Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1(Br)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]>CC(C)=O>[Br-:1].[C:5]1([C:3](=[O:4])[CH2:2][N+:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:9][CH2:8][CH2:7][CH:6]=1
Reactant: O=C(CBr)C1(Br)CCCC1
Reactant: Cc1ccccn1
Solvent: CC(C)=O
Product: Cc1cccc[n+]1CC(=O)C1=CCCC1
Product: [Br-]
Yield: 117.6 %

Procedure:
2-Bromo-1-(1-bromo-cyclopentyl)-ethanone (3.7 g, 13.7 mmol) and α-picoline (1.02 g, 11.0 mmol) in acetone were heated at reflux overnight. The reaction mixture was allowed to cool then concentrated in vacuo. The crude mass was washed with 30% ethyl acetate/petroleum ether and diethyl ether. 1-(2-Cyclopent-1-enyl-2-oxo-ethyl)-2-methyl-pyridinium bromide salt (3.65 g, 94%) was obtained as a semi-solid material and taken for next step without purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:5][CH2:4][CH2:3][CH2:2][N:10]1[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]1
Reactant: CN1CCNCC1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1CCN(CCCO)CC1
Yield: 537.2 %

Procedure:
3-Bromopropan-1-ol (20 ml, 20 mmol) was added dropwise to a solution of 1-methylpiperazine (29 ml, 26 mmol) in ethanol (200 ml). Potasium carbonate (83 gr, 60 mmol) was added and the mixture was refluxed for 20 hours. After cooling, the solid was filtered and the filtrate was evaporated. The residue was triturated with ether, filtrate and evaporated. The residue was distilled at about 60-70° C. under about 0.2 mm Hg to give 1-(3-hydroxypropyl)-4-methylpiperazine (17 g, 53%).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.C(Br)C.N#N.[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1C#N.[NH4+].[Cl-]>O.C1COCC1>[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1
Reactant: CN1CCC(Cl)CC1
Reactant: N#Cc1ccccc1F
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCBr
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(c2ccccc2F)CC1
Temperature: 25 °C
Yield: 64.4 %

Procedure:
800 ml of THF solution of 4-chloro-N-methylpiperidine (245 g, 1.8 mol) is drop-added slowly to 250 ml of tetrahydrofuran wherein Mg powder (55.7 g, 2.3 mol) and small amount of ethyl bromide are added under coverage of N2. After completion of drop-addition, a reaction is carried out at reflux for one hour. The reaction solution is drop-added 440 ml of THF solution of 2-fluorobenzonitrile (222 g, 1.8 mol). After completion of drop-addition, a reaction is carried out at reflux for 3 hours and at room temperature for 13 hours; thereafter the reaction solution is poured into 2.3 L of water containing 700 g of NH4Cl and then reflux for 2 hours. The reaction solution is cooled and then is extracted with diethyl ether, and the extracting solutions are combined, evaporated to dryness and fractioned. The fractions at 124° C. are collected to obtain 224 g of a product.
Reaction SMILES: N1[CH:6]=[CH:5][C:4]2[C:7]([O:9][C:10](=[O:11])[C:3]=2[CH:2]=1)=O.[NH2:12][CH:13]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:14]1=[O:15].[CH2:21](N(CC)CC)C>>[C:10]([C:13]1([NH2:12])[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:14]1=[O:15])([O:9][CH2:7][C:4]1[CH:5]=[CH:6][CH:21]=[CH:2][CH:3]=1)=[O:11]
Reactant: NC1CCC(=O)NC1=O
Reactant: CCN(CC)CC
Reactant: O=C1OC(=O)c2cnccc21
Product: NC1(C(=O)OCc2ccccc2)CCC(=O)NC1=O
Yield: 17 %

Procedure:
With reference to Scheme 4 below, azathalidomide was prepared from aminoglutarimide and commercial pyridine-3,4-dicarboxylic anhydride. Cbz-aminoglutarimide was deprotected by hydrogenolysis with catalyst palladium hydroxide on carbon (10%) to form aminoglutarimide. Pyridine-3,4-dicarboxyic anhydride was refluxed with aminoglutarimide in the presence of triethylamine to yield azathalidomide 11 in the total yield of 17% from Cbz-aminoglutarimide.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][C@@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:26]=2[CH:27]=[CH:28][NH:29]3)O1>>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[C@@H:9]([O:8][C:5]1[N:4]=[CH:3][C:2]([C:25]3[CH:33]=[CH:32][CH:31]=[C:30]4[C:26]=3[CH:27]=[CH:28][NH:29]4)=[CH:7][N:6]=1)[CH2:10]2
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Brc1cnc(O[C@H]2CN3CCC2CC3)nc1
Product: c1cc(-c2cnc(O[C@H]3CN4CCC3CC4)nc2)c2cc[nH]c2c1

