Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[O:15][CH3:16])=[O:4].[ClH:17].[F:18][C:19]1[CH:32]=[CH:31][C:22]([C:23]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>C(O)C>[ClH:17].[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:2][C:3]([C:5]3[CH:14]=[CH:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6]=3[O:15][CH3:16])=[O:4])[CH2:27][CH2:26]2)=[O:24])=[CH:31][CH:32]=1
Reactant: COc1c(C(=O)CBr)ccc2ccccc12
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1c(C(=O)CN2CCC(C(=O)c3ccc(F)cc3)CC2)ccc2ccccc12

Procedure:
1.5 g of 2-bromo-1'-methoxy-2'-acetonaphthone, 1.3 g of 4-(p-fluorobenzoyl)piperidine hydrochloride, and 1.6 g of triethylamine were added to 60 ml of ethanol. The mixture was refluxed for 15 min. The solvent was distilled off, and dichloromethane was added to the residue. The mixture was washed with water and dried. The dichloromethane was distilled off, and the residue was purified by column chromatography (silica gel) to prepare an oleaginous intended compound. The compound was converted into a hydrochloride by an ordinary method and then recrystallized to prepare 1.38 g of an intended hydrochloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.C(=O)([O-])[O-].[K+].[K+].N1CCC[CH2:28][CH2:27]1>ClCCl.CO.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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C.O>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:27]#[CH:28])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C1CCNCC1
Reactant: CCCCCc1ccc(-c2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: C#Cc1ccc(-c2ccc(CCCCC)cc2)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4-bromo-4′-pentylbiphenyl (5.04 g), trimethylsilyacetylene (2.4 ml), tetrakis(triphenylphosphine)palladium (0.96 g), triphenylphosphine (0.22 g) and cuprous iodide (95 mg) in piperidine (10 ml) was heated for an hour under atmospheric pressure of nitrogen at 90° C. The reaction mixture was poured into a mixture of cold water and ethyl acetate, and adjusted to about pH 1 with 6N hydrochloric acid. The separated organic layer was washed with water and brine, and dried over magnesium sulfate. The magnesium sulfate was filtered of, and the filtrate was evaporated under reduced pressure to give crude 2-[4-(4-pentylphenyl)phenyl]-1-trimethylsilylacetylene, which was used for the next reaction without further purification. Crude mixture was dissolved in a mixture of dichloromethane (10 ml) and methanol (10 ml), and to the solution was added potassium carbonate (2.75 g) at 0° C. The mixture was allowed to warm to ambient temperature, and stirred for another 2 hours. The reaction mixture was poured into a mixture of cold water and ethyl acetate, and the resultant precipitate was filtered off. The filtrate was adjusted to about pH 7 with 1N hydrochloric acid, and washed with brine, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give a crude powder, which was subjected to column chromatography on silica gel (300 ml), and eluted with a mixture of (n-hexane:ethyl acetate=99:1-97:3, V/V) to give 4-(4-Pentylphenyl)phenylacetylene (2.09 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-])=O>C(O)C.O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1cccc(N)c1
Reaction time: 24 h
Yield: 97246.3 %

Procedure:
A mixture of methyl 3-nitrobenzoate (18.1 g, 0.10 mmol) in ethanol/tetrahydrofuran (THF) (9:1), and 1.8 g of 10% Pd/C was hydrogenated at atmospheric pressure and ambient temperature for 24 hr. The reaction mixture was filtered through Celite (Celite is a registered trademark of the Johns-Manville Product Corporation for diatomaceous earth) and washed with ethanol. The solvent was removed in vacuo to give the title compound as a pale yellow solid (14.7 g; 97% yield) that was used without further purification in the next reaction. 1H-NMR (200 MHz; CDCl3) δ 7.43 (d, 1H, J=7.6 Hz), 7.35 (t, 1H, J=2.3 Hz), 7.25 (d, 1H, J=2.3 Hz), 7.19 (d, 1H, J=7.7 Hz), 3.89 (s, 3H), 3.7 ppm (bs, 2H).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][NH2:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH:25]=O.[Na]>ClCCl>[CH:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][NH:14][CH2:25][C:16]2[CH:17]=[CH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: NC[C@@H]1CCCN1CC1CCCCC1
Agent: [Na]
Solvent: ClCCl
Product: c1ccc2cc(CNC[C@@H]3CCCN3CC3CCCCC3)ccc2c1
Reaction time: 8 h
Yield: 29.7 %

