Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:19]=[C:20]([CH2:24][C:25]([OH:27])=O)[CH:21]=[CH:22][CH:23]=1.[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([O:38][CH3:39])=[C:35]([CH:37]=1)[NH2:36]>ClCCl>[CH3:39][O:38][C:34]1[CH:33]=[CH:32][C:31]([Cl:30])=[CH:37][C:35]=1[NH:36][C:25](=[O:27])[CH2:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:16])([F:29])[F:28])[CH:19]=1
Reactant: COc1ccc(Cl)cc1N
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(Cl)cc1NC(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
Dicyclohexylcarbodiimide (2.20 g, 10.7 mmol) was added to a solution of 3-(trifluoromethyl)phenylacetic acid (2.00 g, 9.8 mmol) and 5-chloro-2-methoxyaniline (1.55 g, 9.8 mmol) in dichloromethane (50 ml). The reaction was stirred at RT overnight. The reaction mixture was filtered and the filtrate evaporated to dryness. The residue was recrystallized from methanol/water 2:1 (30 ml). 2.05 g (61%) of the title compound was isolated.
Reaction SMILES: [CH3:1][C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[C:10]2([CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[C:9]1=[O:33].[CH3:34][Al](C)C>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>[CH3:34][C:11]1[C:10]2([CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:24][CH2:25]2)[C:9](=[O:33])[N:8]([C:3]2[CH2:4][O:5][C:6](=[O:7])[C:2]=2[CH3:1])[CH:12]=1
Reactant: C[Al](C)C
Reactant: CC1=C(N2C=C(OS(=O)(=O)C(F)(F)F)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1=CN(C2=C(C)C(=O)OC2)C(=O)C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-2,8-diazaspiro[4.5]dec-3-ene-8-carboxylate (180 mg, 0.363 mmol) was dissolved in THF (3.6 mL), and Pd(Ph3P)4 (209 mg, 0.181 mmol) was added, followed by trimethylaluminum (3.6 mL, 7.25 mmol) at 0° C. This reaction was stirred at rt for 2 h before it was quenched with saturated aqueous NaHCO3 solution at 0° C. (highly exothermic). This mixture was diluted with EtOAc, dried over Mg2SO4 and concentrated under reduced pressure. The crude material was purified by column chromatography (0-10% MeOH/DCM) to afford the title compound. LC/MS: [(M+1)]+=363
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:10][CH:11]([CH2:14]Cl)[CH2:12][Cl:13].[OH-].[Na+]>O>[CH2:1]([N:8]1[CH2:14][CH:11]([CH2:12][Cl:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: ClCC(CCl)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCC1CN(Cc2ccccc2)C1
Temperature: 80 °C

Procedure:
59 g of benzylamine was added drop-by-drop over two hours to a stirred, refluxing mixture of 103 g of 1A, 50 ml of water and 200 ml of 100°/120° C. petroleum ether, under nitrogen, at 80° C., the pH of the mixture being maintained at 7-7.5. A solution of 40 g of sodium hydroxide in 60 ml of water was then added slowly to the stirred, refluxing mixture, at a rate sufficient to maintain the pH of the mixture at about 8. The resulting mixture was cooled and the aqueous phase was removed. The organic phase was washed with water, the solvent was evaporated under reduced pressure, and the residue was distilled in a wiped-film evaporator to give 1, as a colorless oil, b.p.: 80° C., 0.01 Torr.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][N:5]=[C:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[N:3]=1.[CH3:23][O:24][CH:25]([O:28][CH3:29])[CH2:26][NH2:27].C(N(CC)C(C)C)(C)C>O1CCOCC1>[CH3:23][O:24][CH:25]([O:28][CH3:29])[CH2:26][NH:27][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][N:5]=[C:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[N:3]=1
Reactant: COC(=O)Cc1cnc(Cc2ccc([N+](=O)[O-])cc2)nc1Cl
Reactant: COC(CN)OC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)Cc1cnc(Cc2ccc([N+](=O)[O-])cc2)nc1NCC(OC)OC
Temperature: 85 °C
Reaction time: 24 h
Yield: 73.6 %

