Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14](F)=[C:13]([C:18]#[N:19])[CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([I:34])[CH:28]=1.Cl>CN(C)C=O>[Cl:1][C:2]1[S:6][C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:33][C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][C:29]=3[I:34])=[C:13]([C:18]#[N:19])[CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1
Reactant: Oc1ccc(F)cc1I
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1Oc1ccc(F)cc1I
Temperature: 80 °C
Yield: 59 %

Procedure:
To a solution of N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-4-fluorobenzenesulfonamide (Preparation 52, 100 mg, 0.32 mmol) and potassium carbonate (109 mg, 0.8 mmol) in dimethylformamide (3 ml) was added 4-fluoro-2-iodophenol (Preparation 218, 0.32 mmol) and the reaction heated at 80° C. for 24 hours. The solution was added dropwise into rapidly stirring hydrochloric acid (2M aqueous solution). The fine dark precipitate was filtered and dried in vacuo to afford the title product as a brown solid, 100 mg, 59% yield.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([C:19]2[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=2)[CH3:18])[N:11]=1)([CH3:3])[CH3:2].[CH:27]12[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH:32]1[CH2:31][CH2:30][NH:29][CH2:28]2>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([C:19]2[CH:26]=[CH:25][C:22]([CH2:23][N:29]3[CH2:30][CH2:31][CH:32]4[CH:27]([N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33]4)[CH2:28]3)=[CH:21][CH:20]=2)[CH3:18])[N:11]=1)([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CCNCC21
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(C=O)cc2)n1
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(CN3CCC4CN(C(=O)OC(C)(C)C)C4C3)cc2)n1

Procedure:
Title compound was prepared as a white solid (64 mg, 58.1% yield), with procedures similar to those used to prepare Intermediate 128, but utilizing 4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzaldehyde and tert-butyl 3,8-diazabicyclo[4.2.0]octane-8-carboxylate.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[CH2:34]([O:41][C:42]1[CH:47]=[C:46]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:45]=[CH:44][C:43]=1[C:56](=[O:58])[CH3:57])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[CH2:34]([O:41][C:42]1[CH:47]=[C:46]([O:48][CH2:49][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:45]=[CH:44][C:43]=1[C:56](=[O:58])[CH2:57][Br:1])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: [Br-]
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 2 h

Procedure:
Phenyltrimethylammonium tribromide (5.6 g, 0.015 mol) was added portionwise to a stirred solution of 1-(2,4-Bis-benzyloxyphenyl)-ethanone (5.0 g, 0.015 mol) in tetrahydrofuran (50 ml) and the mixture was stirred for 2 h. The mixture was partitioned between water (50 ml) and diethyl ether (2×50 ml). The combined organic phases were dried over magnesium sulphate and concentrated to give 1-(2,4-Bis-benzyloxyphenyl)-2-bromo-ethanone as a beige solid which was used without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[N:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[N:22]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccncc3)no2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(-c2noc(C3CCNCC3)n2)ccn1
Reaction time: 2.5 h

Procedure:
Trifluoroacetic acid (20 ml) was added to a stirred solution of 4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester (Example 2, 1.64 g, 4.96 mmol) in CH2Cl2 (35 ml). After 2.5 h at rt, the solvent was evaporated under reduced pressure. The residual solid was suspended in EtOAc (150 ml) and washed with saturated aqueous Na2CO3 (20 ml). The aqueous was separated and extracted with EtOAc (3×30 ml). The combined organic extracts were dried (MgSO4) and evaporated under reduced pressure to afford the title compound: RT=3.48 min, m/z (ES+)=231.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH3:19][NH2:20].S1(CCCC1)(=O)=O>CO>[CH3:19][NH:20][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17]
Reactant: CN
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: O=S1(=O)CCCC1
Solvent: CO
Product: CNc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
11 g of 4-chloro-3-nitro-benzophenone, 20 g of methylamine, 153.4 g of methanol and 27.5 g of sulpholane are warmed to 125° for 15 hours in a closed vessel. The reaction solution is evaporated to dryness, the residue is boiled thoroughly with 400 ml of 2 N hydrochloric acid for 20 minutes and the precipitate is filtered off, washed with water and dissolved in methylene chloride. After drying over sodium sulphate and evaporating, 4-methylamino-3-nitro-benzophenone with a melting point of 198°-201° is obtained.
Reaction SMILES: Br[C:2]1[C:3]([C:12]([OH:14])=[O:13])=[N:4][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[N:6][CH:7]=1.[OH-].[Na+]>CO.[Pd]>[C:8]([C:5]1[N:4]=[C:3]([C:12]([OH:14])=[O:13])[CH:2]=[CH:7][N:6]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)c1ncc(Br)c(C(=O)O)n1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1nccc(C(=O)O)n1
Reaction time: 2 h
Yield: 92.3 %

