Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([N:4]([CH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26])[C@H:5]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)[CH3:3].ClCCl.O.[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37]>FC(F)(F)C(O)=O.CO>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37].[CH3:3][CH:2]([N:4]([CH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25]([F:28])([F:26])[F:27])[C@H:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)[CH3:1]
Reactant: CC(C)N(Cc1cc(F)ccc1C(F)(F)F)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: O=C(O)/C=C/C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(C)N(Cc1cc(F)ccc1C(F)(F)F)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1,1-dimethylethyl (3S)-3-((1-methylethyl)-{[2-(trifluoromethyl)-5-fluorophenyl]-methyl}amino)-pyrrolidine-1-carboxylate (0.26 g) in a mixture of trifluoroacetic acid (2 mL), dichloromethane (8 mL) and water (0.2 mL) was stirred at room temperature for 3 hours. The reaction mixture was evaporated in vacuo. The crude mixture was taken up in methanol and absorbed onto an SCX-2 ion exchange cartridge. After initially washing with methanol, the product was eluted with 2M methanolic ammonia and the collected fractions evaporated in vacuo. The crude product was taken up in methanol and fumaric acid (1 equiv. ) in methanol added. The solvent was removed in vacuo and the resultant gum triturated with diethyl ether. The solid formed was filtered off and dried in vacuo at 50° C. to yield the title compound as an off-white microcrystalline solid. 1H NMR (300 MHz, CD3OD) δH: 1.09 (d, 3H), 1.10 (d, 3H), 1.87 (m, 1H), 2.15 (m, 1H), 3.01 (m, 2H), 3.23 (m, 1H), 3.38 (m, 2H), 3.81 (m, 1H), 3.91 (s, 2H), 6.70 (s, 2H), 7.15 (dt, 1H), 7.73 (m, 2H); MS: [M+H]=305.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1Br)=[O:9])([CH3:6])[CH3:5].[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:29]#[C:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:9])([CH3:6])[CH3:5]
Reactant: C#Cc1ccccc1
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1C#Cc1ccccc1
Yield: 18.9 %

Procedure:
40 mg 2-[(1-Bromo-naphthalene-2-carbonyl)amino]-2-methyl-propionic acid methyl ester and 2 mg Bis(triphenylphosphine)palladium(II)chloride were suspended in 2 ml of DMF and deoxygenated with Argon. 0.26 ml of TMEDA were added, the mixture was again bubbled with Argon, and then 14 mg (0.137 mmol) phenylacetylene were added. After 14 h at 80° the reaction was filtered, purified by RP-HPLC and freeze-dried to give 8 mg of 2-{[1-(Phenylethynyl)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester (19%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](Cl)=[O:26])[N:17]=[CH:16]2)[C@@H:6]1[F:28])(=[O:3])[CH3:2].[N+:29](=[CH2:31])=[N-:30]>C(OCC)C>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:26])[CH:31]=[N+:29]=[N-:30])[N:17]=[CH:16]2)[C@@H:6]1[F:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)Cl)c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)C=[N+]=[N-])c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O
Yield: 75 %

Procedure:
The reaction solution containing compound (19) was then added to a 0.2M diazomethane solution (20 ml) in diethylether and the mixture so obtained was allowed to react at room temperature for 1 hour. The resulting reaction solution was filtered and the filtrate was concentrated to give the titled compound (20) (55 mg) as a syrup.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][C:8](=O)[CH:7](C(OCC)=O)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].[NH2:17][C:18]1[N:22]([CH2:23][CH2:24][C:25]#[C:26][CH3:27])[N:21]=[CH:20][C:19]=1[C:28]#[N:29].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C.C1(C)C=CC=CC=1>[NH2:29][C:28]1[C:7]2[C:6](=[O:16])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:9][C:8]=2[N:17]=[C:18]2[N:22]([CH2:23][CH2:24][C:25]#[C:26][CH3:27])[N:21]=[CH:20][C:19]=12
Reactant: CC#CCCn1ncc(C#N)c1N
Reactant: CCCCN1CC(=O)C(C(=O)OCC)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC#CCCn1ncc2c(N)c3c(nc21)CN(CCCC)C3=O

