Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]([Cl:19])[C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:14]([CH3:16])[CH3:15])[C:10](=[O:13])[NH:11][N:12]=2)=[C:4]([Cl:20])[CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C]=O.[C:59]([O:62][CH2:63]C)(=[O:61])C>C(#N)C.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:63][O:62][C:59](=[O:61])[C:2]1[CH:18]=[C:17]([Cl:19])[C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:14]([CH3:16])[CH3:15])[C:10](=[O:13])[NH:11][N:12]=2)=[C:4]([Cl:20])[CH:3]=1
Reactant: CC(C)c1cc(Cc2c(Cl)cc(Br)cc2Cl)n[nH]c1=O
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Cl)c(Cc2cc(C(C)C)c(=O)[nH]n2)c(Cl)c1
Temperature: 90 °C
Yield: 90 %

Procedure:
A solution of 6-(4-bromo-2,6-dichloro-benzyl)-4-isopropyl-pyridazin-3-one (51) (194 mg, 0.516 mmol) in acetonitrile (10 mL) and methanol (2 mL) at room temperature was treated with palladium(II) acetate (23.7 mg, 0.106 mmol), 1,3-bis(diphenylphosphino)propane (45.7 mg, 0.111 mmol) and triethylamine (360 μL, 2.58 mmol). The sealed tube was then pressurized to 45 psi with carbon monoxide and heated to 90° C. for 1 h. The reaction was cooled to room temperature, the pressure was released and a TLC was taken of the reaction mixture which indicated that starting material was still present. Additional palladium(II) acetate (10 mg) and 1,3-bis(diphenylphosphino)propane (20 mg) were added to the reaction mixture. The sealed tube was then pressurized to 45 psi with carbon monoxide and heated to 90° C. for another 1.5 h. The reaction was cooled to room temperature, the pressure was released and the reaction mixture was diluted with ethyl acetate (100 mL) and was washed with 1:1 solution of water (30 mL) and a saturated aqueous sodium chloride solution (30 mL). The organic layer was separated, dried with magnesium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography using silica gel eluted with a gradient of 4:1 to 1:1 ethyl acetate:hexanes. The desired fractions were collected and concentrated under vacuum to afford a solid which was dried under high vacuum to afford 3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-benzoic acid methyl ester (52) (183 mg, 90%) as an off-white solid; LRMS-ES(+) for C16H16Cl2N2O3 (M+H) m/z=355. MW=355.2235, Exact Mass=354.0538
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=[O:12].[N+:14]([O-])([OH:16])=[O:15]>>[N+:14]([C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH:2]([C:11]([OH:13])=[O:12])[CH2:3][CH2:4][C:5]=2[CH:10]=1)([O-:16])=[O:15]
Reactant: O=C(O)C1CCc2ccccc2O1
Reactant: O=[N+]([O-])O
Product: O=C(O)C1CCc2cc([N+](=O)[O-])ccc2O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
30 Parts of 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid were added slowly, during a 30 minutes-period, to 79 parts of a solution of nitric acid 60% while cooling on an ice bath. The whole was stirred for 10 minutes at room temperature. The reaction mixture was poured onto ice water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of ethanol and water (80:20 by volume), yielding 17 parts (45%) of 3,4-dihydro-6-nitro-2H-1-benzopyran-2-carboxylic acid; mp. 180° C. (intermediate 22).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O)([O-:3])=[O:2]>C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>[N+:1]([CH2:4][CH2:5][CH2:6][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(CC[N+](=O)[O-])c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])CCCc1ccccc1
Temperature: 25 °C
Yield: 88 %