Procedure:
Preparation C1, Step 2: A mixture of 5-Bromo-2-tert-butyl-pyrimidine-4-carboxylic acid (1.65 g, 6.37 mmol) and aqueous sodium hydroxide (1.0 N, 19.1 mL, 19.1 mmol) in methanol (100 ml) was treated with a catalytic amount of 10% palladium on carbon. The mixture was degassed under vacuum/nitrogen, then hydrogenated at 50 psi for 2 hours. The catalyst was removed by filtration, the methanol was removed under vacuum, and the aqueous was acidified by the addition of 1.0 N aqueous hydrochloric acid (40 mL). The resulting suspension was extracted with ethyl acetate (4×50 mL), the combined organic phases were washed with brine, dried over sodium sulfate, and concentrated in-vacuo to yield 1.06 g of 2-tert-butylpyrimidine-4-carboxylic acid as a white powder. MS (ES+)=181 (M+H+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:61])[C@@H:19]([NH:43][C:44](=[O:60])[O:45][CH2:46][CH:47]1[C:59]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:53]2[C:48]1=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:20]([CH3:42])([S:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:21]>C(Cl)Cl>[CH3:42][C:20]([S:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:21])[C@H:19]([NH:43][C:44](=[O:60])[O:45][CH2:46][CH:47]1[C:59]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:53]2[C:48]1=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:18](=[O:61])[NH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[O:11]
Reactant: CC(C)(SC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(SC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCCC=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
To a round bottom dry flask was added DCM (2 mL), and a 2 M solution of oxalyl chloride in DCM (0.100 mL, 0.200 mmol). The reaction was cooled to −78° C. Then slowly was DMSO (0.028 mL, 0.401 mmol) added over 5 min. The reaction was stirred at −78° C. for 30 min. Then (R)-(9H-fluoren-9-yl)methyl 1-(5-hydroxypentylamino)-3-methyl-1-oxo-3-(tritylthio)butan-2-ylcarbamate (100 mg, 0.143 mmol) in DCM (3 mL) was added to the reaction over 5 min and the reaction was stirred at −78° C. for 45 min. Then TEA (0.088 mL, 0.630 mmol) was added to the reaction and the reaction was stirred for additional 30 min at −35° C. The reaction was quenched with EtOAc (2 mL). The reaction was diluted with EtOAc (20 mL) and washed with saturated aqueous NaHCO3 (10 mL), water (10 mL) and saturated aqueous NaCl (10 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated to give (R)-(9H-fluoren-9-yl)methyl 3-methyl-1-oxo-1-(5-oxopentylamino)-3-(tritylthio)butan-2-ylcarbamate (95 mg, 0.14 mmol, 95% yield).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>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.[Cu]I.C(N(CC)CC)C>[C:9]1([C:15]#[C:16][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C#Cc1ccccc1
Reactant: Nc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Nc1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C

