Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@H:4]([CH2:5][CH2:6][NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:3][N:2]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[Cl:22]N1C(=O)CCC1=O>CN(C)C=O>[Cl:22][C:12]1[CH:13]=[CH:14][C:8]2[NH:7][CH2:6][CH2:5][C@@H:4]3[CH2:3][N:2]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:1][C@H:10]3[C:9]=2[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CCNc3ccccc3[C@@H]2C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H]2CCNc3ccc(Cl)cc3[C@@H]2C1
Temperature: 50 °C

Procedure:
To a solution of Example 389B (172 mg, 0.60 mmol) in N,N-dimethylformamide (1 mL) was added N-chlorosuccinimide (80 mg, 0.60 mmol). The mixture was heated at 50° C. for 2 hours and purified by reversed phase HPLC (0.1% trifluoroacetic acid(aq):acetonitrile) to afford the title compound with a shorter retention time than that of Example 392A.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH3:11].[CH3:12][O:13]C(Cl)Cl.Cl>ClCCl>[Br:5][C:6]1[S:7][C:8]([CH:12]=[O:13])=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1ccsc1Br
Reactant: COC(Cl)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C=O)sc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Aluminum chloride (14.6 g) was added portionwise to 2-bromo-3-methylthiophene (8.85 g) and dichloromethyl methyl ether (6.27 g) in dichloromethane (100 ml) under ice-cooling. The mixture was stirred at room temperature for 1 hour and poured into ice water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-bromo-4-methyl-2-thiophenecarbaldehyde (8.0 g). 5-Bromo-4-methyl-2-thiophenecarbaldehyde (6.18 g) was dissolved in acetonitrile (100 ml), and sodium dihydrogen phosphate (1.3 g) in water (20 ml) and 30% aqueous hydrogen peroxide (3.8 ml) were added. Further sodium chlorite (4.07 g) in water (50 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours, alkalified with 1N aqueous sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-bromo-4-methyl-2-thiophenecarboxylic acid (6.01 g) as crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=O)=[C:4]2[N:3]=1.[NH:17]1[CH2:23][C:21](=[O:22])[NH:20][C:18]1=[O:19].N1CCCCC1>C(O)C>[NH2:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:10][CH2:11]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[C:23]3[NH:17][C:18](=[O:19])[NH:20][C:21]3=[O:22])=[C:4]2[N:3]=1
Reactant: Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Nc1cc(NC2CC2)n2ncc(C=C3NC(=O)NC3=O)c2n1
Temperature: 80 °C
Yield: 44 %

Procedure:
To 5-amino-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (75 mg, 0.34 mmol) in 1.0 mL ethanol was added hydantoin (34 mg, 0.34 mmol) and piperidine (33 ul). The reaction was heated at 80° C. overnight. The reaction mixture was cooled to room temperature and yellow precipitate was filtered, washed with ethanol to yield 45 mg (44% yield) Z)-5-((5-amino-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=300)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:31][CH3:32])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]3S[CH:28]=[CH:29][N:30]=3)[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16].Br[C:34]1[CH:39]=CC=CN=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:31][CH3:32])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]3[CH:39]=[CH:34][CH:28]=[CH:29][N:30]=3)[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: Brc1ccccn1
Reactant: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CN(c2ccccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine but substituting 2-bromo pyridine provided the title compound as an amporphous solid: 1 H NMR (400 MHz, CDCl3) δ) 8.20, 7.50, 7.32, 7.28, 6.69, 6.53, 5.33, 4.92, 4.28, 4.05, 3.92–3.78, 3.58, 3.42, 2.73, 2.50, 1.33–1.25,1.16; HRMS (ESI) calcd for C25H29N5OCl2+H1 486.1827. found 486.1827.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)[N:12]=[N:11][C:10]=1[C:25]([NH:27][CH:28]1[CH2:30][CH2:29]1)=[O:26])(=O)=O.[C-:31]#[N:32].[K+]>CS(C)=O>[C:31]([CH2:6][CH2:7][CH2:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)[N:12]=[N:11][C:10]=1[C:25]([NH:27][CH:28]1[CH2:30][CH2:29]1)=[O:26])#[N:32]
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCOS(C)(=O)=O)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCC#N)cc1
Temperature: 0 °C
Yield: 84.1 %

