Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([NH2:20])[N:10]([CH3:21])[N:9]=1)(=[O:3])[CH3:2].[H-].[Na+].[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25].[Cl-].[NH4+]>O1CCCC1.O>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[C:11]([NH:20][S:34]([C:31]2[CH:32]=[CH:33][C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[N:10]([CH3:21])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOc1nn(C)c(N)c1C(=O)OC(C)(C)C
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCCOc1nn(C)c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
To tert-butyl 3-[2-(acetyloxy)ethoxy]-5-amino-1-methyl-1H-pyrazole-4-carboxylate (Preparation 10) (70 g) in solution in tetrahydrofuran (1 lit.) at 0° C. was added sodium hydride (20.2 g of a 60% dispersion in oil). The reaction mixture was stirred at room temperature for one hour and then 4-(tert-butyl)benzenesulfonyl chloride (58.88 g) was added dropwise. The reaction mixture was stirred at room temperature overnight and was then diluted with water (200 ml) at 0° C., followed by a saturated solution of ammonium chloride (200 ml) while allowing the mixture to warm to room temperature. The white precipitate was filtered off and disposed of. The aqueous and organic layers were separated and the aqueous extracted with ethyl acetate (100 ml). The combined organics were dried on magnesium sulfate, filtered and concentrated under reduced pressure. The crude was purified by chromatography on a suction column packed with silica eluted with ethyl acetate:hexane (1:4) to yield the desired product as white solid (16 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:52]([C:56]#[CH:57])([CH3:55])([CH3:54])[CH3:53]>[Pd](Cl)Cl.C(#N)C.C(#N)C.C(#N)C>[C:52]([C:56]1[O:11][C:3]2[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=2[CH:57]=1)([CH3:55])([CH3:54])[CH3:53]
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Reactant: C#CC(C)(C)C
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CC(C)(C)c1cc2cccc([N+](=O)[O-])c2o1
Temperature: 75 °C
Yield: 36.8 %

Procedure:
2-Bromo-6-nitrophenol (500 mg, 2.29 mmol), bis(acetonitrile) palladium (II) chloride (12 mg, 0.05 mmol), 2-dicylohexylphosphino-2′,4′,6′-triisopropylbiphenyl (68 mg, 0.14 mmol), cesium carbonate (1.95 g, 6 mmol) and tert-butylacetylene (577 mg, 7 mmol) were dissolved 5 mL acetonitrile in a sealed tube and heated at 75° C. overnight. The reaction mixture was directly chromatographed (silica gel, heptane/ethyl acetate 9:1/4:1/1:1) to yield 2-tert-butyl-7-nitro-benzofuran as an off-white solid (185 mg, 37%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][NH:15][C:16](OC(C)(C)C)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27](C=O)=[C:26]([Cl:33])[N:25]=1.N1C(=O)CC(=O)NC1=O>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:28]3=[N:29][C:24]([Cl:23])=[N:25][C:26]([Cl:33])=[C:27]3[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=Cc1c(Cl)nc(Cl)nc1Cl
Agent: O=C1CC(=O)NC(=O)N1
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)nc(Cl)nc32)CC1

Procedure:
4-(4,6-Dichloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester was prepared using Method C described for the preparation of Intermediate 19, by the reaction of 4-(tert-butoxycarbonyl-hydrazino)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 15) with 2,4,6-trichloro-pyrimidine-5-carbaldehyde (which can be prepared from barbituric acid using the procedure of J. Dehnert DE 3603797).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:14].ClCCl.CO>C(O)C>[CH2:1]([C@@H:8]([CH2:13][CH2:12][OH:11])[C:9]([NH2:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OCC[C@@H]1Cc1ccccc1
Reactant: N
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: NC(=O)[C@H](CCO)Cc1ccccc1
Yield: 63.8 %