Procedure:
The product of Example 11A (170 mg, 0.6 mmol) was coupled with 4-(4,4,5,5-tetra-methyl-[1,3,2]dioxaborolan-2-yl)-1H-indole ((ref. WO02055517, 146 mg, 0.6 mmol) according to the procedure in Example 8A. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.10) as a solid (76 mg, yield, 40%). 1H NMR (300 MHz, CD3OD) δ 1.50–1.64 (m, 1H), 1.67–1.93 (m, 2H), 2.05–2.19 (m, 1H), 2.25–2.33 (m, 1H), 2.73–3.12 (m, 5H), 3.39–3.50 (m, 1H), 5.17–5.25 (m, 1H), 6.55 (dd, J=3.4, 1.0 Hz, 1H), 7.11 (dd, J=7.1, 1.0, Hz, 1H), 7.23 (t, J=8.1 Hz, 1H), 7.35 (d, J=3.1 Hz, 1H), 7.44–7.49 (m, 1H), 8.85 (s, 2H) ppm. MS (DCl/NH3): m/z 321 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:18]([F:21])([F:20])[F:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[CH3:23]C([N-]C(C)C)C.CI>C1COCC1>[Si:1]([O:8][CH:9]([C:18]([F:19])([F:21])[F:20])[CH2:10][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(CCc1ccccn1)C(F)(F)F
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(CC(O[Si](C)(C)C(C)(C)C)C(F)(F)F)c1ccccn1
Temperature: -75 °C
Reaction time: 0.75 h
Yield: 88.5 %

Procedure:
A solution of 810 mg (2.54 mmol) of 2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluorobutyl]pyridine in 8 mL of THF was treated with 2.54 mL (3.81 mmol, 1.5 eq.) of LDA (1.5 M solution in cyclohexane) at −75° C. After stirring at −75° C. for 45 minutes, 474 μL (7,61 mmol, 3.0 eq.) of methyl iodide was added at −75° C. The resulting mixture was stirred at this temperature for 10 minutes and quenched with saturated NH4Cl solution. The product was extracted into ether. The ethereal layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 750 mg (89%) of 2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluoro-1-methylbutyl]pyridine (a mixture of two diastereomers) as a brown oil.
Reaction SMILES: [Br-].C(OC([NH:9][C:10]([C:13]1[N:14]=[N:15][N:16]([CH2:18][CH2:19][N+:20]([CH3:23])([CH3:22])[CH3:21])[CH:17]=1)([CH3:12])[CH3:11])=O)(C)(C)C.[ClH:24]>CO.O1CCOCC1>[ClH:24].[NH2:9][C:10]([C:13]1[N:14]=[N:15][N:16]([CH2:18][CH2:19][N+:20]([CH3:22])([CH3:21])[CH3:23])[CH:17]=1)([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1cn(CC[N+](C)(C)C)nn1
Agent: Cl
Agent: [Br-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(N)c1cn(CC[N+](C)(C)C)nn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
2-(4-(2-(tert-Butoxycarbonylamino)propan-2-yl)-1H-1,2,3-triazol-1-yl)-N,N,N-trimethylethanaminium bromide (6.20 g, 15.8 mmol) was dissolved in methanol (15 ml). To the solution was added 4M hydrogen chloride in dioxane (150 ml), and the combined reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was concentrated and dissolved in water. Silver oxide (6.0 g) was added to the aqueous solution and the mixture was stirred at room temperature for 30 minutes. The solution was filtered through Celite®, and concentrated hydrochloric acid (2 ml) was added to the solution. The solution was filtered through Celite® a second time, and the aqueous solution was concentrated in vacuo. The crude material was purified by prep-HPLC (5-95% gradient of water/methanol with 0.05% acetic acid) to give 3.29 g (84%) 2-(4-(2-aminopropan-2-yl)-1H-1,2,3-triazol-1-yl)-N,N,N-trimethylethanaminium hydrochloride. 1H NMR (D2O) δ 8.27 (s, 1H), 5.07 (t, J=5.0 Hz, 2 H), 4.03 (t, J=5.1 Hz, 2 H), 3.21 (s, 9 H), 1.78 (s, 6 H); MS (ESI+) calculated for C10H22N5+: 212.19. Found: 212.2 (M+).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5]([Cl:14])=[N:6][C:7]2[N:8]([N:11]=[CH:12][CH:13]=2)[C:9]=1Cl.[CH:15]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>C(N(CC)CC)C>[Cl:14][C:5]1[C:4]2[CH2:3][CH2:2][N:20]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:9]=2[N:8]2[N:11]=[CH:12][CH:13]=[C:7]2[N:6]=1
Reactant: ClCCc1c(Cl)nc2ccnn2c1Cl
Reactant: NC1CCCC1
Solvent: CCN(CC)CC
Product: Clc1nc2ccnn2c2c1CCN2C1CCCC1
Yield: 187.6 %