Procedure:
A solution of (4-[(cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)propyl methanesulfonate (1.31 g, 3 mmol) obtained in Example 1201a) and potassium cyanide (235 mg, 3.6 mmol, 1.2 eq.) in DMSO (10 ml) was stirred for 15 hr, ice water (20 ml) was added, and the precipitated crystals were collected by filtration and dried to give the title compound as a colorless powder (925 mg, 84%).
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].C([O-])(=O)C.[Na+].O>C1C=CC=CC=1.CCCCCC.CCOCC>[C:13]([O:1][CH2:2][C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([CH:9]=[O:10])=[CH:11][CH:12]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccc(C#CCO)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CCCCCC
Product: CC(=O)OCC#Cc1ccc(C=O)cc1

Procedure:
To 4-(3-hydroxyprop-1-ynyl)benzaldehyde (500 mg.) in dry benzene (20 ml.) was added acetic anhydride (326 mg.) and anhydrous sodium acetate (112 mg.). The mixture was heated at reflux for 4 hours. After cooling, water (50 ml.) was added followed by ether (50 ml.). The organic layer was separated and washed with sodium carbonate solution (2×50 ml.), washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The product was isolated by column chromatography on silica eluting with ether:hexane; 1:1. Nuclear Magnetic Resonance (NMR) was as follows; 2.2, 3H, s; 5.0, 2H, s; 7.5, 4H, dd; 10.0, 1H, s.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][N:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=O)[CH:6]=[CH:7][CH:8]=1.[BH4-].[Na+]>O=P(Cl)(Cl)Cl.C(Cl)Cl>[CH:14]1([CH:12]2[C:6]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:9][CH2:10][N:11]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cccc(CCN(C(=O)C2CCCCC2)c2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)CCN(c1ccccc1)C2C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A stirred solution of cyclohexanecarboxylic acid [2-(3-methoxy-phenyl)-ethyl]-phenyl-amide in POCl3 under an atmosphere of N2 was heated at reflux for 14 hours. The solution was allowed to cool to rt and concentrated in vacuo. The residue was taken up in CH2Cl2 (30 ml) and washed with sat. NaHCO3 until CO2 evolution ceased. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (20 ml), cooled to 0° C., and NaBH4 (0.105 g, 2.77 mmol) was added in a portionwise manner. The reaction was stirred for 2 hours at 0° C., then additional NaBH4 (0.105 g, 2.77 mmol) was added. The reaction was stirred at rt overnight, diluted with CH2Cl2 (50 ml), and washed with sat. NaHCO3 solution (1×50 ml). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo, to give the desired compound as a yellow oil (0.234 g, 0.729 mmol, 73% yield).
Reaction SMILES: [C:1]1([N:7]([C:65]2[C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[CH:68]=[CH:67][CH:66]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]([C:30]5[CH:35]=[CH:34][C:33]([C:36]6[CH:41]=[CH:40][C:39]([C:42]7[CH:47]=[CH:46][C:45]([N:48]([C:55]8[C:64]9[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=9)[CH:58]=[CH:57][CH:56]=8)[C:49]8[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=8)=[CH:44][CH:43]=7)=[CH:38][CH:37]=6)=[CH:32][CH:31]=5)C(=O)C)=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(C1C=CC=CC=1CC)C.O>CCCCCC>[C:1]1([N:7]([C:65]2[C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[CH:68]=[CH:67][CH:66]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:21]=[CH:22][C:23]([NH:26][C:30]5[CH:31]=[CH:32][C:33]([C:36]6[CH:41]=[CH:40][C:39]([C:42]7[CH:47]=[CH:46][C:45]([N:48]([C:55]8[C:64]9[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=9)[CH:58]=[CH:57][CH:56]=8)[C:49]8[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=8)=[CH:44][CH:43]=7)=[CH:38][CH:37]=6)=[CH:34][CH:35]=5)=[CH:24][CH:25]=4)=[CH:18][CH:19]=3)=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)N(c1ccc(-c2ccc(-c3ccc(N(c4ccccc4)c4cccc5ccccc45)cc3)cc2)cc1)c1ccc(-c2ccc(-c3ccc(N(c4ccccc4)c4cccc5ccccc45)cc3)cc2)cc1
Agent: CCc1ccccc1CC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Product: c1ccc(N(c2ccc(-c3ccc(-c4ccc(Nc5ccc(-c6ccc(-c7ccc(N(c8ccccc8)c8cccc9ccccc89)cc7)cc6)cc5)cc4)cc3)cc2)c2cccc3ccccc23)cc1
Yield: 85.5 %