Procedure:
(S)-2-benzylbutyrolactone (1 gram) was dissolved in 5 ml of absolute ethanol, followed by the addition of 0.5 gram of gaseous ammonia. The solution was kept in a stoppered flask, and the progress of the reaction was followed by thin layer chromatography (eluent dichloromethane/methanol 20:1). After the reaction was judged complete, the ethanol was evaporated and the resulting residue redissolved in ethyl acetate. Ammonia was removed by extraction with 1% HCl, and the ethyl acetate solution was dried over MgSO4, filtered, and rotary evaporated to leave 0.7 grams of (S)-2-benzyl-4-hydroxybutyramide.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14]C2CCCCO2)=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH:6]2.Cl.O.N>O1CCCC1>[OH:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]2[C:7]=1[NH:6][C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:4]2
Reactant: CCOC(=O)c1cc2c(C)ccc(OCCOC3CCCCO3)c2[nH]1
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc2c(C)ccc(OCCO)c2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
Ethyl 4-methyl-7-[2-(2-tetrahydro-2H-pyranyl) oxyethoxy]-1H- indole-2-carboxylate (3.20 g, 9.21 mmol) was dissolved in tetrahydrofuran (70 ml), followed by adding thereto 2N hydrochloric acid (30 ml) at room temperature. The mixture was stirred at room temperature for 3 hours, after which water (200 ml) and then 28% aqueous ammonia were added thereto to neutralize (pH=7 to 8) the reaction mixture. Subsequently, the reaction mixture was extracted twice with ethyl acetate and the extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was crystallized from ethyl acetate to obtain ethyl 7-(2-hydroxyethoxy)-4-methyl-1H-indole-2-carboxylate (1.93 g).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[H-].[Na+].CS(O[CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)(=O)=O>CN(C=O)C.C(Cl)Cl>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]1[N:3]=[CH:2][N:1]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH:5]=1
Reactant: c1ccc(-c2c[nH]cn2)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccccn3)c2)CC1
Temperature: 25 °C

Procedure:
To a solution of 2-(1H-imidazol-4-yl)pyridine (0.87 g, 6 mmol) in DMF (12 mL) at 0° C. was added sodium hydride (346 mg, 7.2 mmol). The reaction mixture was allowed to warm to room temperature and stirred for an additional 20 min. tert-Butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (1.34 g, 4.8 mmol) was added and the resulting mixture was heated at 80° C. for 48 h. The reaction was cooled to room temperature, diluted with CH2Cl2, and washed with water and brine. The combined organic layers were dried over magnesium sulfate and the solvents removed in vacuo. The residue was purified by silica gel chromatography (0%-100% MeOH/CH2Cl2) and then by HPLC (phenomenex column, 30%-100% acetonitrile/water+0.1% TFA) to afford tert-butyl 4-(4-pyridin-2-yl-1H-imidazol-1-yl)piperidine-1-carboxylate as an oil. 1H NMR (500 MHz, CD3OD) δ 8.88 (m, 1H), 8.70 (m, 1H), 8.40 (m, 1H), 8.10 (m, 1H), 8.00 (m, 1H), 7.55 (m, 1H), 4.58 (m, 1H), 4.32 (m, 2H), 3.01 (m, 2H), 2.24 (m, 2H), 2.00 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH2:20]OS(C)(=O)=O)[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:26]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[C:35]([O:34][C:32]([N:26]1[CH2:31][CH2:30][N:29]([CH2:20][C:11]2[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:17])[CH3:18])[N:14]=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)[CH:10]=2)[CH2:28][CH2:27]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)Cn1nc(-c2ccc(F)c(F)c2)cc(COS(C)(=O)=O)c1=O
Product: CC(C)Cn1nc(-c2ccc(F)c(F)c2)cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1=O
Yield: 85.5 %

Procedure:
Following the procedure of Example 1(10), 6-(3,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 85.5%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Br[CH:13]([CH:33]([CH3:35])[CH3:34])[C:14]([O:16]C(C#N)C1C=CC=C(OC2C=CC=CC=2)C=1)=[O:15]>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C@H:13]([C:14]([OH:16])=[O:15])[CH:33]([CH3:35])[CH3:34])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)C(Br)C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Product: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O