Procedure:
A solution of 1-(n-butyl)-3-ethoxycarbonyl-pyrrolidin-2,4-dione (1.02 g.) in wet acetonitrile (23 ml.) was heated under reflux for 1.5 hours. The acetonitrile was evaporated under reduced pressure, leaving a clear oil which was immediately dissolved in toluene (28 ml.). To this solution was added 5-amino-1-(pent-3-ynyl)-4-cyanopyrazole (0.6 g.) and a catalytic amount of toluene-p-sulphonic acid (0.05 g.). The mixture was heated under reflux overnight, collecting water in a Dean-Stark trap. The reaction mixture was cooled to 0° and diluted with ether. The resulting precipitate was collected by filtration, giving 0.89 g. of 5-[N-(n-butyl)-2-oxo-3-pyrrolin-4-yl]amino-1-(pent-3-ynyl)-4-cyanopyrazole, which was used without further purification.
Reaction SMILES: Cl.[CH2:2]([O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].O.O.[Sn](Cl)Cl>C(O)C>[CH2:2]([O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCOc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCOc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
Ethanol (100 ml) and concentrated hydrochloric acid (5 ml) were added to the 4-decyloxynitrobenzene 2 (28.3 g, 101 mmol) thus obtained to prepare a solution which was then cooled in an ice bath. A hydrochloric acid solution of tin(II) chloride dihydrate (101.3 g, 450 mmol/HCl 50 ml) was added thereto. The mixture was stirred at room temperature for about 2 hr and was then stirred with heating at 60° C. for about 30 min. After the completion of the reaction, the resultant precipitate was collected by filtration. A 3 N aqueous sodium hydroxide solution was added to the collected precipitate, followed by extraction with ether. The filtrate was concentrated, and a 3 N aqueous sodium hydroxide solution was then added to the concentrate. The mixture was extracted with ether. The extract was washed with water, was then dried over sodium sulfate, and was concentrated to give 4-decyloxyaniline 3 as a reddish orange liquid (23.4 g, 92.7%).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[Cl:32][C:33]1[CH:41]=[C:40]2[C:36]([C:37](B3OC(C)(C)C(C)(C)O3)=[CH:38][N:39]2C(OC(C)(C)C)=O)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:37]4[C:36]5[C:40](=[CH:41][C:33]([Cl:32])=[CH:34][CH:35]=5)[NH:39][CH:38]=4)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)c2ccc(Cl)cc21
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3c[nH]c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
A vial was charged with 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (158 mg, 0.31 mmol), tert-butyl 6-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (176 mg, 0.47 mmol) and tetrakis(triphenylphosphine)palladium(0) (18.0 mg, 0.016 mmol). The vial was evacuated and backfilled with argon then 1,2-dimethoxyethane (1.8 ml) and aqueous 2 M sodium carbonate (0.47 ml, 0.940 mmol) were added. The vial was sealed and the reaction was stirred at 90° C. in an oil bath overnight. The reaction mixture was cooled to room temperature, quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-3% MeOH) to isolate 93 mg (52%) 2-(6-chloro-1H-indol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a light green foam. A minor amount of impure 6-chloro-3-[7-[(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethylcarbamoyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-indole-1-carboxylic acid tert-butyl ester was also insolated as a light brown solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:10]=2)=[N:7][CH:8]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][C:30]1=[O:35].[H-].[Na+]>C1COCC1>[F:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:6]3[N:7]=[CH:8][C:3]([CH2:2][N:29]4[CH2:34][CH2:33][O:32][CH2:31][C:30]4=[O:35])=[CH:4][CH:5]=3)[S:17][C:16]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CCl)cn4)sc23)c(F)c1
Reactant: O=C1COCCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COCCN1Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Yield: 33.4 %