Procedure:
Charged were N,N-bis[4″-(N-phenyl-1-naphthylamino)-p-terphenyl-4-yl]acetamide 82.0 g, a 50% potassium hydroxide aqueous solution 39 g and diethylbenzene 100 ml, and the mixture was heated and refluxed for 3 days. After finishing the reaction, the mixture was left cooling down, and water 100 ml and hexane 500 ml were added thereto. The brown solid matter deposited was filtered off and dried under reduced pressure to obtain 67 g of N,N-bis[4″-(N-phenyl-1-naphthylamino)-p-terphenyl-4-yl]amine.
Reaction SMILES: [CH2:1]1[S:16][CH:5]([CH2:6][C@@H:7]([NH2:15])[C@H](C(O)=O)[C@@H](C)O)[S:4][CH2:3][CH2:2]1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[CH2:1]1[S:16][C:5]2([CH2:6][CH2:7][NH:15]2)[S:4][CH2:3][CH2:2]1
Reactant: C[C@@H](O)[C@@H](C(=O)O)[C@H](N)CC1SCCCS1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: C1CSC2(CCN2)SC1
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
A mixture of 3-amino-4-C-carboxy-2,3,4,6-tetradeoxy-D-arabino-hexose trimethylene dithioacetal (810 mg, 3.05 mmol) in acetonitrile (15 ml) is treated with N,N'-dicyclohexylcarbodiimide (689 mg, 3.34 mmol). The resulting mixture is kept at room temperature for 10 minutes and then heated at 60° for 5 hours. The reaction mixture is concentrated, the residue is slurried in ethyl acetate, and the precipitated urea is removed by filtration. The filtrate is washed successively with N aqueous hydrochloric acid, saturated aqueous sodium hydrogen-carbonate, water, dried (magnesium sulfate), and evaporated under vacuum to yield 385 mg (51%) of the desired 2-azetidinone trimethylene dithioacetal.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:21])[C:11]=1B1OC(C)(C)C(C)(C)O1)[C:5]([O:7][CH3:8])=[O:6].Br[C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[N:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].O1CCOCC1>[CH3:30][O:29][C:26]1[N:27]=[CH:28][C:23]([C:11]2[C:10]([CH3:21])=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[CH3:1])=[CH:24][CH:25]=1
Reactant: COC(=O)c1cc(C)c(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1COCCO1
Product: COC(=O)c1cc(C)c(-c2ccc(OC)nc2)c(C)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Methyl 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (Step A, 2.79 g, 7.20 mmol), 1,1′-bis(di-tert-butylphoshino)ferrocene palladium dichloride (0.391 g, 0.600 mmol) and 5-bromo-2-methoxypyridine (0.776 mL, 6 mmol) were mixed in a reaction flask which was then evacuated and charged with nitrogen three times. Added 1,4-dioxane (30.0 mL) and 3.0M aqueous potassium carbonate (6.00 mL, 18.00 mmol), evacuated and charged with nitrogen (3×), then stirred overnight at 80° C. The reaction was then partitioned between ethyl acetate and water. After a second water wash, the organic was dried over sodium sulfate, filtered and evaporated. The crude was purified by silica gel chromatography, eluting with 10 column volumes of 4% ethyl acetate/hexanes followed by a gradient of 4-10% ethyl acetate/hexanes over 10 column volumes to give the title compound. 1H NMR (CDCl3, 500 MHz) δ7.94 (d, 1H), 67.79 (s, 2H), 67.36 (dd, 1H), 66.84 (d, 1H), 64.00 (s, 3H), 63.93 (s, 3H), 62.09 (s, 6H).
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][OH:19])[O:15][C:14]3=[O:20])=[CH:9][C:8]=2[F:21])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[S:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][O:19][S:30]([CH3:29])(=[O:32])=[O:31])[O:15][C:14]3=[O:20])=[CH:9][C:8]=2[F:21])[CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1O[C@@H](CO)CN1c1ccc(C2=CCSCC2)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(C3=CCSCC3)c(F)c2)C(=O)O1
Temperature: -20 °C