Procedure:
(S)—C-(1-Cyclohexylmethyl-pyrrolidin-2-yl)-methylamine (prepared according to scheme 2) 0.24 g (1 mmol), and naphthalene-2-carbaldehyde 0.19 g (1.2 mmol), were dissolved in 10 mL dichloromethane. To this mixture was added sodium triacethoxyborohydride 0.51 g (2 mmol), and molecular sieve. The reaction was stirred overnight under nitrogen. Molecular sieve was filtered, washed with 3 mL HCl, acidic layer was transformed to basic pH, with powder sodium bicarbonate, and extracted with ethyl acetate. The combined organic layer dried over magnesium sulfate, filtered and concentrated, yield to 100 mg of yellow oil.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:55][C:56]1[CH:57]=[C:58]([C:63]([CH3:68])([CH3:67])[C:64](=[O:66])[CH3:65])[CH:59]=[CH:60][C:61]=1[Cl:62]>CO.C(Cl)Cl>[Br:1][CH2:65][C:64](=[O:66])[C:63]([C:58]1[CH:59]=[CH:60][C:61]([Cl:62])=[C:56]([Cl:55])[CH:57]=1)([CH3:68])[CH3:67]
Reactant: [Br-]
Reactant: CC(=O)C(C)(C)c1ccc(Cl)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C(=O)CBr)c1ccc(Cl)c(Cl)c1
Reaction time: 24 h
Yield: 91.7 %

Procedure:
Tetrabutylammonium tribromide (20.4 g, 41.5 mmol) was added to a solution of 3-(3,4-dichlorophenyl)-3-methylbutan-2-one (9.60 g, 41.5 mmol) in MeOH-DCM (160 mL, 1:2, v/v). After stirring 24 h, the reaction mixture was concentrated under reduced pressure and then combined with EtOAc (80 mL). The organic layer was washed with H2O (50 mL), 1N HCl (50 mL), and H2O (20 mL) successively. The organic layer was washed with brine, dried over Na2SO4, and concentrated. Purification by column chromatography afforded 1-bromo-3-(3,4-dichlorophenyl)-3-methylbutan-2-one (11.8 g, 91%). 1H NMR (400 MHz, CDCl3) δ 7.45 (d, 1H), 7.38 (d, 1H), 7.08 (d, 1H), 3.86 (s, 2H), 1.56 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.Cl.C[O:22][C:23](=[O:31])[C@H:24]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[NH2:25].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:30][O:29][C:27](=[O:28])[CH2:26][CH:24]([NH:25][C:13](=[O:15])[CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:16]([F:19])([F:18])[F:17])[C:23]([OH:31])=[O:22]
Reactant: COC(=O)C[C@H](N)C(=O)OC
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CC(NC(=O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F)C(=O)O

