Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5](=[O:21])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C=C.CC1C2C(=CC=CC=2)C(C)=C2C=1C=CC1C2=CC=CC=1.[C:42]([NH:45][CH:46]([CH:61]([CH3:63])[CH3:62])[C:47]([CH:49]1[N:53]=[C:52]([C:54]([CH3:57])([CH3:56])[CH3:55])[S:51][N:50]1C(O)=O)=[O:48])(=[O:44])[CH3:43].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(Cl)Cl.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>[CH2:14]([O:13][CH:8]1[CH:7]([NH:6][C:5]([N:50]2[CH:49]([C:47](=[O:48])[CH:46]([NH:45][C:42](=[O:44])[CH3:43])[CH:61]([CH3:63])[CH3:62])[N:53]=[C:52]([C:54]([CH3:56])([CH3:55])[CH3:57])[S:51]2)=[O:21])[CH2:11][C:10](=[O:12])[O:9]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCc1ccccc1
Reactant: CC(=O)NC(C(=O)C1N=C(C(C)(C)C)SN1C(=O)O)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1c2ccccc2c(C)c2c1ccc1ccccc12
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(=O)NC(C(=O)C1N=C(C(C)(C)C)SN1C(=O)NC1CC(=O)OC1OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a solution of (2-benzyloxy-5-oxo-tetrahydrofuran-3-yl)-carbamic acid allyl ester (40) (0.385 g, 1.32 mmol) in DMF (2 ml) and CH2Cl2 (2 ml) was added DMBA (0.456 g, 2.92 mmol) and Pd(PPh3)4 (0.136 g, 0.12 mmol) and the solution was stirred at room temperature for 15 min. A solution of (39) in CH2Cl2 (4.5 ml) and DMF (0.5 ml) was added, followed by HOBT (0.168 g, 1.24 mmol) and EDC (0.256 g, 1.33 mmol). The reaction was stirred at room temperature for 18 hours under N2. The solvent was evaporated. The crude material was dissolved in EtOAc and washed with 0.5N NaHSO4 (2×), saturated NaHCO3 (2×) and brine and was dried over anhydrous Na2SO4, filtered and evaporated to give a yellow solid. Purification by flash column chromatography gave the title compound (41) as a mixture of diastereomers (374 mg, 88% yield). 1H-NMR (500 MHz, CDCl3) δ 0.75-1.05 (m, 6H), 1.19-1.34 (m, 9H), 1.93-2.08 (m, 3H), 2.19-2.50 (m, 2H), 2.80-3.03 (m, 1H), 4.56-4.93 (m, 3H), 5.02-5.20 (m, 1H), 5.46-5.56 (m, 1H), 5.95-6.16 (m, 2H), 6.86-6.95 (m, 1H), 7.20-7.43 (m, 5H). Analytical HPLC (C18 column), (mixture of diastereomers) 8.58 min. LC-MS (ES+) m/e=519.2 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([S:10]([C:13]2[S:17][C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25]#[C:26][CH2:27][O:28][CH3:29])[N:22]=[C:21]([CH3:30])[N:20]=3)=[N:15][CH:14]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)[CH3:2]>C1COCC1.CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([S:10]([C:13]2[S:17][C:16]([NH:18][C:19]3[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[N:22]=[C:21]([CH3:30])[N:20]=3)=[N:15][CH:14]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(S(=O)(=O)c2cnc(Nc3cc(C#CCOC)nc(C)n3)s2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1cccc(S(=O)(=O)c2cnc(Nc3cc(CCCOC)nc(C)n3)s2)c1
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
A mixture of [5-(3-Ethoxy-benzenesulfonyl)-thiazol-2-yl]-[6-(3-methoxy-prop-1-ynyl)-2-methyl-pyrimidin-4-yl]-amine (32.0 mg, 0.072 mol) and Pd—C (10%, 2.0 mg) in THF (1.00 mL) and EtOAc (1.00 mL) was stirred under H2 (70 psi, Parr) for 30 min. The reaction mixture was filtered through Celite using EtOAc (ca. 50 mL). The filtrate concentrated under reduced pressure to give the title compound (30 mg, 93%) as an off-white solid. LCMS (m/z): 449 (M+H)+
Reaction SMILES: [CH:1]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:17]1[CH:18]=[C:19]([C:23]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:26]=[C:25]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:24]=2)[CH:20]=[CH:21][CH:22]=1.N1C=CC=CC=1C(=O)CC(C1C=CC=CN=1)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.[Cu](I)I>[C:35]1([C:25]2[N:24]=[C:23]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:17][CH:18]=3)[N:28]=[C:27]([C:29]3[CH:34]=[C:33]([N:6]4[C:7](=[O:15])[C:8]5[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=5)[C:14]5[CH:1]=[CH:2][CH:3]=[CH:4][C:5]4=5)[CH:32]=[CH:31][CH:30]=3)[N:26]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Brc1cccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c1
Reactant: O=c1[nH]c2ccccc2c2ccccc12
Agent: I[Cu]I
Agent: O=C(CC(=O)c1ccccn1)c1ccccn1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2ccccc2c2ccccc2n1-c1cccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c1