Procedure:
To a solution of methyl [4-chloro-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (2.70 g, 8.39 mmol) and aminoacetoaldehyde dimethyl acetal (1.83 mL, 16.78 mmol) in dioxane (40 mL) was added N,N-diisopropylethylamine (1.46 mL, 8.39 mmol). The mixture was stirred at 85° C. for 1 day. After cooling to room temperature, the reaction was quenched with water, and extracted with ethyl acetate. The extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica-gel, (ethyl acetate) to give methyl [4-[(2,2-dimethoxyethyl)amino]-2-(4-nitrobenzyl)-pyrimidin-5-yl]acetate (2.41 g, 74%) as brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10](=[O:18])[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:31][C:32]([F:35])([F:34])[F:33])(=O)=O.O>C(#N)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]([O:18][CH2:31][C:32]([F:35])([F:34])[F:33])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1cc(=O)[nH]n1-c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cc(OCC(F)(F)F)nn1-c1ncccc1Cl
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
To a suspension of ethyl 1-(3-chloro-2-pyridinyl)-2,3-dihydro-3-oxo-1H-pyrazole-5-carboxylate (i.e. product of Step A) (0.8 g, 3 mmol) stirred in dry acetonitrile (15 mL) at −5° C. was added potassium carbonate (0.85 g, 6.15 mmol). The suspension was stirred for 15 minutes at 20° C. The stirred suspension was then cooled to 5° C., and 2,2,2-trifluoro-ethyl trifluoromethanesulfonate (0.8 g, 3.45 mmol) was added dropwise. The reaction mixture was warmed to room temperature and then heated to reflux, at which time thin layer chromatography showed the reaction to be complete. Water (25 mL) was added to the reaction mixture, which was then extracted with ethyl ether. The ether extract was dried over magnesium sulfate and concentrated to yield the title product compound (1.05 g) as a pale yellow oil.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[C:10](=[O:20])[C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(OCC)(=O)C>[C:21]([O:8][C:9]1[C:10](=[O:20])[C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:23])[CH3:22]
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)OC1=CC(=O)c2ccccc2C1=O
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
595 g (5.89 moles) of triethylamine are added dropwise in 30 minutes to a suspension of 500 g (2.87 moles) of 2-hydroxy-1,4-naphthoquinone (lawsone) in 2200 ml of ethyl acetate, cooled to +5° C., maintaining the temperature below +10° C. At the end of the dripping a dark red solution is obtained. The solution is kept at +5-10° C. for 30 minutes. 550 g (5.39 moles) of acetic anhydride are added dropwise in 30 minutes, maintaining the temperature between +5 and +10° C. At the end of the dripping, the mixture is left under agitation at +5° C. for 4 hours. The solid is filtered and washed with a mixture of 250 ml of ethyl acetate and 250 ml of hexane pre-cooled to +5° C. The damp product is dried at +40° C. at reduced pressure for 6 hours providing 496 g (yield 80%) of 2-acetoxy-1,4-naphthoquinone (acetyl-lawsone) as a yellow solid with melting point −131°-134° C.
Reaction SMILES: [Cl-].[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[O:17][N:16]=[C:15]([C:18]2[N:19]=[C:20]([CH:23]3[CH2:28][CH2:27][NH2+:26][CH2:25][CH2:24]3)[S:21][CH:22]=2)[CH2:14]1)(=[O:5])=[O:4].[CH3:29][N:30]([CH3:35])[CH2:31][C:32](O)=[O:33].C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[O:17][N:16]=[C:15]([C:18]2[N:19]=[C:20]([CH:23]3[CH2:28][CH2:27][N:26]([C:32](=[O:33])[CH2:31][N:30]([CH3:35])[CH3:29])[CH2:25][CH2:24]3)[S:21][CH:22]=2)[CH2:14]1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)Oc1ccccc1C1CC(c2csc(C3CC[NH2+]CC3)n2)=NO1
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4OS(C)(=O)=O)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 4-[4-(5-{2-[(methylsulphonyl)oxy]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidinium chloride (500 mg) in dimethylformamide (6 ml) under argon were added N,N-dimethylglycine (122 mg), diisopropylethylamine (582 mg) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU, 542 mg). The reaction mixture was stirred at room temperature for 18 hours. Then ice-cold sodium hydrogencarbonate solution was added thereto, the mixture was filtered, and the aqueous phase was removed and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. This gave 2-(3-{2-[1-(N,N-dimethylglycyl)piperidin-4-yl]-1,3-thiazol-4-yl}-4,5-dihydro-1,2-oxazol-5-yl)phenyl methanesulphonate (310 mg, 55%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([Cl:26])[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[Cl-].[NH4+]>[Fe].O>[C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]1[CH2:9][CH2:10][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([Cl:26])[CH:18]=2)(=[O:16])=[O:15])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])c(Cl)c2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(N)c(Cl)c2)CC1
Temperature: 80 °C
Yield: 26.9 %