Procedure:
Under the conditions of Example 2(a), 3.012 g (10 mmol) of 2-[2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]acetic acid, 1.836 g (10 mmol) of L-aspartic acid dimethyl ester hydrochoride, 1,531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is purified by column chromatography on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:27][C:28]1[N:33]=[C:32]([C:34](=[N:36][NH2:37])[NH2:35])[CH:31]=[CH:30][CH:29]=1>ClCCl>[NH2:35][C:34]([C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:27])[N:33]=1)=[N:36][NH:37][C:12]([CH:10]1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:11]1)=[O:14]
Reactant: Cc1cccc(C(N)=NN)n1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: Cc1cccc(C(N)=NNC(=O)C2CN(C(=O)OC(C)(C)C)C2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
To a solution of 8.21 g (54.7 mmol) 1-(tert-butoxycarbonyl) azetidine-3-carboxylic acid in 80 mL dichloromethane are added 8.86 g (54.7 mmol) carbonyl diimidazole within 30 min. After stirring for five minutes 11 g (54.7 mmol) 6-methylpyridine-2-carbohydrazonamide are added and the reaction mixture is stirred at room temperature for 3 hours. The solvent has been evaporated and the residue is treated with water. The formed precipitate has been filtered off and dried yielding 16.47 g (81.3%) of the desired compound as a mixture of tautomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][CH2:13][OH:14].N1C=CC=CC=1.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)Cl>[CH3:24][S:21]([O:14][CH2:13][CH2:12][C:3]1[CH:4]=[C:5]([O:10][CH3:11])[C:6]([C:8]#[N:9])=[CH:7][C:2]=1[Cl:1])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(CCO)c(Cl)cc1C#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(CCOS(C)(=O)=O)c(Cl)cc1C#N
Reaction time: 2 h

Procedure:
A solution of 2-(2-chloro-4-cyano-5-methoxyphenyl)ethanol (205 mg, 0.969 mmol) DIPEA (0.846 mL, 4.84 mmol) and pyridine (0.0780 mL, 0.969 mmol) in DCM (3 mL) was treated dropwise with mesyl chloride (0.110 mL, 1.42 mmol). The reaction was stirred for 2 hours and was then diluted with DCM and washed twice with aq. citric acid, then washed with brine, and dried over sodium sulfate. Purification of the residue by flash chromatography (20-50% ethyl acetate/hexanes) afforded the title intermediate. 1H-NMR (500 MHz, CDCl3) δ ppm 2.99 (s, 3H), 3.24 (t, J=6.6 Hz, 2H), 3.95 (s, 3H), 4.49 (t, J=6.6 Hz, 2H), 6.962 (s, 1H), 7.563 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[N:6][CH:7]=1.[CH3:11][C:12]([S@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4](/[C:8](=[N:17]/[S@@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])/[CH3:9])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cncc(Br)c1
Solvent: ClCCl
Product: C/C(=N\[S@](=O)C(C)(C)C)c1cncc(Br)c1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 69.4 %