Procedure:
20 g (102 4 mmol) of 5H-phenanthridin-6-one, 43 g (112 mmol) of 2-(3-bromophenyl)-4,6-diphenyl-1,3,5-triazine, 2.3 g (10 2 mmol) of 1,3-bis[2-pyridyl]-1,3-propanedione, 28.3 g (204 mmol) of potassium carbonate and 1.9 g (10.2) of copper iodide are stirred under reflux in 1000 ml of DMF for 90 h. The solution is diluted with water and extracted twice with ethyl acetate, the combined organic phases are dried over Na2SO4, evaporated in a rotary evaporator and purified by chromatography (EtOAc/hexane: 2/3). The residue is recrystallised from toluene and from dichloromethane and finally sublimed in a high vacuum, purity is 99.9%. The yield is 31 g (62 mmol), corresponding to 61% of theory.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]1[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(C2C=CC=CC=2)[CH2:18]C[CH2:16][C:11]21OCCO2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.S(=O)(=O)(O)O.[OH-].[Na+].[CH2:41]([OH:43])[CH3:42]>>[CH2:1]([N:8]1[CH2:16][CH:11]2[CH:10]([C:19]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:18][CH2:42][C:41]2=[O:43])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: c1ccc(CNCC2C3(CCCC2(c2ccccc2)c2ccccc2)OCCO3)cc1
Agent: C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC12
Reaction time: 48 h

Procedure:
A solution of (RS)-6-benzylaminomethyl-7,7-diphenyl-1,4-dioxaspiro[4.5]decane (0.41 g) in ethanol (0.4 cc) is added to a solution, brought to reflux, of paraformaldehyde (0.14 g) in 2% strength aqueous sulphuric acid solution (20 cc), and heating to reflux is continued for 48 hours. The reaction mixture is cooled to +25° C., alkalinized with 4N aqueous sodium hydroxide solution (5 cc) and extracted with ethyl acetate (4×40 cc) and the organic phases are combined, washed with distilled water (100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel with a slight excess pressure of nitrogen (0.04-0.063 mm, diameter 2 cm, height 15 cm), eluting with a mixture of cyclohexane and ethyl acetate (60:40 by volume) and collecting 20-cc fractions. Fractions 4 and 5 are combined and concentrated to dryness under reduced pressure (2.7 kPa). (3aRS,7aRS)-2-Benzyl-7,7-diphenylperhydro-4-isoindolone (0.23 g) is obtained in the form of white crystals, m.p. 132° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[H-].[Na+].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15]>CN(C=O)C.C(OCC)(=O)C>[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:7]2[C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=3[N:4]=[C:3]2[CH2:2][OH:1])=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: OCc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Cn2c(CO)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.1 %

Procedure:
To a solution of 3 g of 2-hydroxymethylbenzimidazole in 20 mL of dried DMF at 0° was added portionwise 1 g of NaH (50% oil dispersion). After stirring at room temperature for 15 minutes, 4.3 g of p-nitrobenzyl bromide was added. The reaction mixture was stirred for 16 hours and then diluted with ethyl acetate and washed with water. The organic layers were dried and evaporated. Recrystallization from acetonitrile afforded 3.5 g of a brownish solid; m.p. 162.5-165°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([OH:17])=O)[CH2:10]1)=[O:8].S(Cl)([Cl:20])=O>ClCCl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([Cl:20])=[O:17])[CH2:10]1)=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCCN(C(=O)Cc2cccs2)C1
Solvent: ClCCl
Product: O=C(Cl)C1CCCN(C(=O)Cc2cccs2)C1
Temperature: 25 °C