Procedure:
Under an inert atmosphere, 3-nitro-1-phenylpropan-1-one (15) (12.5 g, 70.0 mmol) was dissolved in TFA (100 ml) and Et3SiH (30 ml). This mixture was stirred at room temperature under TLC and GC control. After reaction completion, the mixture was concentrated under reduced pressure and residue was distilled in vacuum to give 3-nitropropylbenzene (16) with 88% yield, bp. 120-123° C./4 mm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH:12]([OH:14])[CH3:13]>CO>[OH:14][CH2:12][CH2:13][S:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(S)cc1
Reactant: CC(O)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCCSc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
To a solution of 10.9 g 4-hydroxythiophenol (87 mmol) in 200 ml MeOH was added at 0-5° C. 87 ml 1N NaOH (87 mmol). After the reaction mixture was stirred for 10 min 6.1 ml bromoethanol (86 mmol) dissolved in 100 ml MeOH was added. The reaction mixture was stirred for 3 h at r.t. and the methanol was partly removed under reduced pressure. The residue was poured to a 1:1 mixture of ethyl acetate and saturated NaHCO3−solution and the organic phase was separated, dried over MgSO4, filtrated and the solvent was removed under reduced pressure. The residue was purified by chromatography over silica gel (ethyl acetate/hexane 3/2 to 2/1) to give 13.4 g product (78.7 mmol, 91%) as a white solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:26][CH2:27][CH3:28])[CH:5]1[CH2:25][C:8]2=[CH:9][C:10]3[C:11](=[O:24])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:13](=O)[C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:2][CH3:3].Cl>CC(O)=O.[Zn]>[CH2:26]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:25][C:8]2=[CH:9][C:10]3[C:11](=[O:24])[N:12]([CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:13][C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:27][CH3:28]
Reactant: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccccc1)C3=O
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccccc1)C3

Procedure:
Using procedure 47, 6-(Dipropylamino)-6,7-dihydro-2-(phenylmethyl)cyclopent[f]isoindole-1,3(2H,5H)-dione (124, 0.41 g, 1.0 mmol) was reduced with Zinc dust (0.65 g, 10.0 mmol) in glacial HOAc (20 mL). Purification on silica gel, eluting with 3:1 hexane/acetone gave an oil that was converted to an HCl salt and recrystallized from EtOAc/MeOH to give 125 as a white solid (m.p. 235-236° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:14])=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:14])=[O:6]
Reactant: COc1ccccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccccc1C(=O)Cl

Procedure:
A mixture of 2-methoxybenzoic acid (45.6 g, 0.3 mol), thionyl chloride (53.5 g, 33 ml, 0.45 mol) and dimethylformamide (two drops) was refluxed for an hour. Excess thionyl chloride was then distilled off under reduced pressure. Benzene (50 ml) was added to the residue and the solvent was distilled off until the weight of the residue remained unchanged (about 51 g).
Reaction SMILES: [C:1](=[S:9])([S-:8])[S:2][CH2:3][CH2:4][O:5][CH2:6][CH3:7].[K+].[CH2:11]([S:13][CH:14]1[N:17]([CH:18](Cl)[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C:16](=[O:33])[CH2:15]1)[CH3:12]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[CH2:11]([S:13][CH:14]1[N:17]([CH:18]([S:9][C:1]([S:2][CH2:3][CH2:4][O:5][CH2:6][CH3:7])=[S:8])[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C:16](=[O:33])[CH2:15]1)[CH3:12]
Reactant: CCOCCSC(=S)[S-]
Reactant: CCSC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Product: CCOCCSC(=S)SC(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1SCC
Reaction time: 1 h
Yield: 30.9 %

Procedure:
A solution of 3.58 g potassium 2-ethoxyethyl trithiocarbonate and 3.7 g benzyltriethylammonium chloride in 100 ml methylene chloride was cooled to 0° C. under a nitrogen atmosphere and a solution of 5.3 g of p-nitrobenzyl 2-(4-ethylthio-2-oxo-1-azetidinyl)-2-chloroacetate in 50 ml methylene chloride was added dropwise. The reaction mixture was stirred for 1 hour, then washed with three 50 ml portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo to an oil. (8.6 g). The crude product was chromatographed on silica gel eluting with 5% ethyl acetate in chloroform to yield 2.3 g of the title compound as an oil. The IR spectrum of a chloroform solution of the title compound had an absorption at 5.65 micron; and the NMR spectrum in deuterochloroform showed peeks at 1.2(m, 6H); 2.34-3.77(c, 10H); 4.7,4.98(m, 1H); 5.26(s, 2H); 6.62, 6.86(s, 1H); 7.43(m, 2H); and 8.16(m, 2H). ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9]C)=O.[NH2:11][CH2:12][CH2:13][OH:14]>C(OCC)(=O)C>[OH:14][CH2:13][CH2:12][NH:11][C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: NCCO
Reactant: COC(=O)c1cnccn1
Solvent: CCOC(C)=O
Product: O=C(NCCO)c1cnccn1
Reaction time: 8 h
Yield: 80 %