Procedure:
Following the procedure of Example 6, 4-trifluoromethylaniline is reacted with α-cyano-m-phenoxybenzyl α-bromoisovalerate to yield the α-cyano-m-phenoxybenzyl ester of N-(4-trifluoromethylphenyl)valine, MS m/e 468.2 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH:17]3[CH2:20][O:19][CH2:18]3)[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:21]([O:24][CH2:25][C:26]1[C:27]([N:41]2[CH2:52][CH2:51][N:50]3[C:43](=[CH:44][C:45]4[CH2:46][C:47]([CH3:54])([CH3:53])[CH2:48][C:49]=43)[C:42]2=[O:55])=[N:28][CH:29]=[CH:30][C:31]=1B1OC(C)(C)C(C)(C)O1)(=[O:23])[CH3:22].CC(O[Na])=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:21]([O:24][CH2:25][C:26]1[C:27]([N:41]2[CH2:52][CH2:51][N:50]3[C:43](=[CH:44][C:45]4[CH2:46][C:47]([CH3:54])([CH3:53])[CH2:48][C:49]=43)[C:42]2=[O:55])=[N:28][CH:29]=[CH:30][C:31]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH:17]3[CH2:20][O:19][CH2:18]3)[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:23])[CH3:22]
Reactant: Cc1cc(Nc2cc(Br)cn(C)c2=O)nn1C1COC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)O[Na]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C)n(C4COC4)n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 56.2 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 312a (170 mg, 0.50 mmol), (2-{4,4-dimethyl-9-oxo-1,{3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (200 mg, 0.50 mmol), CH3COONa (82 mg, 1.00 mmol), PdCl2(dppf) (41 mg, 0.050 mmol), K3PO4 (212 mg, 1.00 mmol), acetonitrile (10 mL), and water (0.5 mL). After bubbling nitrogen through the resulting mixture for 20 minutes, it was heated at 100° C. under nitrogen atmosphere for 2 h. The mixture was cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 312b as white solid (172 mg, 56%). MS-ESI: [M+H]+ 612.4
Reaction SMILES: CO[C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:12]=1[C:13]([O:15]C)=[O:14].B(Br)(Br)Br.CO>C(Cl)Cl>[OH:9][C:7]1[CH:8]=[C:3]2[C:4]([C:11]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:12]=3[C:13](=[O:14])[O:15]2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1ccc(OC)cc1OC
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=c1oc2cc(O)ccc2c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of methyl 2-(2,4-dimethoxyphenyl)-5-nitrobenzoate (Reference Compound No. 1-(1), 43.5 g, 137 mmol) in anhydrous methylene dichloride (250 mL) was cooled to −78° C., boron tribromide (96.2 g, 384 mmol) was added thereto, and then the mixture was stirred at room temperature for 1 hour. The mixture was cooled to −50° C. and methanol (300 mL) was added thereto. The resulting precipitates were filtered off with methanol to give the titled reference compound (18.0 g) as a yellow solid. (Yield 51%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:60]1[C:64]([C:65]2[CH:70]=[CH:69][C:68]([NH2:71])=[CH:67][CH:66]=2)=[N:63][N:62]=[N:61]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([NH:71][C:68]3[CH:69]=[CH:70][C:65]([C:64]4[NH:60][N:61]=[N:62][N:63]=4)=[CH:66][CH:67]=3)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Reactant: Nc1ccc(-c2nnn[nH]2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2nnn[nH]2)cc1)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid (250 mg, 0.67 mmol; example 5.1) in dry DMF (12 mL) was added dry DIPEA (0.375 ml, 2.32 mmol) followed by HATU (510 mg, 1.34 mmol) at 0° C. Then the reaction mixture was allowed to warm to rt and stirred for 45 min at that temperature. TLC shows total consumption of acid and formation of a new spot. 4-(1H-Tetrazol-5-yl)-phenylamine (162.5 mg, 1.02 mmol) was added to this reaction mixture at 0° C. Then the cooling bath was removed and the reaction mixture was stirred at room temperature for 16 h. TLC shows total consumption of [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid and DMF was removed in vacuo at 50° C. It was then diluted with H2O (15 ml). Aqueous layer was extracted with EtOAc (4×20 mL) and combined organic layers were washed with brine (20 ml), dried over Na2SO4 and concentrated in vacuo. Crude product (355.0 mg) was subjected to column chromatography [SiO2 (230-400 mesh), McOH:DCM 5:95] to give the title compound as brownish sticky solid. Yield (170 mg, 52%). MS: m/e=516.0 [M+H+].
Reaction SMILES: [C:1]([O:4][C:5]1[CH2:11][CH:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[C:6]=1[C:13]([O-:15])=[O:14])(=[O:3])[CH3:2].[Na+].[C:17]([O:23][CH2:24]Br)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>CN(C)P(N(C)C)(N(C)C)=O.C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[CH2:11][CH:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[C:6]=1[C:13]([O:15][CH2:24][O:23][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(C)(C)C(=O)OCBr
Reactant: CC(=O)OC1=C(C(=O)[O-])N2C(=O)CC2C1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(=O)OC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)CC2C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of sodium 3-acetoxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (23 mg) and bromomethyl pivalate (29 mg) in hexamethylphosphoramide (0.5 ml) is stirred at room temperature and under a N2 atmosphere for 2.5 hrs. The mixture is diluted with toluene (10 ml), washed with H2O (5×2 ml) and brine, dried with MgSO4, filtered, and evaporated in vacuo. The residue is purified by silica gel plc to afford pivaloyloxymethyl 3-acetoxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: O=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].Cl>>[C@@H:11]12[O:12][CH2:2][C@H:3]([O:4]1)[C@@H:5]([OH:6])[C@H:7]([OH:8])[C@@H:9]2[OH:10]
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: Cl
Product: O[C@@H]1[C@H](O)[C@@H]2OC[C@H](O2)[C@H]1O
Yield: 35.5 %