Procedure:
To a solution of 102 (350 mg, 0.842 mmol, scheme 26) in THF (10 mL) was added a solution of the anion [made from morpholin-3-one (340 mg, 4 eq., 3.37 mmol) and NaH (81 mg, 4 eq., 3.37 mmol)] in THF (5 mL)) and the mixture was heated to reflux for 8 hours. The mixture was quenched with saturated NH4Cl solution and extracted with DCM. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated. The resultant solid was triturated with acetone to give title compound 121 (135 mg, 33% yield) which was used in the next step with no additional purification. MS (m/z)=481.2 (M+H)
Reaction SMILES: Br[C:2]1[C:28]([CH3:29])=[CH:27][C:5]([O:6][C@H:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[C:8]2=[O:26])=[C:4]([F:30])[CH:3]=1.[C@@H]1(N)CCCC[C@H]1N.[CH3:39][S:40]([O-:42])=[O:41].[Na+]>CS(C)=O>[CH2:24]([C:21]1[CH:20]=[N:19][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([N:9]3[CH2:10][CH2:11][C@H:7]([O:6][C:5]4[CH:27]=[C:28]([CH3:29])[C:2]([S:40]([CH3:39])(=[O:42])=[O:41])=[CH:3][C:4]=4[F:30])[C:8]3=[O:26])[CH2:13][CH2:14]2)=[N:23][CH:22]=1)[CH3:25]
Reactant: CS(=O)[O-]
Reactant: CCc1cnc(N2CCC(N3CC[C@H](Oc4cc(C)c(Br)cc4F)C3=O)CC2)nc1
Agent: N[C@@H]1CCCC[C@H]1N
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1cnc(N2CCC(N3CC[C@H](Oc4cc(C)c(S(C)(=O)=O)cc4F)C3=O)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
(S)-3-(4-bromo-2-fluoro-5-methylphenoxy)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (200 mg, 0.42 mmol), trans-cyclohexane-1,2-diamine (20 μL, 0.17 mmol), sodium methanesulfinate (64 mg, 0.63 mmol) was dissolved in DMSO (3 mL) and nitrogen bubbled through for 15 minutes. Cu(I) triflate benzene-complex (21 mg, 0.04 mmol) was added and the reaction was plunged into 110° C. oil bath and stirred under nitrogen overnight. Additional trans-cyclohexane-1,2-diamine (20 μL, 0.17 mmol), sodium methanesulfinate (64 mg, 0.63 mmol) and Cu(I) triflate benzene-complex (21 mg, 0.04 mmol) were added and stirred for another 4 hours at 110° C. The reaction was cooled to ambient temperature, partitioned between water and EtOAc, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (100% EtOAc) to afford (S)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenoxy)pyrrolidin-2-one (119.8 mg, 0.25 mmol, 60% yield) as a white solid. Mass spectrum (apci) m/z=477.3 (M+H).
Reaction SMILES: N1C=CN=[CH:2]1.[H-].[Na+].[C:8]([NH:27][C@@H:28]([C:31]([OH:33])=[O:32])[CH2:29][OH:30])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CI>C(O)(=O)C.O.O1CCCC1>[CH3:2][O:30][CH2:29][C@H:28]([C:31]([OH:33])=[O:32])[NH:27][C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: c1c[nH]cn1
Reactant: O=C(O)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CI
Product: COC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reaction time: 0.25 h