Procedure:
1-(2-thiopheneacetyl)-3-piperidine carboxylic acid (1.3 g; 5.1 mmol) was dissolved in dry dichloromethane (35 ml) under a nitrogen atmosphere. Thionyl chloride (3 ml. 41.3 mmol) was added and the mixture was heated to reflux for approximately 1 hour. It was then cooled to ambient temperature and evaporated under reduced pressure, giving 1-(2-thiopheneacetyl)-3-piperidinecarbonyl chloride as a brownish oil. MS m/z (positive ion; run in CH3CN) 274 ([M+2]H+; 50), 272 (MH+; 100).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[N:11][CH:12]=1.[N+:17]([C:20]1[C:21]([CH:30]=[O:31])=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[CH:27][CH:26]=[CH:25]2)([O-:19])=[O:18]>C1COCC1>[N+:17]([C:20]1[C:21]([CH:30]([C:7]2[CH:12]=[N:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[OH:31])=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[CH:27][CH:26]=[CH:25]2)([O-:19])=[O:18]
Reactant: O=Cc1ccc2cccnc2c1[N+](=O)[O-]
Reactant: FC(F)(F)c1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(C(O)c2ccc(C(F)(F)F)nc2)ccc2cccnc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 22.7 %

Procedure:
n-BuLi (1.6M in hexane; 2.77 ml, 4.43 mmol) was added dropwise to a solution of 5-bromo-2-(trifluoromethyl)pyridine (1 g, 4.42 mmol) in THF (5 ml) at −78° C. The mixture was stirred at −78° C. for 30 min before 8-nitroquinoline-7-carbaldehyde (Intermediate 204) (0.89 g, 4.42 mmol) in THF (10 ml) was added and the mixture was stirred at −78° C. for 10 min. The mixture was quenched with sat. NH4Cl (5 ml) at −78° C. and allowed to warm to room temperature. The resulting mixture was extracted with EtOAc (50 ml, ×2), the organic phase was washed with brine (20 ml), dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with heptane/EtOAc (50:50) as the eluent to give the title compound (350 mg, 23%).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]2([CH3:21])[CH:13]3[CH:9]2[CH2:10][N:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:12]3=[O:14])[CH:5]=[CH:6][CH:7]=1.N([O-])=[O:23].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>Cl.O>[CH2:15]([N:11]1[CH2:10][CH:9]2[CH:13]([C:8]2([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:23])[CH:3]=2)[CH3:21])[C:12]1=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
6-(3-Aminophenyl)-3-hexyl-6-methyl-3-azabicyclo[3.1.0]hexan-2-one (Preparation 84, 1.0 g, 3.5 mmol) was dissolved in aqueous hydrochloric acid (2.5 M, 3.5 ml) and cooled to 0° C. Sodium nitrite (0.25 g, 3.6 mmol) dissolved in water (1 ml) was added to the reaction mixture and stirred for 30 min. The reaction mixture was neutralised with solid sodium carbonate and then diluted with water (5 ml). The reaction mixture was heated to 60° C. for 1 h during which time a dark brown oil formed on top of the aqueous layer. The product was extracted with dichloromethane (50 ml), and the organic extracts were dried (Na2SO4) and concentrated in vacuo to give a brown oil. The crude product was purified by chromatography on silica gel (20 g) eluting with ethyl acetate:hexane (1:1) to give the title compound (0.34 g, 34%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH3:19]>CN(C)C=O>[CH2:18]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[OH:1])[CH3:19]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C=O)cc1O
Temperature: 0 °C
Reaction time: 48 h
Yield: 59.9 %

Procedure:
Commercially available 3,4-dihydroxy benzaldehyde (35.8 g, 259 mmol) and potassium carbonate (37.6 g, 272 mmol) were dissolved in N,N-dimethylformamide (150 mL), then commercially available iodoethane (22 mL, 275 mmol) was added under nitrogen atmosphere at 0° C., and then the mixture was stirred for 2 days. The solvent was evaporated under vacuum, the resultant was cooled to 0° C., and then 5 M hydrochloric acid, ethyl acetate, and water were added for partition. The aqueous layer was extracted with ethyl acetate, the combined organic layer was washed with water twice and then with a saturated saline solution, and the mixture was dried over anhydrous magnesium sulfate and then filtered. The solvent was evaporated, then dichloromethane was added, and then the precipitate was collected by filteration to obtain the title compound (25.8 g, 60%). The filtrate was purified with silica gel column chromatography (n-heptane:ethyl acetate=9:1-4:1-1:1). The target fraction was concentrated under vacuum, then diethyl ether and dichloromethane were added to the residue, and the precipitate was collected by filteration to obtain the title compound (3.45 g, 8.0%).
Reaction SMILES: C[O-:2].[Na+].[N+](C)([O-])=O.Br[CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([O:20][CH3:21])[CH:11]=1>CO>[CH:9]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([O:20][CH3:21])[CH:11]=1)=[O:2]
Reactant: C[O-]
Reactant: COC(=O)c1ccc(CBr)cc1OC
Agent: [Na+]
Solvent: C[N+](=O)[O-]
Solvent: CO
Product: COC(=O)c1ccc(C=O)cc1OC
Yield: 641 %