Procedure:
To a solution of 1-(5-bromopyridin-3-yl)ethanone (1.01 g, 5.04 mmol) in DCM (20 mL) was added (R)-2-methylpropane-2-sulfinamide (0.555 g, 4.58 mmol) followed by Ti(OEt)4 (1.23 g, 4.58 mmol) dropwise and the reaction mixture was heated to 40° C. over night. After cooling, the solvent was removed under vacuum and the residue taken up in EtOAc (80 mL). This solution was vigorously stirred while a saturated solution of brine (20 mL) was slowly added. After 15 min, the mixture was filtered through a plug of Dicalite and washed with EtOAc. The organic phase was separated, dried over Na2SO4 and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 50% EtOAc-heptane gradient to give the title compound (0.964 g, 69%) as a yellow oil. MS: 303.1 and 305.0 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[C:16][Si](C)(C)C)=[CH:11][CH:10]=2)=[CH:5][C:4]=1[CH:21]1[C:26](=[O:27])[C:25]([CH3:29])([CH3:28])[O:24][C:23]([CH3:31])([CH3:30])[C:22]1=[O:32])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CO>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]#[CH:16])=[CH:13][CH:14]=2)=[CH:5][C:4]=1[CH:21]1[C:22](=[O:32])[C:23]([CH3:31])([CH3:30])[O:24][C:25]([CH3:29])([CH3:28])[C:26]1=[O:27])[CH3:2]
Reactant: CCc1ccc(-c2ccc(C#C[Si](C)(C)C)cc2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1ccc(-c2ccc(CC)c(C3C(=O)C(C)(C)OC(C)(C)C3=O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
To a solution of 4-[4-ethyl-4′-(trimethylsilylethynyl)biphenyl-3-yl]-2,2,6,6-tetramethyl-pyran-3,5-dione (0.143 g, 0.32 mmol) in methanol (6.5 ml) is added powdered potassium carbonate (0.177 g, 1.28 mmol), and the mixture is stirred at room temperature for 1 hour. Water is then added to dissolve all inorganics, and the mixture is concentrated in vacuo. 2M hydrochloric acid is added to achieve pH 2-3, then the desired material is extracted with ethyl acetate (×3). All organics are combined, washed with brine, dried over anhydrous magnesium sulfate then concentrated in vacuo. The residue is further purified by flash column chromatography on silica gel (hexane/ethyl acetate 4:1 ratio) to afford 4-(4-ethyl-4′-ethynylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.070 g) as a yellow solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:31]1[C:39]2[C:34](=[N:35][CH:36]=[C:37]([C:40]3[CH:41]=[C:42]([CH:50]=[CH:51][C:52]=3[CH3:53])[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:38]=2)[O:33][C:32]=1[C:54]1[CH:59]=[CH:58][C:57]([F:60])=[CH:56][CH:55]=1>CO.CS(C)=O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:46]([O:45][C:43]([C:42]1[CH:50]=[CH:51][C:52]([CH3:53])=[C:40]([C:37]2[CH:38]=[C:39]3[C:31]([C:43]([O:45][CH3:46])=[O:44])=[C:32]([C:54]4[CH:55]=[CH:56][C:57]([F:60])=[CH:58][CH:59]=4)[O:33][C:34]3=[N:35][CH:36]=2)[CH:41]=1)=[O:44])([CH3:48])([CH3:49])[CH3:47]
Reactant: Cc1ccc(C(=O)OC(C)(C)C)cc1-c1cnc2oc(-c3ccc(F)cc3)c(Br)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cc(C(=O)OC(C)(C)C)ccc3C)cc12
Reaction time: 8 h
Yield: 190.8 %

Procedure:
1,3-bis(diphenylphosphino)propane (119 mg, 0.287 mmol) was added to a stirring solution of palladium(II) acetate (32 mg, 0.144 mmol) and tert-butyl 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoate (231 mg, 0.479 mmol) in MeOH (1.6 mL) and DMSO (3 mL) at 80° C. in a PARR bomb which was then charged with 300 psi CO (g) and allowed to stir overnight. The mixture was diluted with EtOAc and filtered through a pad of celite. The filtrate was washed with sat. aq. NaHCO3, and brine. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product methyl 5-(5-(tert-butoxycarbonyl)-2-methylphenyl)-2-(4-fluorophenyl)furo[2,3-b]pyridine-3-carboxylate (211 mg, 0.457 mmol, 95% yield) crude by LCMS which was used directly in the next step. LC-MS retention time: 2.32 min; m/z (MH+): 462. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 mM, a hold time of 1 mM, and an analysis time of 4 min where solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(N3CCOCC3)cc2C1

