyl-3-(p-hydroxyphenyl)cyclopropaneacetate (0.560 g, 0.2.39 mmol) and triphenylphosphine (0.1.26 g, 4.8 mmol) in dimethylformamide (10 mL) and was stirred for 4 h at rt. The solvent was removed and the residue was purified by hplc to afford the desired ester along with some triphenylphosphine oxide. The residue in ethanol (20 mL) water (20 mL) was added lithium hydroxide (1 g) and was stirred for 18 h. The reaction mixture was concentrated and the residue in water was added trifluoroacetic acid (2 mL) and was purified on hplc to afford the desired product as a solid. 1H NMR (CD3OD) δ 7.58 (d, 1H, J=7.4 Hz), 7.06 (m, 2H), 6.80(m, 2H), 6.70 (d, 1H, J=7.3 Hz), 4.24 (t, 2H, J=5.9 Hz), 3.48 (m, 2H), 3.13 (t, 2H, J=5.9 Hz), 2.8 (m, 2H), 1.99-2.02 and 2.27-2.33 (m, 2H), 1.93 (m, 2H), 1.83 (d, 1H, J=9 Hz), 1.23 (s, 3H), 1.18 (m, 1H), 0.89 (s, 3H). Anal. Calcd for C23H28N2O3: Mol. Wt, 380.2100. Found: 379.2036 (M−H, HRMS).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:32]=[CH:31][C:11]3=[N:12][N:13]([C:15]4[CH:16]=[C:17]([CH:23]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=4[OH:26])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[N:14]=[C:10]3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:44]1([CH3:51])[C:45]([CH3:50])=[CH:46][CH:47]=[CH:48][CH:49]=1>C(OCC)(=O)C>[C:1]1([S:7][C:8]2[CH:32]=[CH:31][C:11]3=[N:12][N:13]([C:15]4[CH:16]=[C:17]([CH2:18][CH2:19][C:20]([O:22][CH2:50][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:44][CH3:51])=[O:21])[CH:23]=[C:24]([C:27]([CH3:29])([CH3:28])[CH3:30])[C:25]=4[OH:26])[N:14]=[C:10]3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(-n2nc3ccc(Sc4ccccc4)cc3n2)c1O
Reactant: Cc1ccccc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: CCCCCCCCOC(=O)CCc1cc(-n2nc3ccc(Sc4ccccc4)cc3n2)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
Likewise, to a 250 mL round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet, condenser, and a Dean-Stark trap are charged 4.3 g (0.0096 mol) of 3-(5-phenylthio-2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyhydrocinnamic acid, 3.4 g (0.026 mol) of Exxel 8, an isomeric mixture of octanols available from Exxon Chemicals, 70 mg of p-toluenesulfonic acid, and 20 mL of xylene. The mixture is refluxed 3.5 hours, is cooled to room temperature, and a portion of ethyl acetate is added. The solution is washed once with water, twice with saturated sodium bicarbonate solution, and once with brine. After drying over anhydrous magnesium sulfate, the solvent is removed under reduced pressure to afford 5.17 g (96% yield) of the title compound as a viscous yellow oil. Analysis by nmr (CDCl3) is consistent with the structure of the title compound.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12]>[OH-].[Na+]>[CH3:10][Si:11]([CH2:14][NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:13])[CH3:12]
Reactant: C[Si](C)(C)CCl
Reactant: NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: C[Si](C)(C)CNCc1ccccc1
Temperature: 10 °C
Yield: 81.5 %

Procedure:
A mixture of 264 mL (2.42 mol) of benzylamine and 97.7 g. (0.796 mol) of chloromethyltrimethylsilane was heated to 200° C. for 2.5 h then cooled to 10° C. A 0.1M sodium hydroxide solution (400 mL) was added and the product was extracted with 3×200 mL of diethyl ether. The combined organic phase was washed with 100 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The product was distilled at 115°-125° C. and 5 mm of Hg to give 125.4 g (81% yield) of N-trimethylsilylmethyl benzylamine as a clear liquid; 1H NMR (CDCl3) δ: 0.0 (s, 9H), 1.1 (br s, 1H), 2.01 (s, 2H), 3.76 (s, 2H), 7.1-7.3 (m, 5H).
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH3:24][CH:25]([CH3:29])[CH2:26][C:27]#[CH:28]>>[OH:23][C:18]([C:15]1[CH:16]=[CH:17][C:12]([N:2]([CH3:1])[S:3]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)(=[O:5])=[O:4])=[CH:13][CH:14]=1)([C:19]([F:21])([F:22])[F:20])[C:28]#[C:27][CH2:26][CH:25]([CH3:29])[CH3:24]
Reactant: C#CCC(C)C
Reactant: CN(c1ccc(C(=O)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Product: CC(C)CC#CC(O)(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F

Procedure:
The compound was prepared from N-methyl-N-(4-trifluoroacetyl-phenyl)-benzenesulfonamide (Example 22, Step A) and 4-methyl-pent-1-yne following the procedure described in Example 29. 1H NMR (CDCl3) δ 1.01 (d, J=6.6 Hz, 6H), 1.90 (sept, J=6.6 Hz, 1H), 2.21 (d, J=7.7 Hz, 2H), 3.17 (s, 3H), 3.24 (br s, 1H), 7.12–7.68 (m, 9H). Mass Spectrum (CI+) m/e=426 (M+1).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[Cl:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:2]2[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=2)=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1cc(B(O)O)ccc1Cl
Reactant: Nc1c(F)cc(Br)cc1F
Product: COc1cc(-c2cc(F)c(N)c(F)c2)ccc1Cl
Yield: 62.6 %

Procedure:
The title compound (81 mg) was prepared from 4-bromo-2,6-difluoroaniline (100 mg, 0.48 mmol) and 4-chloro-5-methoxyphenylboronic acid (116 mg, 0.62 mmol) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:11]=2)[CH:8]=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.C([O-])([O-])=O.[K+].[K+].[F:37][C:38]([F:42])([F:41])[CH2:39]O>C(Cl)Cl>[F:37][C:38]([F:42])([F:41])[CH2:39][O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:11]=2)[CH:8]=1
Reactant: CCOC(=O)c1cnc2ccc(CO)cn12
Reactant: OCC(F)(F)F
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc2ccc(COCC(F)(F)F)cn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 6-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxylate (59) (460 mg, 2.2 mmol) and DIEA (0.78 mL, 4.4 mmol) in DCM (5 mL) was added MsCl (303 mg, 2.64 mmol). The mixture was stirred at room temperature for 10 minutes then subjected to standard aqueous work up to give a residue. The crude product was dissolved in 2,2,2-trifluoroethanol (2 mL) and was added K2CO3 (608 mg, 4.4 mmol). The reaction mixture was heated at 80° C. for 2 hours. Once complete, the reaction mixture was diluted and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated to afford a residue which was purified by silica chromatography to yield ethyl 6-((2,2,2-trifluoroethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate (97). 1H NMR (400 MHz, CDCl3) δ 9.33 (m, 1H), 8.32 (s, 1H), 7.76 (dd, J=0.8, 9.2 Hz, 1H), 7.47 (dd, J=2.0, 9.2 Hz, 1H), 4.76 (s, 2H), 4.44 (q, J=7.2 Hz, 2H), 3.92 (q, J=8.4 Hz, 2H), 1.45 (t, J=7.2 Hz, 3H). MS m/z 303.1 (M+1)+.