Procedure:
A mixture of 55.2 parts of methyl 2-pyrazinecarboxylate, 48.9 parts of 2-aminoethanol and 360 parts of ethyl acetate was allowed to stand overnight at room temperature. The precipitated product was filtered off, washed with ethyl acetate and dried, yielding 54.5 parts (80%) of N-(2-hydroxyethyl)-2-pyrazinecarboxamide; mp. 125° C. (intermediate 22).
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH2:41][O:42][CH3:43])[CH:35]=O.O>C1COCC1>[CH3:30][O:31][C:32]1[CH:33]=[C:34](/[CH:35]=[CH:10]/[CH2:9][CH2:8][OH:7])[CH:37]=[CH:38][C:39]=1[O:40][CH2:41][O:42][CH3:43]
Reactant: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COCOc1ccc(C=O)cc1OC
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COCOc1ccc(/C=C/CCO)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35.5 %

Procedure:
n-Butyllithium (1.6 M in hexane, 25 ml) was added dropwise to a stirred suspension of (3-hydroxypropyl)triphenylphosphonium bromide (8.03 g) in dry THF (50 ml) cooled to 0° under nitrogen. The resulting blood-red solution was stirred at 0° for 10 min and then 3methoxy-4-(methoxymethoxy)benzaldehyde (3.60 g) in dry THF (10 ml) was added dropwise over 5 min. The mixture was allowed to warm to room temperature, stirred for 4 h water (10 ml) was added and the majority of the solvent was removed in vacuo at 40°. A solution of the residual oil in ER (200 ml) was washed with water (150 ml), dried, treated with charcoal, concentrated and purified by [FCS] eluting with EA/hexane (1:1) to give the title compound (1.55 g). T.l.c. (EA-hexane 1:1) Rf 0.30.
Reaction SMILES: FC(F)(F)C([O-])=O.C([NH:10][C@@H:11]1[C:33](=[O:34])[N:13]2[C:14]([C:30]([OH:32])=[O:31])=[C:15](/[CH:18]=[CH:19]/[CH2:20][N+:21]([C@@H:24]([C:27](=[O:29])[NH2:28])[CH2:25][OH:26])([CH3:23])[CH3:22])[CH2:16][S:17][C@H:12]12)=O.[ClH:35].CO>>[ClH:35].[NH2:10][C@@H:11]1[C:33](=[O:34])[N:13]2[C:14]([C:30]([O-:32])=[O:31])=[C:15](/[CH:18]=[CH:19]/[CH2:20][N+:21]([C@@H:24]([C:27](=[O:29])[NH2:28])[CH2:25][OH:26])([CH3:23])[CH3:22])[CH2:16][S:17][C@H:12]12
Reactant: C[N+](C)(C/C=C/C1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1)[C@H](CO)C(N)=O
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CO
Product: C[N+](C)(C/C=C/C1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1)[C@H](CO)C(N)=O