Procedure:
[1-(3-Chloro-4-nitro-benzenesulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.44 g, 1.05 mmol) was suspended in a 5:1 mixture of ethanol and water (30 ml). To this solution was added iron powder (0.29 g, 5.24 mmol) followed by saturated ammonium chloride solution (3 ml) and the mixture was heated to 80° C. for three hours. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of celite, the celite was washed with ethanol (10 ml) and EtOAc (50 ml) and the solution was concentrated under vacuum. The resulting residue was suspended in water (10 ml) and the solid precipitate collected by filtration and dried under vacuum to give the title compound (0.11 g, 18% yield) as a white solid. Tr=2.12 min, m/z (ES+) (M+Na)+ 412.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[Mg].[O:11]1CCC[CH2:12]1.C=O>C(O)(=O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:12][OH:11])=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(F)ccc1Br
Reactant: C1CCOC1
Agent: C=O
Agent: [Mg]
Solvent: CC(=O)O
Product: Cc1cc(F)ccc1CO
Reaction time: 1 h
Yield: 47.6 %

Procedure:
To a stirred and refluxing Grignard-complex, previously prepared starting from 39.7 parts of 1-bromo-4-fluoro-2-methylbenzene and 5.1 parts of magnesium in 225 parts of tetrahydrofuran, are added portionwise 8.4 parts of paraformaldehyde. Upon completion, stirring is continued for 1 hour at reflux. The reaction mixture is cooled and poured onto a mixture of crushed ice and acetic acid. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is distilled, yielding 14 parts (47.6%) of 4-fluoro-2-methylbenzenemethanol; bp. 110° C. (water-jet).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:7]2[CH:23]=[C:22]([OH:24])[C:21]([OH:25])=[CH:20][C:8]=2[S:9][C:10]=1[C:11]([N:13]1[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]1)=[O:12]>ClCCl.C(OCC)(=O)C>[Cl:5][C:6]1[C:7]2[CH:23]=[C:22]([OH:24])[C:21]([OH:25])=[C:20]([N+:1]([O-:4])=[O:2])[C:8]=2[S:9][C:10]=1[C:11]([N:13]1[CH2:14][CH2:15][CH:16]([OH:19])[CH2:17][CH2:18]1)=[O:12]
Reactant: O=C(c1sc2cc(O)c(O)cc2c1Cl)N1CCC(O)CC1
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1sc2c([N+](=O)[O-])c(O)c(O)cc2c1Cl)N1CCC(O)CC1
Reaction time: 3 h

Procedure:
A solution of 1 M HNO3 in dichloromethane (0.67 ml) was added to a solution of (3-chloro-5,6-dihydroxy-benzo[b]thiophen-2-yl)-(4-hydroxy-piperidin-1-yl)-methanone (0.17 g) in ethyl acetate (10 ml). Stirring was continued at 60° C. for 3 hours and then at room temperature overnight. The mixture was concentrated to smaller volume and the precipitate filtered and washed with water. The crude product was recrystallized from N,N-dimethylformamide/ethanol (25:75).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[NH2:15]>>[NH2:15][C:14]1[CH:13]=[C:12]([O:11][CH3:10])[C:18]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:17][C:16]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: O=Cc1ccccc1Cl
Reactant: COCCOc1ccc(N)cc1OC
Product: COCCOc1cc(C(=O)c2ccccc2Cl)c(N)cc1OC