Procedure:
(5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one (14 g, 45.3 mmol) was dissolved in dichloromethane (300 ml) and triethylamine (8.8 ml, 63.3 mmol) was added. It was cooled to −20° C. and methanesulfonyl chloride (4.22 ml, 54.4 mmol), dissolved in dichloromethane (50 ml), was added dropwise. The reaction mixture was allowed to warm to room temperature and was quenched with potassium phosphate buffer (pH 7). Dichloromethane was removed under vacuum and it was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The title compound (16.9 g) was precipitated from dichloromethane by addition of hexane.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[Cl:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:17])[C:15]=1Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:17][C:14]1[CH:13]=[N:12][CH:11]=[C:10]([Cl:9])[C:15]=1[N:6]1[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]1
Reactant: CCN1CCNCC1
Reactant: Clc1cncc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCN1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 66.9 %

Procedure:
General procedure C was followed using N-ethylpiperazine (31 mg, 0.27 mmol), 3,4,5-trichloropyridine (50 mg, 0.27 mmol), triethylamine (0.76 μL, 0.54 mmol) and NMP (1.5 mL). The crude product was purified by flash column chromatography on silica gel (hexane/EtOAc, 1:1) to furnish the title compound as a colourless oil (47 mg, 66%), umax (CHCl3)/cm−1 2975, 2820, 1559, 1448, 1245, 1151, 957; m/z (ESI) C11H16Cl2N3 requires 260.0716, found [M+H]+ 260.0719.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[C:8](Cl)(=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>ClCCl.C(N(CC)CC)C>[OH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:8](=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: NCCOCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)NCCOCCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
To a cooled solution of 11 g of 2-(2-aminoethoxy)-ethanol in 75 ml of dichloromethane and excess triethylamine was added dropwise 13 g of dodecanoyl chloride in 25 ml of dichloromethane. After stirring at room temperature for 3 hours the reaction mixture was concentrated and then diluted with 100 ml of ethyl acetate and 100 ml of water. The organic layer was washed with 2×50 ml of water and brine, dried, filtered and concentrated to give 13.7 g of crude product. Recrystallization from ethyl acetate/hexane gave 11.2 g of product, m.p. 62°-64° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:9]=[CH:10][NH:11][C:4]=12.[Cl:12][CH2:13][CH2:14][C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)O>C(Cl)(Cl)Cl>[Cl:12][CH2:13][CH2:14][C@H:15]([N:11]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:9]=[CH:10]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O[C@H](CCCl)c1ccccc1
Reactant: COc1ccnc2cc[nH]c12
Solvent: ClC(Cl)Cl
Product: COc1ccnc2ccn([C@@H](CCCl)c3ccccc3)c12
Yield: 33 %

Procedure:
1-(3-Chloro-1-(S)-phenyl-propyl)-7-methoxy-1H-pyrrolo[3,2-b]pyridine 79 was prepared from 7-methoxy-1H-pyrrolo[3,2-b]pyridine and 3-chloro-1-(R)-phenyl-propan-1-ol following the procedure of steps 1 and 2 of Example 11 (33% yield, 170 mg, [αD=−149° (CHCl3, c=1)])
Reaction SMILES: C([O-])(O)=O.[Na+].[ClH:6].[CH:7]([N:20]1[CH2:23][C:22]([CH:25]2[CH2:27][CH2:26]2)(O)[CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.COCCN(S(F)(F)[F:38])CCOC>C(OCC)(=O)C>[ClH:6].[CH:7]([N:20]1[CH2:23][C:22]([CH:25]2[CH2:27][CH2:26]2)([F:38])[CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OC1(C2CC2)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: FC1(C2CC2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Yield: 60.5 %