Procedure:
More particularly, 4-iodoaniline (17.38 g), phenyl acetylene (10.4 g), and triphenyl phosphine (193 mg) are added to a three-necked 500 mL flask, which is fitted with a reflux condenser, nitrogen blanket, and an overhead mechanical stirrer. Bis(triphenylphosphine)-palladium(II)dichloride (“Pd(PPH3)2Cl2]”) (94 mg) and CuI (38 mg) are then added with 100 mL of triethylamine (“Et3N”). The flask is maintained at room temperature overnight under a nitrogen atmosphere. Afterwards, the reaction mixture is cooled and filtered to remove the precipitate. The precipitate is washed with methylene chloride and the soluble portions are recombined with the filtrate. The solvent is then evaporated to yield 4-phenylethynyl aniline (“Compound E”) as a yellowish solid. Further purification, typically involves repeated re-crystallization from hexanes to give the final product as a pale yellow colored solid.
Reaction SMILES: C([O:5][C:6](=[O:27])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C@H:14]([OH:26])/[CH:15]=[CH:16]/[C@H:17]([OH:25])[C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(C)(C)C.[OH-].[K+].Cl>C(O)C.O>[CH3:23][CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]([OH:24])[C@@H:17]([OH:25])/[CH:16]=[CH:15]/[C@@H:14]([OH:26])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:27])=[O:5]
Reactant: CCCCC[C@H](O)[C@@H](O)/C=C/[C@@H](O)CCCCCCCC(=O)OC(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCC[C@H](O)[C@@H](O)/C=C/[C@@H](O)CCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 46 h

Procedure:
(9S,12S,13S)-(E)-9,12,13-trihydroxy-10-octadecaenoic acid t-butyl ester (13) (6.5 mg, 0.0168 mmol) was added to an ethanol-water (4:1) solution (500 μL) of 2.0 N potassium hydroxide at room temperature, and the mixture was stirred at room temperature for 46 hours. The reaction solution was cooled to 0° C., 1.0 N hydrochloric acid solution (500 μL) was added to the reaction solution to make it weakly acidic, and the mixture was extracted with chloroform (5 mL) three times. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution (5 mL), dried over sodium sulfate, and concentrated. The resulting colorless oily crude product (10 mg) was separated and purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain 9S,12S,13S-trihydroxy-10E-octadecenoic acid (14) as a while solid (4.5 mg, 82%).
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])/[CH:8]=[CH:9]/[CH3:10].C(N(CC)CC)C>O>[C:13]([O:12][C:7](=[O:11])[CH2:8][CH:9]([CH3:10])[S:1][CH2:2][CH:3]([OH:4])[CH2:5][OH:6])([CH3:16])([CH3:15])[CH3:14]
Reactant: C/C=C/C(=O)OC(C)(C)C
Reactant: OCC(O)CS
Solvent: CCN(CC)CC
Solvent: O
Product: CC(CC(=O)OC(C)(C)C)SCC(O)CO
Temperature: 60 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
To thioglycerol (0.835 ml), t-butyl crotonate (10 ml) and triethylamine (1 ml) were added, followed by stirring at 60° C. for 48 hours. After cooling and addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off, to yield the title compound (1.82 g, yield 73%) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[N:14][C:15]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:10][CH:9]=2)=[CH:4][CH:3]=1.IC.[CH2:29](Cl)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[N:14][C:15]=3[NH:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:10]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: ClCc1ccccc1
Reactant: O=c1c(-c2ccc(Cl)cc2)c[nH]c2ccnc(NCc3ccccc3)c12
Solvent: CI
Product: O=c1c(-c2ccc(Cl)cc2)cn(Cc2ccccc2)c2ccnc(NCc3ccccc3)c12