Procedure:
In a similar manner as in Example 24, the compound (4 g) of Example 29 was stirred in a 4% (w/w) hydrochloric acid-methanol solution (40 ml) to obtain the target product (2.57 g).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:48]=[CH:49][C:50]=1[CH2:51][O:52][Si](C(C)(C)C)(C)C)[O:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:39]([CH3:47])[CH2:40][CH2:41][CH2:42][C:43]([CH3:46])([OH:45])[CH3:44])[CH:36]=[CH:37][CH:38]=1)(C(C)(C)C)(C)C>C1COCC1>[OH:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:48]=[CH:49][C:50]=1[CH2:51][OH:52])[O:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:39]([CH3:47])[CH2:40][CH2:41][CH2:42][C:43]([CH3:44])([OH:45])[CH3:46])[CH:36]=[CH:37][CH:38]=1
Reactant: CC(CCCC(C)(C)O)c1cccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(CCCC(C)(C)O)c1cccc(COc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner similar to Example 3(i), by reacting 1.25 ml of tetrabutylammonium fluoride with 250 mg (0.41 mmol) of 6-{3-[3,4-bis-(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]phenyl}-2-methylheptan-2-ol in 7 ml of THF, after purification on a silica column (ethyl acetate 30-heptane 70), a colourless oil (m=130 mg; Y=85%) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:44]=[CH:43][C:32]([C:33]([NH:35][CH:36]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:34])=[C:31]([CH3:45])[CH:30]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:44]=[CH:43][C:32]([C:33](=[O:34])[NH:35][CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)=[C:31]([CH3:45])[CH:30]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: Cc1cc(CN)ccc1C(=O)NC1CCCCCC1
Solvent: Cc1ccccc1
Product: Cc1cc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)ccc1C(=O)NC1CCCCCC1
Yield: 80.5 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (660 mg, 1.6 mmol) with 4-aminomethyl-N-cycloheptyl-2-methyl-benzamide (810 mg, 3.1 mmol) in anhydrous toluene (18 mL). Purify the crude mixture by chromatography on silica gel eluting with hexane/THF (19:1 to 7:3 gradient) to obtain 7-chloro-6-(4-cycloheptylcarbamoyl-3-methyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (690 mg, 83%). MS (ES+) m/z: 536.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[Mg].Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.Cl>C(OCC)C.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>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: ClCc1ccccc1Cl
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: Clc1ccccc1Cc1ccccn1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
The Grignard reagent, generated from o-chlorobenzyl chloride (52.0 g, 0.32 moles) and magnesium turnings (8.4 g, 0.35 g atoms) in dry diethyl ether (350 ml), was added dropwise to a refluxing solution of 2-bromopyridine (34.2 g, 0.22 moles) and tetrakis(triphenylphosphine)palladium (0) (5.0 g) in dry diethyl ether (200 ml) under a nitrogen atmosphere. A white precipitate was produced and the reaction mixture was heated at reflux for 1 hour. After cooling to room temperature, 1N hydrochloric acid was added carefully to dissolve the white solid and the ether layer separated off. The ethereal extract was washed with 1N hydrochloric acid, neutralised with 2N sodium hydroxide solution, washed with water and dried over anhydrous magnesium sulphate. Removal of the solvent gave an orange oil which was purified by column chromatography (silica gel eluted with tetrahydrofuran:chloroform 5:95) to give 2-(o-chlorobenzyl)-pyridine (32 g, 73%) as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[N:11][C:12]=2[NH2:14])[NH:7][N:6]=1)#[N:4].[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C=O)C>[CH:21]1([N:7]2[C:8]3=[N:9][C:10]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)=[N:11][C:12]([NH2:14])=[C:13]3[C:5]([C:3]#[N:4])=[N:6]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrC1CCCC1
Reactant: N#Cc1n[nH]c2nc(-c3ccncc3)nc(N)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1nn(C2CCCC2)c2nc(-c3ccncc3)nc(N)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.4 %