Procedure:
Saturated NaHCO3 (100 ml) was added to a suspension of 1-Benzhydryl-3-cyclopropylazetidin-3-ol hydrochloride (7.78 g, 24.50 mmol) in ethyl acetate (100 ml). The mixture was transferred to a separating funnel and shaken vigorously until all of the solid had dissolved. The organic layer was separated and the aqueous layer extracted further with ethyl acetate (50 ml). The combined organic extracts were dried (Na2SO4) and concentrated to an oil. The oil was dissolved in dichloromethane (100 ml) and cooled to −78° C. [bis(2-methoxyethyl)amino]sulfur trifluoride (5.98 g, 27.05 mmol, 5.0 ml) was added dropwise and the solution stirred for 30 mins at −78° C. and then warmed to 0° C. and stirred for a further 1 hr. Reaction was quenched with Saturated NaHCO3 (50 ml) and brine (50 ml) and the aqueous layer extracted with dichloromethane (50 ml). The combined organic extracts were dried (Na2SO4) and concentrated to give a yellow oil. The crude was purified on silica gel, eluting with 5% ethyl acetate/petrol. The resulting alcohol was dissolved in ether (100 ml) and the solution cooled to 0° C. A solution of HCl in ether (2M, 25 ml) was then added dropwise over 5 minutes. The HCl salt precipitated from solution. The resulting slurry was stirred at 0° C. for an additional 10 minutes then filtered. The filter cake was washed with ether (20 ml) and the solid dried under vacuum. This furnished the product as a white solid (4.71 g, 61%). 1H NMR d4-MeOH δ 0.30-0.52 (4H, m), 1.22 (1H, brs), 4.01-4.23 (4H, m), 5.50-5.60 (1H, brs), 7.13-7.46 (10H, m); ES+ 282.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[N:15][CH:16]=2)[C:11]1=[O:20]>C(#N)C>[Cl:1][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[N:15][CH:16]=2)[C:11](=[O:20])[N:10]([CH3:9])[CH:19]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1ccc2cnccc2c1=O
Solvent: CC#N
Product: Cn1cc(Cl)c2cnccc2c1=O
Temperature: 65 °C
Yield: 49.7 %

Procedure:
N-chlorosuccinimide (0.8 g, 6.2 mmol) was added in portions to a solution of 2-methyl-2,6-naphthyridin-1-one (1.0 g, 6.2 mmol) in acetonitrile (25 mL) which was then heated at 65° C. for 18 h. Extractive work up with ethyl acetate and purification by silica gel chromatography (PE: EA=5:1-1:1) gave the title compound of step 1 (0.6 g, 56%) as a yellow solid. 1H NMR: (CDCl3, 400 MHz) δ 9.29 (s, 1H), 8.81 (d, J=3.6 Hz, 1H), 8.21 (d, J=5.2 Hz, 1H), 7.31 (s, 1H), 3.63 (s, 3H). LCMS: 195.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.CC([O-])(C)C.[Na+]>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:2]1([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: c1ccc(C2CCNCC2)cc1
Reaction time: 5 h
Yield: 10.5 %