Procedure:
To the stirred and cooled (at −15° C. to −10° C.) suspension of tetrahydrofuran (250 ml), imidazole (1.95 g) and sodium hydride (12.66 g), solid N-trityl-D-serine (50 g) was added in lots at an interval of 10 minutes. It was stirred for 45 minutes at −15° C. to −10° C. and then methyl iodide (40.85 g) was added to it at the same temperature (mild exothermic reaction was observed). The temperature of the reaction mass was raised to −5° C. to 0° C. and then it was stirred for 3 hours at the same temperature. De-ionized water (100 ml) was added to it and the reaction mass was cooled to 0° C. to 5° C. Acetic acid (9.8 ml) was added to the reaction mass and pH of the mass was adjusted to 6.5 to 7.0. Tetrahydrofuran was recovered completely under vacuum at 30° C. to 35° C. and dichloromethane (100 ml) and de-ionized water (100 ml) were added to the reaction mass at ambient temperature. This was stirred and allowed to settle for 15 minutes. The layers were separated. Dichloromethane (50 ml×2) was added to the aqueous layer, stirred, allowed to settle and layers were separated. The obtained organic layers were combined and de-ionized water (100 ml) was added to it. This was stirred, allowed to settle and then organic layer was separated. Anhydrous sodium sulphate (5 g) was added to the organic layer. It was stirred for 20 minutes and filtered through hyflo bed.
Reaction SMILES: [O:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=[O:19])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[O:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][OH:19])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Oc2ccccc2)c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc(Oc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
To a solution of 134 (0.28 g, 1.12 mmol) in ethanol (20 mL) was added sodium borohydride (0.042 g, 1.12 mmol). After stirring at room temperature for 15 min, the reaction was quenched with water and extracted with ethyl ether. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude mixture was purified via flash SiO2 chromatography (ethyl acetate/hexanes (25%/75%) to give 135 (0.28 g, 95% yield): 1H-NMR (400 MHz, chloroform-d) δ 8.29 (d, J=8.3 Hz, 1 H), 8.17 (d, J=8.3 Hz, 1 H), 7.61 (m, 1 H), 7.53 (m, 1 H), 7.41 (d, J=7.8 Hz, 1 H), 7.35 (t, J=7.8 Hz, 2 H), 7.13 (t, J=7.3 Hz, 1 H), 7.05 (dd, J=8.6, 1.2 Hz, 2 H), 6.88 (d, J=7.8 Hz, 1 H), 5.12 (s, 2 H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.ClC1[N:19]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]3([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:32][CH2:31][CH:30]=[CH:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)[C:18]2[CH:39]=[CH:40][CH:41]=[CH:42][C:17]=2[N:16]=1.Cl>>[C:33]1([C:26]2([N:23]3[CH2:24][CH2:25][CH:20]([N:19]4[C:18]5[CH:39]=[CH:40][CH:41]=[CH:42][C:17]=5[N:16]=[C:6]4[N:8]4[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]4)[CH2:21][CH2:22]3)[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=[CH:27]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Clc1nc2ccccc2n1C1CCN(C2(c3ccccc3)CCC=CCC2)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Product: C1=CC(c2ccccc2)(N2CCC(n3c(N4CCNCC4)nc4ccccc43)CC2)CCCC1
Yield: 40.3 %

Procedure:
This was prepared according to the procedure described in Example 67 using 1-N-t-butoxycarbonylpiperazine instead of 4-t-butoxycarbonylaminopiperidine, and 2-chloro-1-[1-(1-phenyl-4-cyclohepten-1-yl)-4-piperidinyl]benzimidazole as starting material which was prepared in Preparation 9. Overall yield was 40.3%. HCl salt was amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[C:3]=1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1.O>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[CH:7][CH:8]=2)[C:3]=1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)Nc1c(Br)ccc2ccc(O)cc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1c(Br)ccc2ccc(O[Si](C)(C)C(C)(C)C)cc12
Reaction time: 18 h

Procedure:
2-Bromo-1-(tert-butoxycarbonylamino)-7-hydroxynaphthalene, as described above in Step F, (4.80 g, 14.19 mmol), tert-butyldimethylsilyl chloride (2.8 g, 18.45 mmol) and imidazole (2.2 g, 32.64 mmol) were dissolved in DMF (25 mL) and stirred for 18 hours. The mixture was poured into H2O and extracted with Et2O (2×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with CH2Cl2—50% hexanes, to yield the above-titled compound.
Reaction SMILES: [OH:1][P:2](O)([OH:4])=[O:3].C([O-])([O-])=O.[Ca+2:10]>>[O-:4][P:2](=[O:3])=[O:1].[O-:4][P:2](=[O:3])=[O:1].[Ca+2:10]
Reactant: O=P(O)(O)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Product: O=P(=O)[O-]
Temperature: 200 °C
Reaction time: 2 h