Procedure:
(2-amino-4-methoxy-5-(2-methoxyethoxy)phenyl)-(2-chlorophenyl)-methanone (Xkk) was prepared by reacting 2-chlorobenzaldehyde with 0.0242 moles of 3-methoxy-4-(2-methoxyethoxy) aniline in a manner analogous to Example 1. MH+/Z=336.
Reaction SMILES: Cl[B:2](Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][Si:11]([C:14]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15]1)([CH3:13])[CH3:12]>C(OCC)C>[CH3:10][Si:11]([C:14]1([B:2]([C:14]2([Si:11]([CH3:13])([CH3:12])[CH3:10])[CH:18]=[CH:17][CH:16]=[CH:15]2)[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:18]=[CH:17][CH:16]=[CH:15]1)([CH3:13])[CH3:12]
Reactant: ClB(Cl)c1ccccc1
Reactant: [Li]C1([Si](C)(C)C)C=CC=C1
Solvent: CCOCC
Product: C[Si](C)(C)C1(B(c2ccccc2)C2([Si](C)(C)C)C=CC=C2)C=CC=C1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
To 4.80 g (30.2 mmol) of dichloro(phenyl)borane, dissolved in 70 ml of diethyl ether, a suspension of 8.36 g (60.4 mmol) of trimethylsilylcyclopentadienyllithium in 100 ml of diethyl ether is slowly added at -78° C. The mixture is allowed to warm to room temperature in the cooling bath, and insolubles are filtered off. After concentrating the yellow filtrate to dryness in an oil-pump vacuum, 10.8 g of bis(trimethylsilylcyclopentadienyl) (phenyl)borane is obtained as a yellow viscous oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:13])=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=1.C(OC([N:21]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39]C(=O)OC(C)(C)C)=[CH:35][CH:34]=1)[C:22]1[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][C:23]=1[O:30][CH3:31])=O)(C)(C)C.N1CCCCC1>CCO>[NH2:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][NH:21][C:22]2[CH:27]=[CH:26][C:25](/[CH:28]=[CH:13]/[C:4]3[O:3][C:2]([CH3:1])=[CH:7][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:5]=3)=[CH:24][C:23]=2[O:30][CH3:31])=[CH:34][CH:35]=1
Reactant: COc1cc(C=O)ccc1N(Cc1ccc(NC(=O)OC(C)(C)C)cc1)C(=O)OC(C)(C)C
Reactant: CC1=CC(=C(C#N)C#N)C=C(C)O1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(/C=C/C2=CC(=C(C#N)C#N)C=C(C)O2)ccc1NCc1ccc(N)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of 2-(2,6-dimethyl-4H-pyran-4-ylidene) malononitrile (1, 16.5 mg, 96 μmol) and aldehyde 2d (34.9 mg, 76.5 μmol) were dissolved in anhydrous EtOH (0.5 ml) at 65 C. Piperidine (1 μl) was added and the mixture was stirred at 80° C. for 6 hrs. The solvent was removed with a stream of N2 and the crude mixture was purified by reverse phase HPLC using water/acetonitrile 40-100% gradient. Yield: 8.1 mg (17.4%). LCMS: m/z 611 (M+H+), 623 (M+Na+). H-NMR (400 MHz, CD2Cl2): 7.45 (1H, d, J=16 Hz) 7.29 (2H, d, J=12 Hz) 7.17 (2H, d, J=8 Hz) 7.03-7.12 (2H, m) 6.69-6.79 (2H, m) 6.52-6.61 (2H, m) 4.76 (2H, brs) 3.89 (3H, s) 2.43 (3H, s) 1.52, (9H, s) 1.41 (9H, brs). C-NMR (400 MHz, CD2Cl2): 162.54, 159.01, 156.35, 152.56, 137.61, 137.21, 134.39, 133.06, 132.89, 128.82, 120.38, 118.39, 117.99, 115.03, 114.99, 107.37, 106.31, 80.21, 58.97, 55.49, 29.68, 28.00, 27.93, 19.75. The purified product (8.1 mg) was treated with a 4N HCl solution in dioxane (4 N, 0.65 ml) for 3 hrs. The mixture was diluted with hexanes, the precipitate centrifuged, re-suspended and washed with hexanes, then dried under vacuum. LCMS ESI+ m/z: 411 (M+H+). H-NMR (400 MHz, DMSO-D6) 7.22-7.28 (5H, m) 6.83-6.89 (2H, m) 6.65 (1H, d, J=16 Hz) 6.54 (1H, d, J=16 Hz) 5.54 91H, s) 5.32 (1H, s) 4.22-4.38 (2H, brs) 3.92 (3H, s) 2.39 (3H, s).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].N1C=CN=C1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>CN(C)C=O>[Si:11]([O:5][CH2:1][CH2:2][C:3]#[CH:4])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 86.5 %

Procedure:
A mixture of 21 g of 3-butyn-1-ol and 27 g of imidazole in 100 ml of dimethyl formamide was treated with 45 g of t-butyldimethylsilyl chloride in several portions over a one hour period. After stirring under nitrogen for 18 hours the reaction mixture was diluted with 500 ml of ice water. The resulting aqueous solution was extracted with 300 ml of ether and the ethereal solution washed with water and then brine. The ethereal solution was dried over potassium carbonate. Evaporation of the ether and distillation of the residue gave 47.6 g of 3-butyn-1-ol t-butyldimethylsilyl ether, bp 80°-83° C./25 mm.
Reaction SMILES: CS([O:5][CH2:6][C@@H:7]1[CH2:13][CH2:12][C:9]2([CH2:11][CH2:10]2)[N:8]1[CH3:14])(=O)=O.O[C:16]1[CH:25]=[C:24]2[C:19]([C:20]([O:26][C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]4[C:37](=[O:49])[N:38]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)[N:39]([CH3:42])[C:40]=4[CH3:41])=[O:35])=[CH:29][C:28]=3[F:50])=[CH:21][CH:22]=[N:23]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH3:14][N:8]1[C@H:7]([CH2:6][O:5][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([O:26][C:27]4[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]5[C:37](=[O:49])[N:38]([C:43]6[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=6)[N:39]([CH3:42])[C:40]=5[CH3:41])=[O:35])=[CH:29][C:28]=4[F:50])=[CH:21][CH:22]=[N:23]3)=[CH:18][CH:17]=2)[CH2:13][CH2:12][C:9]21[CH2:11][CH2:10]2
Reactant: CN1[C@H](COS(C)(=O)=O)CCC12CC2
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OC[C@@H]5CCC6(CC6)N5C)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 40 °C
Reaction time: 72 h
Yield: 6 %