Procedure:
Prepared in analogy to Example A3(d) from 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) and morpholine. Yellow solid. MS (m/e): 341.3 ({37Cl}M+H+, 20%), 339.1 ({35Cl}M+H+, 100%).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([NH:6][C:7]2[C:12]([F:13])=[CH:11][N:10]=[C:9]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[C:20]([Cl:23])[CH:21]=4)[N:16](S(C4C=CC(C)=CC=4)(=O)=O)[CH:15]=3)[N:8]=2)[CH2:3]1.CCN(C(C)C)C(C)C.[CH:43]1([CH2:48][S:49](Cl)(=[O:51])=[O:50])[CH2:47][CH2:46][CH2:45][CH2:44]1.N1CCOCC1>ClCCl>[Cl:23][C:20]1[CH:21]=[C:22]2[C:14]([C:9]3[N:8]=[C:7]([NH:6][CH:4]4[CH2:5][N:2]([S:49]([CH2:48][CH:43]5[CH2:47][CH2:46][CH2:45][CH2:44]5)(=[O:51])=[O:50])[CH2:3]4)[C:12]([F:13])=[CH:11][N:10]=3)=[CH:15][NH:16][C:17]2=[N:18][CH:19]=1
Reactant: O=S(=O)(Cl)CC1CCCC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CNC4)n3)c3cc(Cl)cnc32)cc1
Agent: Cl
Solvent: C1COCCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CC1CCCC1)N1CC(Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a stirred solution of N-(azetidin-3-yl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine hydrochloride, 6c, (0.03 g, 0.06 mmol) in dichloromethane (1 mL) was added iPr2NEt (0.33 μL, 1.90 mmol) followed by cyclopentylmethanesulfonyl chloride (0.01 g, 0.06 mmol). The resulting mixture was stirred 30 minutes at room temperature at which time LCMS showed complete reaction. Morpholine (0.20 mL) was added and the solution evaporated to dryness. The resulting residue was dissolved in methanol (2 mL) then treated with 25% sodium methoxide/methanol (0.5 mL) and heated at 60° C. in sealed tube for 10 minutes. The solution was quenched with aqueous saturated NH4Cl solution (0.5 mL) then evaporated to dryness. The resulting residue was dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to afford 27.4 mg (88% yield) of the desired product, 469, as a solid. LCMS RT=3.1 min, ES+465.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][C:12]=3[O:21][CH3:22])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.COC(=O)C1C=CC(OC)=C(C23CC4CC(CC(C4)C2)C3)C=1>>[C:1]12([C:11]3[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=3[O:21][CH3:22])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COC(=O)c1ccc(C23CC4CC(CC(C4)C2)C3)c(OC)c1
Agent: COC(=O)c1ccc(OC)c(C23CC4CC(CC(C4)C2)C3)c1
Product: COc1cc(C(=O)O)ccc1C12CC3CC(CC(C3)C1)C2
Yield: 88 %

Procedure:
When the product of Step A was substituted for methyl-3-(1-admantyl)-4-methoxybenzoate in Example 30, Step B the similar process afforded the title compound in 88% yield. 1H-NMR (CDCl3) 1.7 (s, 6H); 2.01 (s, 3H); 2.06 (s, 6H); 3.81 (s, 3H); 7.19 (d, 1H, J=8.1 Hz); 7.45 (d, 1H, J=1.49 Hz); 7.53 (d, 1H, J=1.61, 8.11 Hz).
Reaction SMILES: O[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>C(Cl)Cl>[Br:13][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)CCC/C=C\CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCC/C=C\CBr
Reaction time: 0.67 h
Yield: 95.7 %

Procedure:
To a solution of alcohol 39 (1.48 g, 9.36 mmol) and carbon tetrabromide (3.40 g, 10.25 mmol) in dry CH2Cl2 (50 mL) was added triphenylphosphine (2.70 g, 10.30 mmol) in portions. The reaction mixture was stirred for 40 min and MeOH (1 mL) was added. Concentration on a rotary evaporator, followed by flash chromatography using 50:1 hexane/EtOAc as eluent, gave 40 as a colorless oil (1.98 g, 96%): IR (neat) 3020 (w), 2945, 2860 (w), 1740 (s), 1435, 1370, 1200, 1165 cm-1 ; 1H NMR (CDCl3) δ 5.77 (m, J1 =10.5 Hz, J2 =8.3 Hz, J3 =1.4 Hz, 1H), 5.56 (m, J1 =10.6 Hz, J2 =7.5 Hz, 1H), 3.98 (d, J=8.1 Hz, 2H), 3.67 (s, 3H), 2.34 (t, J=7.4 Hz, 2H), 2.19 (dq, J1 =7.5 Hz, J2 =1.4 Hz, 2H), 1.74 (p. J=7.3 Hz, 2H); 13C NMR (CDCl3) δ 173.55, 134.48, 126.26, 51.37, 33.06, 26.60, 26.01, 24.28. A minor amount (ca. 5%) of methyl trans-7-bromo-5-heptenoate could be seen in the 1H NMR spectrum at δ 3.93.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11](=[O:36])[CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][C@@H:18]1[C@@H:22](/[CH:23]=[CH:24]/[C@@H:25]([OH:33])[C:26]([CH3:32])([CH3:31])[CH2:27][CH2:28][CH2:29][CH3:30])[C@H:21]([OH:34])[CH2:20][C@@H:19]1[OH:35]>C(Cl)(Cl)Cl.O1CCCC1>[CH3:9][O:10][C:11](=[O:36])[CH2:12][CH2:13][CH2:14][CH:15]([Br:1])[CH:16]1[O:35][C@H:19]2[CH2:20][C@@H:21]([OH:34])[C@H:22](/[CH:23]=[CH:24]/[C@@H:25]([OH:33])[C:26]([CH3:32])([CH3:31])[CH2:27][CH2:28][CH2:29][CH3:30])[C@H:18]2[CH2:17]1
Reactant: CCCCC(C)(C)[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](O)C[C@H]1O
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCCCC(C)(C)[C@H](O)/C=C/[C@@H]1[C@H]2CC(C(Br)CCCC(=O)OC)O[C@H]2C[C@H]1O
Yield: 70.4 %