Procedure:
Representative acicular crystalline calcium metaphosphate fibers were prepared from a composition consisting of 1473.7 parts of 86.13% H3PO4, 128.4 parts of NaH2PO4H2O, 450.0 parts CaCO3, 9.6 parts Fe PO4 and about 500 parts distilled water providing a mole percent ratio of 58.3% P2O5, 37.6% CaO, 3.9% Na2O and 0.3% Fe2O3. The ingredients were thoroughly mixed and the composition was dried at a temperature of about 200° C. Then the composition was placed in a shallow high-temperature ceramic dish and placed in a furnance and heated to 200° C. overnight to drive off residual water. The temperature was increased over a period of about six hours to 1000° C. and maintained at 1000° C. for about one hour to form a melt. The temperature of the melt was then reduced to about 710° C. over a period of about 2 hours and crystallization was induced by quick chilling by opening the furnance door for about five seconds. After the crystallization was induced the temperature was maintained at 710° C. overnight and the crystallized composition was cooled and removed from the furnance. Acicular crystalline calcium metaphosphate fibers were then recovered from the crystallized composition by breaking it into small chunks and boiling in water to dissolve the soluble matrix and filtering drying the separated fibers. The recovered acicular crystalline calcium metaphosphate fibers are relatively uniform and were not further classified. These acicular fibers are thermally stable to about 970° C., have an average density of about 2.87 g/cc and generally a mean aspect ratio of about 100:1. The acicular fibers had an average diameter of 7.2 microns and an average surface area of 2013 cm2 /g as determined using the above described Sub-Sieve Sizer.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:8][C:7]1=[O:21].[Br:25]Br>CC(O)=O>[Br:25][C:8]1[C:7](=[O:21])[N:6]([CH2:5][C:4]2[CH:22]=[CH:23][CH:24]=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:10][C:9]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1
Reactant: BrBr
Reactant: O=c1cc(OCc2cccc(F)c2)ccn1Cc1cccc(F)c1
Solvent: CC(=O)O
Product: O=c1c(Br)c(OCc2cccc(F)c2)ccn1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To an ice-cold solution of 1-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-1H-pyridin-2-one (0.14 g, 0.43 mmol) in AcOH (2 mL) was added a solution of bromine (72 mg, 0.45 mmol) in AcOH (1 mL), and the reaction mixture was stirred for 5 min. The reaction mixture was warmed to room temperature and the solvent was removed under reduced pressure. 1H NMR (300 MHz, CDCl3) δ 7.45-6.95 (m, 9H), 6.05 (d, J=8 Hz, 1H), 5.21 (s, 2H), 5.14 (s, 2H). ESHRMS m/z 406.0254 (M+H C19H15BrF2NO2 requires 406.0249).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([C:10](=[O:12])[CH3:11])[C:7](=[O:9])[CH3:8])[CH3:2].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].C(O)(=O)C>N12CCCN=C1CCCCC2.C(OCC)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([C:7](=[O:9])[CH3:8])([C:10](=[O:12])[CH3:11])[CH2:16][CH2:15][C:14]([O:18][CH2:19][CH3:20])=[O:17])[CH3:2]
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Reactant: C=CC(=O)OCC
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)O
Product: CCOC(=O)CCC(CC(=O)OCC)(C(C)=O)C(C)=O
Reaction time: 24 h
Yield: 81.2 %

Procedure:
37 g of 3-acetyl-4-oxo-pentanoic acid ethyl ester, synthesized according to the procedure given in Example 15, and 0.3 g of 1,8-diazabicyclo-[5.4.0]-undec-7-ene were mixed, and 30 g of ethyl acrylate was added dropwise over 30 minutes. After stirring for 24 hours, the base was neutralized by adding acetic acid. 80 ml of diethyl ether was added, and the mixture was extracted with 60 ml of an aqueous sodium carbonate solution and 150 ml of water. Fractional distillation of the water-free organic layer yielded 46.2 g of 3,3-diacetyl-hexanedioic acid diethyl ester (boiling point: 150° C./0.03 mbar; purity: >99%; colorless).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C1COCC1>[NH2:8][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([Cl:9])[C:2]=1[NH:1][C:10](=[O:12])[CH3:11]
Reactant: Nc1ccnc(Cl)c1N
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1c(N)ccnc1Cl

Procedure:
1.1 A solution of 10.0 g of 3,4-diamino-2-chloropyridine and 6.62 ml of acetic anhydride in 100 ml of THF is stirred at room temperature for 16 hours. The product is separated off and dried, giving 7.3 g of N-(4-amino-2-chloropyridin-3-yl)acetamide (“1”).