Procedure:
To a solution of sodium methoxide (0.260 g, 4.82 mmol) in methanol (200 mL) was added nitromethane (4.03 g, 11.58 mmol) under nitrogen atmosphere and the reaction mixture was stirred and reflux for 30 minutes. Methyl 4-(bromomethyl)-2-methoxybenzoate (10.00 g, 9.65 mmol) in methanol was added and the reaction mixture was refluxed for 7-8 h. The reaction mass was concentrated and diluted with CHCl3. The diluted reaction mass was washed with 2N NaOH solution. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 6.00 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.83 (m, 6H), 7.36 (d, J=6.6 Hz, 2H), 7.79 (d, J=7.8 Hz, 1H), 10.04 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.S(O[CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(=O)(=O)C.CN(C)P(N(C)C)(N(C)C)=O.O1CCCC1>O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][CH2:18][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NCCCc2ccc(Cl)cc2)cc1

Procedure:
A solution of 49.5 g. of ethyl 4-aminobenzoate, 34.9 g. of 3-(p-chlorophenyl)propanol O-mesylate in 100 ml. of hexamethylphosphoramide is heated at 125°-130° C. for 16 hours. The solution is diluted with 50 ml. of tetrahydrofuran and with 150 ml. of water. Chilling and filtering gives crystals which are washed with water and recrystallized from ethanol to give 28.3 g. of light yellow crystals. Recrystallizations give the product as crystals, m.p. 122°-124° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH:12]2[CH2:14][CH2:13]2)[C:3]=1[CH3:15].[CH3:16][C:17]1([CH3:32])[C:21]2=[N:22][CH:23]=[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:25]=[C:20]2[NH:19][CH2:18]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[CH:12]1([C:4]2[C:3]([CH3:15])=[C:2]([N:19]3[C:20]4[C:21](=[N:22][CH:23]=[C:24]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)[CH:25]=4)[C:17]([CH3:32])([CH3:16])[CH2:18]3)[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:14][CH2:13]1
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Reactant: Cc1c(C2CC2)nc2ncccc2c1Cl
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(C2CC2)nc2ncccc2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y using 4-chloro-2-cyclopropyl-3-methyl-1,8-naphthyridine (40 mg, 0.183 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (42.7 mg, 0.183 mmol), XPhos precatalyst (13.52 mg, 0.018 mmol) and sodium tert-butoxide (35.2 mg, 0.366 mmol) by heating in toluene (4 mL) for 2 hours at 110° C. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 2-cyclopropyl-4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-methyl-1,8-naphthyridine. 1H NMR (400 MHz, chloroform-d) δ ppm 8.98 (1H, dd, J=4.1, 2.0 Hz), 8.05 (1H, dd, J=8.2, 2.0 Hz), 7.59 (1H, d, J=2.3 Hz), 7.31 (1H, dd, J=8.3, 4.2 Hz), 5.69-5.74 (1H, m), 3.70-3.78 (6H, m), 2.90-3.03 (4H, m), 2.43-2.48 (3H, m), 2.30-2.40 (1H, m), 1.54-1.59 (4H, m), 1.45-1.53 (4H, m), 1.12-1.17 (2H, m). Mass Spectrum (ESI) m/e=416.2 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][CH:15]=1.C1C(=O)N([Br:24])C(=O)C1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:16])=[N:12][CH:13]=[C:14]([Br:24])[CH:15]=1
Reactant: Nc1ncccc1-c1nc2ccccc2s1
Reactant: O=C1CCC(=O)N1Br
Product: Nc1ncc(Br)cc1-c1nc2ccccc2s1