Procedure:
A mixture of L-gulose (1) (33 g,0.127 mol) and 0.5 N HCl (330 mL, 0.165 mol) was refluxed for 20 hours. The mixture was cooled and neutralized to pH 6 by a resin (Dowex-2, HCO3 -form) with air bubbling. The resin was recycled by washing with 10% HCl, water, methanol, water and saturated NaHCO3 solution. The reaction mixture was filtered and the resin was washed with water (500 mL). The combined filtrate was concentrated to dryness and dried in vacuo overnight. The residue was purified over a column (5 cm depth, silica gel, mesh, CHCl3 --CH3OH, 10:1) to give a slightly yellow solid, which was recrystallized from absolute alcohol to give a colorless solid (2) [Rf =0.43 (CHCl3 --CH3OH, 5:1), 7.3 g, 35.52%]. The L-gulose Rf =0.07, 11 g) obtained was recycled to give (2) (5 g, total yield 60%):mp 142.5-145° C.; 1H NMR (DMSO-d6) δ 3.22-3.68 (m, 4H, H-2, -3, -4 and -6a), 3.83 (d,J6b,6a =7.25 Hz, 1H, Hb -6), 4.22 (pseudo t, J5,6a =4.61 and 4.18 Hz, H, H-5), 4.46 (d, J2-OH,2 =6.59 Hz, 1H, 2-OH, exchangeable with D2O), 4.62 (d, J3-OH,3 =5.28 Hz, 1H, 3-OH, exchangeable with D2O), 5.07 (d, J4-OH,4 =4.84 Hz, 1H, 4-OH, exchangeable with D2O), 5.20 (d, J1,2 =2.19 Hz, 1H, H-1). [α]D25 -50.011 (c, 1.61, CH3OH).
Reaction SMILES: [CH3:1][C:2]([F:13])([C:6]([F:12])([F:11])[C:7](F)([F:9])[F:8])[CH:3](Cl)[F:4].CC(C#C)=C>>[CH3:1][C:2]([F:13])([C:6]([F:11])([F:12])[CH:7]([F:8])[F:9])[CH2:3][F:4]
Reactant: CC(F)(C(F)Cl)C(F)(F)C(F)(F)F
Agent: C#CC(=C)C
Product: CC(F)(CF)C(F)(F)C(F)F

Procedure:
As another example, 2-methyl-1-chloro-1,2,3,3,4,4,4-heptafluorobutane may be prepared by fluorinating commercially available 2-methyl-1-buten-3-yne to form 2-methyl-1,2,3,3,4,4-hexafluorobutane which may then be dehydrohalogenated to form 2-methyl-1,3,4,4-tetrafluoro-1,3-butadiene. The 2-methyl-1,3,4,4-tetrafluoro-1,3-butadiene may then be fluorinated to form 2-methyl-1,1,2,3,3,4,4,4-octafluorobutane which may then be dehalogenated to form 2-methyl-1,3,3,4,4,4-hexafluoro-1-butene. The 2-methyl-1,3,3,4,4,4-hexafluoro-1-butene may then be chlorofluorinated to form 2-methyl-1-chloro-1,2,3,3,4,4,4-heptafluorobutane.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[N:4]=[C:5]([CH:13]2[CH2:16][C:15]([CH3:18])([OH:17])[CH2:14]2)[N:6]2[CH:11]=[CH:10][N:9]=[C:8](Cl)[C:7]=12>CC(O)CC>[NH2:1][C:8]1[C:7]2[N:6]([C:5]([CH:13]3[CH2:16][C:15]([CH3:18])([OH:17])[CH2:14]3)=[N:4][C:3]=2[Br:2])[CH:11]=[CH:10][N:9]=1
Reactant: N
Reactant: CC1(O)CC(c2nc(Br)c3c(Cl)nccn23)C1
Solvent: CCC(C)O
Product: CC1(O)CC(c2nc(Br)c3c(N)nccn23)C1
Temperature: 90 °C