Procedure:
The general procedure from Example 1 was followed using chlorobenzene (135 mg, 1.2 mmol) and piperidine (86 mg, 1.0 mmol) with Pd2(dba)3 (20 mg, 0.0218 mmol) and (Me2CH)PH(O)(Ph) from Experiment 1, (7.1 mg, 0.0424 mmol) and NaOtBu (144 mg, 1.5 mmol) in 2.0 mL of 1,2-dimethoxyethane. After 5 h, the reaction mixture was chromatographed with 5% ethyl acetate/hexane to give 17 mg (11% yield) of 4-phenylpiperidine. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDCl3): δ 7.15 (m, 2H), 6.84 (m, 2H), 6.72 (m, 1H), 3.06 (t, J=5.48 Hz, 4H), 1.61 (m, 4H), 1.48 (m, 2H) ppm. 13C NMR (125 MHz, CDCl3): δ 152.3, 129.0, 119.2, 116.5, 50.7, 25.9, 24.4 3 ppm. MS: Calculated for C11H15N(M+): 161.3. Found: 162.3 (M++H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH2:27][CH2:28][NH2:29])=[CH:22][CH:21]=1)([O-:19])=[O:18]>COCCOCCOC>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:29][CH2:28][CH2:27][NH:26][C:23]2[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:25][CH:24]=2)[CH:3]=1
Reactant: Cc1cc(C)nc(OS(=O)(=O)C(F)(F)F)c1
Reactant: NCCNc1ccc([N+](=O)[O-])cc1
Solvent: COCCOCCOC
Product: Cc1cc(C)nc(NCCNc2ccc([N+](=O)[O-])cc2)c1
Temperature: 165 °C
Yield: 56.5 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 4,6-dimethyl-pyridin-2-yl ester (0.6 g, 2.35 mmol) in diglyme (2 mL) was added N*1*-(4-nitro-phenyl)-ethane-1,2-diamine (0.51 g, 2.82 mmol). The reaction mixture was heated to 165° C. for 24 h. The resulting reaction mixture was concentrated under reduced pressure and the residue diluted with chloroform. The organic layer was washed with brine and water and dried over sodium sulfate. The solvent was evaporated and the crude residue was purified by column chromatography (60-120 mesh) using 20% ethyl acetate/petroleum ether as eluent to afford N-(4,6-dimethyl-pyridin-2-yl)-N′-(4-nitro-phenyl)-ethane-1,2-diamine (0.38 g, 55%) as a cream solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8][N:7]=1.[O:19]1[CH2:24][O:23][CH2:22][O:21][CH2:20]1.FC(F)(F)C(O)=O.C(OO)(C)(C)C>C(#N)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:20]2[O:21][CH2:22][O:23][CH2:24][O:19]2)=[N:8][N:7]=1
Reactant: C1OCOCO1
Reactant: Cc1cccc(Nc2nncc3ccccc23)c1
Agent: CC(C)(C)OO
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1cccc(Nc2nnc(C3OCOCO3)c3ccccc23)c1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
To a suspension of 9.6 g (40.8 mmol) 1-(3-methylanilino)phthalazine and 173 g 1,3,5-trioxane in 570 ml acetonitrile, 3.12 ml (40.8 mmol) trifluoroacetic acid, 11.0 ml (80% in tBuOOtBu; 87.4 mmol) tBuOOH and 190 mg (0.68 mmol) FeSO4·7 H2O are added, and the mixture stirred for 17 h at 80° C. The cooled reaction mixture is partly evaporated in the RE, diluted with EtOAc and water and adjusted to an alkaline pH with 1 N NaOH. The aqueous phase is separated off and twice extracted with EtOAc. The organic phases are washed twice with water and brine, dried (Na2SO4) and evaporated. Column chromatography (SiO2; EtOAc/toluene 1:3; applied as solution in dichloromethane/acetone 9:1) yields the title compound after crystallization with the addition of DIPE; m.p. 161° C.; DC (EtOAc/toluene 1:3) Rf=0.27; 1H-NMR (DMSO-d6) 9.27 (s, HN), 8.74 (m, 1H), 8.61 (m, 1H), 8.00 (m, 2H), 7.72 (s, 1H), 7.68 (d, 1H), 7.25 (t, 1H), 6.89 (d, 1H), 6.39 (s, 1H), 5.47 (d, 2H), 5.41 (d, 2H), 2.33 (s, 3H); FAB-MS (M+H)+=324; anal. calc.(C18H17N3O3) C, 66.86%; H, 5.30%; N, 13.00%; meas. C, 66.83%; H, 5.36%; N, 12.81%.