Procedure:
By proceeding as described in Example 1 but using 800 mg of N-bromosuccinimide and 1.47 g of (5Z,13E)-(9α,11α,15R)-9,11,15-trihydroxy-16,16-dimethylprosta-5,13-dienoic acid methyl ester dissolved in a mixture of 40 ml of chloroform and 4 ml of tetrahydrofuran, there was obtained 1.24 g of the title compound having the following physical characteristics:
Reaction SMILES: C12[N:8]([C:9]3C=N[C:16]4[C:11](=[CH:12]C=[CH:14][CH:15]=4)[N:10]=3)CC1CCNC2.[CH:19]12[CH2:25][NH:24][CH:23]1[CH2:22][N:21]([C:26]([C:28]1[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][C:29]=1[O:38][CH2:39][CH3:40])=[O:27])[CH2:20]2.ClC1N=C(C)C=C(C)N=1>>[CH3:12][C:11]1[CH:16]=[C:15]([CH3:14])[N:8]=[C:9]([N:24]2[CH2:25][CH:19]3[CH:23]2[CH2:22][N:21]([C:26]([C:28]2[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][C:29]=2[O:38][CH2:39][CH3:40])=[O:27])[CH2:20]3)[N:10]=1
Reactant: CCOc1ccc2ccccc2c1C(=O)N1CC2CNC2C1
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Agent: Cc1cc(C)nc(Cl)n1
Product: CCOc1ccc2ccccc2c1C(=O)N1CC2CN(c3nc(C)cc(C)n3)C2C1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 24 and 2-chloro-4,6-dimethylpyrimidine. MS (ESI) mass calcd. for C24H26N4O2, 402.5; m/z found, 403.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Br.[N-:11]=[N+:12]=[N-:13].[Na+].[N-]=[N+]=[N-]>O>[N:11]([CH2:4][C:3]1[C:2]([F:1])=[CH:9][CH:8]=[CH:7][C:6]=1[F:10])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1cccc(F)c1CBr
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NCc1c(F)cccc1F
Temperature: 25 °C
Yield: 93.6 %

Procedure:
To a 250 ml round bottom flask, 2,6-difluorobenzylbromide (0.024 mol, 5 g), sodium azide (0.026 mol, 1.72 g) and water (50 ml) were charged. The reaction mixture was heated to 70° C. to 75° C. for 30 hours and formation of azide intermediate (99.4%) was monitored by gas chromatography. After completion of the reaction, the contents were cooled to room temperature. The layers of the reaction mixture were separated to obtain an upper water layer and a lower azide intermediate layer. The lower layer was then concentrated and dried under vacuum to obtain 3.8 g of the product.