Procedure:
A 35% ammonia solution (132 ml, 2.9 moles) was added to a suspension of 3-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol (22.0 g, 0.06463 mol) in 2-butanol (81 ml). The mixture was heated at 90° C. in a pressure vessel for 15 hr then concentrated to ˜130 ml, cooled to room temperature and the solid collected by filtration. This material was washed with water (3×22 mL) and dried at 40° C. under vacuum. To afford the desired product. 1H NMR (DMSO-d6, 400 MHz): δ 7.5 (d, 1H), 7.0 (d, 1H), 6.6 (bs, 2H), 5.1 (s, 1H), 3.4 (pentet, 1H), 2.3-2.4 (m, 4H) and 1.4 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1F)#[N:2].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C>[N:20]([C:8]1[CH:7]=[CH:6][C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=1[C:1]#[N:2])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccnc(-c2ccc(F)c(C#N)c2)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(-c2ccc(N=[N+]=[N-])c(C#N)c2)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Methyl 2-(3-cyano-4-fluorophenyl)isonicotinate and sodium azide were dissolved in a DMF solution, followed by stirring at 50° C. for 4 hours to obtain methyl 2-(4-azido-3-cyanophenyl)isonicotinate. NMRC: 7.38 (1H, d), 7.84 (1H, dd), 8.46 (1H, d)
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1)[CH:15]=[CH:14]2)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[N:23]1[CH:22]=[C:21]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[CH:12]=[C:11]([CH2:10][CH2:9][OH:8])[CH:20]=[CH:19]3)[CH:26]=[N:25][CH:24]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc2cc(-c3cncnc3)ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1ccc2cc(-c3cncnc3)ccc2c1
Yield: 83 %

Procedure:
A solution of the product from Example 26C (56 mg, 0.154 mmol) and TBAF H2O (48 mg, 0.184 mmol, 1.2 equiv.) in THF (3 mL) was stirred at room temperature under a dry nitrogen atmosphere for 30 min. The mixture was then partitioned between ethyl acetate and saturated aqueous Na2CO3. The organic layer was washed with brine then dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give the title compound as an off-white solid (32 mg, 83% yield) which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11])#[CH:2].CCN(CC)CC.Cl[C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:53]=[CH:52][C:36]([C:37]([N:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)=[O:38])=[CH:35][CH:34]=2)[N:23]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CCOC(C)=O.[Cu]I>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:26]1[C:27]([C:28]([F:30])([F:29])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([C:37]([N:39]3[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[CH2:43][CH2:44]3)=[O:38])=[CH:52][CH:53]=2)[N:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1ccccc1CC(=O)OC
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A solution of methyl 2-(2-ethynylphenyl)acetate (K1) (0.129 g, 0.741 mmol) in DMF (3 mL) and Et3N (344 μL, 2.47 mmol) was added to a mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoyl)piperazine-1-carboxylate (A22) (0.300 g, 0.617 mmol), PdCl2 (PPh3)2 (0.065 g, 0.093 mmol), CuI (0.018 g, 0.093 mmol) and PPh3 (0.016 g, 0.062 mmol) in DMF (3 mL). The resulting mixture was heated under microwave irradiation at 120° C. for 15 minutes, diluted with EtOAc and passed through a plug of Celite, washing with EtOAc (60 mL). The filtrates were combined and the volatiles were removed in vacuo to give a residue that was purified by silica gel column chromatography (Biotage Isolera, 25 g SiO2 cartridge, 0-80% EtOAc in petroleum benzine 40-60° C.) to give the title compound A23 as a yellow oil (0.337 g, 88%); 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.68 (dd, J=7.7, 1.0 Hz, 1H), 7.61 (s, 1H), 7.48-7.41 (m, 3H), 7.40-7.31 (m, 2H), 3.96 (s, 2H), 3.71 (s, 3H), 3.67-3.37 (m, 8H), 1.47 (s, 9H). LCMS-A: rt 6.393 min; m/z 624.1 [M+H]+.