Procedure:
The title compound was prepared as described in Example 2 above except that 3-(4-chlorophenyl)-1,4-dihydro-4-oxo-5-(2-phenethylamino)-1,6-naphthyridine was replaced with 3-(4-chlorophenyl)-1,4-dihydro-4-oxo-5-benzylamino-1,6-naphthyridine and iodomethane was replaced with benzyl chloride. MS 462 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20](=S)[CH2:21][C:22](=O)[CH3:23])=[O:4].Cl.Cl.[CH2:28]([NH:35][NH2:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:11])=[O:12])[CH2:7][N:6]1[C:20]1[N:35]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:36]=[C:22]([CH3:23])[CH:21]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=S)CC(C)=O
Reactant: NNCc1ccccc1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1Cc1ccccc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 253c) was reacted with benzylhydrazine dihydrochloride (CAS Reg. No. 20570-96-1) to give the title compound as orange oil. MS (ESI): m/z=474.2 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:20]3[C:21]4[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]=4[N:23]=[CH:24][N:25]=3)[CH:17]=[N:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].Cl.O1CCOCC1>ClCCl>[CH3:35][Si:33]([CH3:34])([CH3:36])[CH2:32][CH2:31][O:30][CH2:29][N:26]1[C:22]2[N:23]=[CH:24][N:25]=[C:20]([C:18]3[CH:17]=[N:16][N:15]([C:4]4([CH2:3][C:1]#[N:2])[CH2:5][NH:6][CH2:7]4)[CH:19]=3)[C:21]=2[CH:28]=[CH:27]1
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.6 %

Procedure:
To a solution of tert-butyl 3-(cyanomethyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (15, 389.6 g, 0.765 mol) in dichloromethane (CH2Cl2, 7 L) was added a solution of hydrogen chloride (HCl) in dioxane (4 M, 1.15 L, 4.6 mol, 6.0 equiv) drop wise at room temperature. The resulting reaction mixture was stirred at room temperature for 48 h. When LCMS showed that all of the starting material had been consumed, the reaction mixture was transferred in portions to a 22 L separation funnel containing aqueous ammonium hydroxide (NH4OH, about 4% v/v, 2.5 L). Gas was evolved but the funnel stayed cool to the touch. Ice cubes were periodically added as a precaution. Once all of the reaction mixture was added, stirring was continued for about 15 min. The pH of the aqueous layer was found to be close to 11. The two layers were separated and the organic layer was washed with brine (2 L), dried over anhydrous sodium sulfate (Na2SO4) and concentrated under reduced pressure to a minimum volume. Heptane (about 3 L) was added to the residue and the resulting suspension was concentrated to dryness under reduced pressure to give crude 2-(3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (16, 268.2 g, 313.3 g theoretical, 85.6% yield) as an orange oil which was used directly for the subsequent reaction without further purification. For crude 16: 1H NMR (300 MHz, CDCl3): δ 8.92 (s, 1H), 8.45 (s, 1H), 8.39 (s, 1H), 7.47 (d, 1H), 6.87 (d, 1H), 5.74 ( s, 2H), 4.36 (d, 2H), 3.95 (d, 2H), 3.77 (s, 2H), 3.62 (t, 2H), 1.9 (br. s, 1H), 0.99 (t, 2 H), 0.01 (s, 9H) ppm; C20H27N7OSi (MW, 409.56), LCMS (EI) m/e 410 (M++H).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:12][CH2:13][OH:14])[CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:16][C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1>[CH2:3]([N:10]([CH2:12][CH2:13][O:14][CH2:16][C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CN(CCO)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)COCCN(C)Cc1ccccc1
Reaction time: 1 h
Yield: 102 %

Procedure:
Sodium hydride (60% (by weight) in oil, 8 g) was stirred in dry tetrahydrofuran (THF) (100 ml) under nitrogen while 2-(N-benzyl-N-methylamino)ethanol (17 g) was added slowly. The warm mixture was stirred for 1 hour, then kept cool on a water bath at room temperature (20°) while a solution of ethyl 4-chloroacetoacetate (16.5 g) in dry THF (100 ml) was added dropwise over 3.5 hours. The mixture was stirred overnight at room temperature under nitrogen, then quenched with a little ethanol and poured onto ice (100 g) and concentrated hydrochloric acid (30 ml). The THF was removed by evaporation, and the residue washed with light petroleum (b.p. 60°-80°) to remove mineral oil. The residue was basified with solid sodium carbonate and extracted with ethyl acetate (200 ml and 100 ml). The combined extracts were dried (Na2CO3), filtered and evaporated to give the title compound as an oil (30 g), sufficiently pure for further use. N.m.r. spectrum in CDCl 3, δ values: 7.27 (5H,s); 4.12 (2H,q); 4.06 (2H,s); 3.45-3.70 (6H,m); 2.61 (2H,t); 2.25 (3H,s); 1.23 (3H,t).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[N:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=2)[CH2:3][CH2:2]1>CCOC(C)=O.CO.[Pd]>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[N:12]=[CH:13][C:14]([NH2:17])=[CH:15][N:16]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cnc(NCCCN2CCOCC2)nc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cnc(NCCCN2CCOCC2)nc1
Reaction time: 8 h