Procedure:
To a mixture of ((5S)-4-methyl-4-azaspiro[2.4]heptane-5-yl)methyl methanesulfonate (150 mg, 0.685 mmol) and N-(4-(7-hydroxyquinolin-4-yloxy)-3-fluorophenyl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide (331.5 mg, 0.685 mmol) in 8 mL of N,N-dimethylacetamide was added cesium carbonate (893 mg, 2.74 mmol, Aladdin). After stirring at 40° C. for 3 days, the reaction mixture was concentrated in vacuo and the residue was chromatographed with a silica gel column (50:1 (v/v) CH2Cl2/CH3OH) to give the desired product as a pale yellow solid (25 mg, 6%).
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)[OH:4].[CH3:15][NH2:16]>>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)[CH2:2][NH:16][CH3:15]
Reactant: CN
Reactant: CC(=O)Nc1ccc(C(O)CBr)cc1
Product: CNCC(O)c1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-[4-(2-bromo-1-hydroxyethyl)phenyl]acetamide (0.40 g, in 10 mL of methanol) was introduced methylamine (10 mL, 2.0 M in methanol) at 0° C. The reaction mixture was warmed to room temperature after 30 minutes, and stirred at that temperature for 2 hours. The solvent and excess methylamine was evaporated. The residue was dissolved in methanol (5 mL) and stirred with resin (BioRad 50W×2, 0.5 g) overnight. The resin was collected by filtration, washed with methanol. The product on the resin was washed off with NH4OH/CH3OH (10% NH4OH aqueous solution (Aldrich, 29.4% NH3) in methanol, v/v). The solution was concentrated to give the title compound as a white solid (0.16 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28]OS(C)(=O)=O)=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-:34].[Li+]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][Br:34])=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(COS(C)(=O)=O)cc3)c2CC1
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(CBr)cc3)c2CC1
Reaction time: 8 h

Procedure:
Dissolve the crude 3-tert-butoxycarbonyl-7-chloro-6-(4-methanesulfonyloxymethyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine in anhydrous acetone (3 mL), treat with anhydrous lithium bromide (335 mg, 3.89 mmol) and continue stirring overnight. Add water, extract the reaction mixture three times with ethyl ether, wash with brine, dry over anhydrous MgSO4, and concentrate in vacuo to obtain the desired intermediate that was used without purification.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][O:10][C:11]([NH:13][C:14]2([C:17]([O:19][CH3:20])=[O:18])[CH2:16][CH2:15]2)=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH3:22]>CN(C=O)C.O>[CH3:22][N:13]([C:11]([O:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:12])[C:14]1([C:17]([O:19][CH3:20])=[O:18])[CH2:16][CH2:15]1
Reactant: CI
Reactant: COC(=O)C1(NC(=O)OCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(N(C)C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 247.7 %

Procedure:
Sodium hydride (995 mg, 41.466 mmol) was taken up in DMF (50 mL) and was cooled to 0° C. for 30 min. Then a mixture of methyl 1-({[(phenylmethyl)oxy]carbonyl}amino)cyclopropanecarboxylate (6.46 g, 25.916 mmol) in DMF (25 mL) was slowly added over 10 min. The resulting mixture was allowed to stir for 45 min, and then iodomethane (4.84 mL, 77.74 mmol) was added, and the reaction was allowed to warm to room temperature overnight. The mixture was then carefully diluted with water (10 mL), and the aqueous layer was extracted with Et2O (5×50 mL). The organic extracts were washed with water (5×50 mL), then dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via Combiflash, utilizing a 0%-50 EtOAc/Hex gradient to provide methyl 1-(methyl{[(phenylmethyl)oxy]carbonyl}amino)cyclopropanecarboxylate (16.9 g, >100%) LCMS: (M+H)+: 264.1.