Procedure:
The title compound was prepared from 3-benzothiazol-2-ylpyridin-2-ylamine (22.7 g, 100 mmol) and NBS (17.8 g, 100 mmol) as a brown solid following the General Procedure for the Bromination of Aminopyridines with NBS. 1H NMR (CDCl3, 300 MHz): δ=7.17 (brs, 2H), 7.41 (t, J=6.9 Hz, 1H), 7.50 (t, J=6.9 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.95 (d, J=2.4 Hz, 1H), 8.03 (d, J=2.1 Hz, 1H), 8.20 (d, J=2.1 Hz, 1H). MS(ES+): m/z=305.98/307.94 (91/100) [MH+]. HPLC: tR=3.62 min (nonpolar—5 min, ZQ3).
Reaction SMILES: [Cl-].C([P+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.Cl[CH2:23][Si:24]([Cl:27])([Cl:26])[Cl:25].[Cl:28][SiH:29]([Cl:31])[Cl:30]>>[Cl:25][Si:24]([Cl:27])([Cl:26])[CH2:23][Si:29]([Cl:31])([Cl:30])[Cl:28]
Reactant: ClC[Si](Cl)(Cl)Cl
Reactant: Cl[SiH](Cl)Cl
Agent: CCCC[P+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Product: Cl[Si](Cl)(Cl)C[Si](Cl)(Cl)Cl
Yield: 59.7 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.22 g (0.67 mmol) of benzyltributylphosphonium chloride, 1.23 g (6.69 mmol) of (chloromethyl)trichlorosilane, and 2.71 g (20.0 mmol) of trichlorosilane were reacted at 160° C. for 15 hrs. The resulting mixture was distilled to give 1.13 g of 1,1,1,3,3,3-hexachloro-1,3-disilapropane (yield; 68%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[C:7]([OH:9])=[O:8])[CH3:2].C(O)C>[Pd].CN(C=O)C>[NH2:13][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOc1cc(C(=O)O)ccc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3-ethoxy-4-nitrobenzoic acid (Intermediate 165; 1.0 g, 4.74 mmol) ethanol:DMF (50 mL:5 mL) over 5% Pd/C catalyst (100 mg) was hydrogenated with stirring at ambient temperature for 4 hours. The mixture was filtered and the catalyst washed with ethanol and the solvent evaporated and the residue that on trituration with diethyl ether yielded the title compound as an off white solid (688 mg, 81%)
Reaction SMILES: Br[C:2]1[CH:20]=[N:19][C:5]2[NH:6][CH2:7][CH2:8][CH2:9][N:10](C(OC(C)(C)C)=O)[CH2:11][C:4]=2[CH:3]=1.[CH3:21][N:22]([CH2:27][C:28]1[O:29][C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[C:32]=1[CH3:33])[C:23](=[O:26])[CH:24]=[CH2:25].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH:6]1[CH2:7][CH2:8][CH2:9][NH:10][CH2:11][C:4]2[CH:3]=[C:2](/[CH:25]=[CH:24]/[C:23]([N:22]([CH3:21])[CH2:27][C:28]3[O:29][C:30]4[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=4[C:32]=3[CH3:33])=[O:26])[CH:20]=[N:19][C:5]1=2
Reactant: CC(C)(C)OC(=O)N1CCCNc2ncc(Br)cc2C1
Reactant: C=CC(=O)N(C)Cc1oc2ccccc2c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNCCCN3)oc2ccccc12
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A suspension of tert-butyl 8-bromo-1,2,3,4-tetrahydropyrido[2,3-b][1,5]diazocine-5(6H)-carboxylate (45 mg, 0.13 mmol), N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (90 mg, 0.39 mmol) and (i-Pr)2EtN (0.11 mL, 0.66 mmol) in 3.75 mL of DMF:propionitrile (4:1) was de-oxygenated with Ar for 30 min. The mixture was treated with Pd(OAc)2 (3.0 mg, 0.013 mmol) and P(o-tol)3 (8.0 mg, 0.926 mmol) then heated to 110° C. for 20 h. The hot mixture was filtered through a pad of celite and washed with ethyl acetate 2×20 mL. The filtrate was concentrated in vacuo to obtain crude brown oil product. The resulting crude product was subjected to prep HPLC purification to obtain pure product as an off-white solid. Yield 39 mg (60%); ESI MS m/z 491 [C28H34N4O4+H]+
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].O.[OH-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2cccnc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)NCCC2
Reaction time: 18 h
Yield: 45.5 %

Procedure:
A solution of 7-bromoquinoline (J. Amer. Chem. Soc., 1947, 69, 705) (362 mg, 1.74 mmol) in glacial acetic acid (10 ml) was treated portion-wise with sodium cyanoborohydride (437 mg, 7.0 mmol) under argon at room temperature. After 18 h at this temperature, the mixture was cooled in an ice bath and to it was added water (35 ml) and 50% aq. sodium hydroxide until pH 14 was attained. The mixture was extracted with dichloromethane and the organic phase washed with saturated sodium chloride solution, dried (Na2SO4) and concentrated in vacuo to a residue which was purified by column chromatography over silica gel eluting with a gradient of methanol/dichloromethane to give the title compound (D15) (168 mg, 46%). MH+ 212/214.