Procedure:
The crude N-(3-morpholinopropyl)-5-nitropyrimidin-2-amine was combined with 10% Pd/C (500 mg) in EtOAc (20 mL) and MeOH (10 mL) was added. The mixture was purged with H2 and allowed to stir under 1 atm H2 overnight. Filtration through a pad of celite and concentration afforded N2-(1-methylpiperidin-4-yl)pyrimidine-2,5-diamine 16 as a thick rust colored oil, which may be used without further purification. MS: m/z found 270 [MH+].
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31](/[CH:34]=[CH:35]/[C:36]3[CH:41]=[CH:40][C:39](Br)=[CH:38][CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=[O:3])[CH3:2].[C:43]([OH:48])(=[O:47])[CH2:44][CH:45]=[CH2:46].C(N(CC)CC)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31](/[CH:34]=[CH:35]/[C:36]3[CH:41]=[CH:40][C:39](/[CH:46]=[CH:45]/[CH2:44][C:43]([OH:48])=[O:47])=[CH:38][CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=[O:3])[CH3:2]
Reactant: C=CCC(=O)O
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(/C=C/c4ccc(Br)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(/C=C/c4ccc(/C=C/CC(=O)O)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C

Procedure:
A mixture of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-[(E)-2-(4-bromophenyl)vinyl]benzofuran (0.2 g), 3-butenoic acid (0.053 mL), triethylamine (0.22 mL), palladium (II) acetate (7 mg) and tris(2-methylphenyl)phosphine (19 mg) in acetonitrile (4 mL) was heated for reflux under an argon atmosphere for 8 hours. The reaction mixture was cooled to room temperature, and the insoluble material was removed by filtration. The filtrate was diluted with ethyl acetate. The solution was washed with 0.5 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1-dichloromethane/methanol=20/1) to give the title compound (0.17 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[Cl:13][C:14]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17]>>[Cl:13][C:14]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Cl)c2ccccc2n1
Reactant: NCc1cccc(Cl)c1Cl
Product: Cc1cc(NCc2cccc(Cl)c2Cl)c2ccccc2n1

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-2-methylquinoline and 2,3-dichlorobenzylamine.
Reaction SMILES: [NH2:1][CH:2]([CH3:6])[CH2:3][O:4][CH3:5].[CH2:7]1[CH2:13][S:10](=[O:12])(=[O:11])[O:9][CH2:8]1>O1CCCC1>[CH3:5][O:4][CH2:3][CH:2]([NH:1][CH2:8][CH2:7][CH2:13][S:10]([OH:12])(=[O:11])=[O:9])[CH3:6]
Reactant: O=S1(=O)CCCO1
Reactant: COCC(C)N
Solvent: C1CCOC1
Product: COCC(C)NCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of 2-amino-1-methoxypropane (5.0 g, 17.8 mmol) in tetrahydrofuran (25 mL) was slowly added 1,3-propane sultone (2.12 g, 17.0 mmol). The mixture was stirred at reflux for 4 h. The reaction mixture was cooled to room temperature. The solid product was collected by filtration, washed with acetone (2×25 mL), and dried in a vacuum oven (50° C.), to afford compound EI (3.1 g, 86%). 1H NMR (D2O, 500 MHz) δ ppm 3.53 (m, 1H), 3.41 (m, 2H), 3.27 (s, 3H), 3.11 (m, 2H), 2.89 (t, 2H, J=7.3 Hz), 2.00 (m, 2H), 1.18 (d, 3H, J=5.9 Hz). 13C NMR (D2O, 125 MHz) δ ppm 71.73, 58.80, 53.79, 48.08, 43.55, 21.52, 12.79. ES-MS 210 (M−1).