Procedure:
To a suspension of 97% NaH (0.64 g, 0.026 mol) in DMF (75 ml) was added 3-cyano-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-amine (4.7 g, 0.02 mol). The reaction mixture was stirred at room temperature for 30 minutes then cyclopentyl bromide (3.1 g, 0.021 mol) in DMF (25 ml) was added dropwise. The reaction mixture was heated on a steam bath for 3 hours, cooled to room temperature and stirred for 24 hours. Inorganic salts were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica eluting with ethyl acetate (100%) followed by preparative thin layer chromatography on silica eluting with ethyl acetate/hexanes (75/25) to afford 0.45 g (7%) of 1-cyclopentyl-3-cyano-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-amine, m.p. 219°-221° C. when recrystallized from ether and dried for 16 hours at 90° C. in high vacuum.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:13]([OH:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=CC=C(C)N=1.FC(F)(F)S(O[Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])(=O)=O.Cl.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.[Cl-].[Na+].O.CO.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:13]([O:15][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of (2R,3S)-2-((tert-butoxycarbonyl)amino)-3-hydroxybutanoic acid (Frontier Scientific, Utah) (9.94 g, 45.3 mmol) in DCM (100 mL) was treated with 2,6-dimethylpyridine (Fluka) (15.79 mL, 136 mmol). A solution of tert-butyldimethylsilyl trifluoromethanesulfonate (Fluka) (22.9 mL, 100 mmol) in DCM (50 mL) was added dropwise over 1 h. The mixture was stirred for an additional 2 h, after which time the reaction was complete by LC-MS analysis. The mixture was diluted with saturated brine (100 mL) and acidified with a slight excess of 1.0 M aq. HCl. The mixture was stirred for 30 min, the layers were separated, and the aq. layer was extracted with DCM (100 mL). The combined organic extracts were dried (MgSO4) and concentrated to give crude product as a white semi-solid (26 g). The crude product was dissolved in MeOH (25 mL) and a solution of anhydrous Na2CO3 (4.80 g, 45.3 mmol) in water (25 mL) was added dropwise. The solution was stirred for 15 min and then concentrated to remove the MeOH. The resulting oily solution was diluted with water (175 mL) and hexane (200 mL) and stirred for 15 min. The aq. layer was separated and washed with a further 200 mL of hexane. The aq. layer was separated, diluted with DCM (200 mL), and 1.0 M aq. HCl was added dropwise to the stirred mixture. The mixture was separated and the aq. layer extracted with DCM (100 mL). The combined organic layers were dried (MgSO4) and concentrated to give (2R,3S)-2-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)butanoic acid (615a) (14.52 g, 43.5 mmol, 96% yield) as a colorless viscous oil. LC-MS m/z 356.1 [M+Na]1.
Reaction SMILES: [F:1][CH:2]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=2[F:31])=[C:19]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[N:18]=1)[CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])[CH:7]=[CH:8][CH:9]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:34][C:33]([CH3:36])([CH3:35])[CH2:32][C:19]1[N:18]=[C:17]([CH:2]([F:1])[CH2:3][C:4]2[CH:5]=[C:6]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:22]=[CH:21][C:20]=1[C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1[F:31]
Reactant: CCOC(=O)CCc1cccc(CC(F)c2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(C(F)Cc3cccc(CCC(=O)O)c3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 3-(3-(2-fluoro-2-(5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)ethyl)phenyl)propanoate (90 mg) in THF (2.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added, at room temperature, 1N hydrochloric acid (2.0 mL), and the mixture was extracted with ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[OH-].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>CN(C)C=O>[C:17]([C:10]1[C:11]2[NH:12][C:13]3[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:14]=3)[C:6]=2[CH:7]=[CH:8][N:9]=1)(=[O:19])[CH3:18]
Reactant: Brc1ccc2c(c1)[nH]c1cnccc12
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(=O)c1nccc2c1[nH]c1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
A solution of Example 1 (25 mg, 0.1 mmol) in dimetylformamide (DMF; 2 ml) was treated with 0.10 ml of 1 M aqueous NaOH (0.10 mmol). After stirring at RT for 30 minutes, acetic anhydride (0.010 ml, 0.095 mmol) was added and reaction stirred 18 h at RT. The reaction was partitioned in EtOAc and 5% citric acid and the organic layer washed with water, dried (brine; MgSO4), and concentrated to give 23 mg of crude product. The crude product was chromatographed (7:3 hexane-acetone) on silica gel to give 10 mg of 1-acetyl-7-bromo-β-carboline.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[C:16]1([C:22](=O)[CH:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][C:25](=O)[CH3:26])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C.C(Cl)Cl>[CH3:26][C:25]1[N:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=1
Reactant: CC(=O)CC(C(=O)c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)Cn1c(C)cc(-c2ccccc2)c1-c1ccccc1
Temperature: 100 °C
Yield: 68.4 %

Procedure:
Ethyl 2-aminoacetate hydrochloride (0.548 g, 3.92 mmol) was diluted with Ethanol (10 ml) then charged with triethylamine (0.746 ml, 5.35 mmol) and 1,2-diphenylpentane-1,4-dione (0.900 g, 3.57 mmol), added as a solution in DCM. The reaction was heated at 100° C. overnight, after which TLC showed a new spot (less polar, Rf˜0.9 in 20% EtOAc/hexanes). The reaction was diluted with 10 mL DCM and washed with water (10 mL). The aqueous layer was back-extracted with DCM (10 mL×2). The organics were combined, dried, filtered, and concentrated to yield a crude orange oil. This oil was loaded on a SiO2 column and purified using a 0-20% gradient of EtOAc in hexanes, affording ethyl 2-(5-methyl-2,3-diphenyl-1H-pyrrol-1-yl)acetate (0.780 g, 2.442 mmol, 68.5% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.37-7.33 (m, 3H), 7.27-7.24 (m, 2H), 7.16-7.11 (m, 4H), 7.07-7.04 (m, 1H), 6.24 (b, 1H), 4.42 (s, 2H), 4.21 (q, 2H), 2.27 (s, 3H), 1.25 (t, 3H).