Procedure:
Synthesis was performed by the reaction of 11.0 g of 6-(2-chloroethyl)-5,7-dichloropyrazolo[1,5-a]pyrimidine with 1.80 g of cyclopentylamine and 8.87 g of triethylamine in accordance with the synthetic process in Example 54 to obtain 10.42 g (yield: 90.4%) of the intended product. White crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]2[O:9][C:8]([C:10]#[N:11])=[CH:7][C:6]=2[CH:12]=1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:13][C:3]1[C:2]([F:1])=[CH:12][C:6]2[CH:7]=[C:8]([C:10]#[N:11])[O:9][C:5]=2[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2oc(C#N)cc2cc1F
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc2cc(F)c(CBr)cc2o1
Yield: 76.6 %

Procedure:
To the solution of 5-fluoro-6-methylbenzofuran-2-carbonitrile (1.44 g, 8.22 mmol) in 82 mL of CCl4 was added NBS (1.536 g, 8.63 mmol) and AlBN (0.067 g, 0.411 mmol). After the reaction mixture was refluxed overnight, the solvent was removed. The residue was purified by silica gel flash chromatography (100% heptane-7% ethyl acetate/heptane) to give 6-(bromomethyl)-5-fluorobenzofuran-2-carbonitrile (1.6 g). 1H NMR (400 MHz, DMSO-d6) δ 4.82 (d, J=1.1 Hz, 2H), 7.75 (d, J=9.5 Hz, 1H), 8.02 (d, J=5.9 Hz, 1H), 8.10 (d, J=0.86 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10]([Cl:22])=[N:11][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:13][C:14]=1[Cl:15].[CH3:23][CH:24]([NH2:27])[CH2:25][CH3:26]>>[Cl:15][C:14]1[CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:11]=[C:10]([NH:27][CH:24]([CH2:25][CH3:26])[CH3:23])[C:9]=1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1].[Cl:22][C:10]1[C:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[C:14]([NH:27][CH:24]([CH2:25][CH3:26])[CH3:23])[CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:11]=1
Reactant: CCC(C)N
Reactant: Fc1cccc(Cl)c1-c1c(Cl)cc(-c2ccccn2)nc1Cl
Product: CCC(C)Nc1cc(-c2ccccn2)nc(Cl)c1-c1c(F)cccc1Cl
Product: CCC(C)Nc1nc(-c2ccccn2)cc(Cl)c1-c1c(F)cccc1Cl

Procedure:
In a stainless steel autoclave, 2.0 g (5.7 mmol) of 3-(2-chloro-6-fluorophenyl)-2,4-dichloro-6-(pyridin-2-yl)pyridine (Example B) and 15 g of racemic 2-butylamine were heated at 180° C. for 12 h. The volatile components were removed under reduced pressure and the residue was chromatographed on silica gel using cyclohexane/ethyl acetate. It was possible to isolate 450 mg of 4-chloro-3-(2-chloro-6-fluorophenyl)-2-(2-butylamino)-6-(pyridin-2-yl)pyridine (1H-NMR (CDCl3) δ=0.90 (m); 1.20 (m); 1.55 (m); 3.80 (broad); 4.27 (m); 7.15-7.45 (m); 7.80 (t); 7.90 (s); 8.42 (d); 8.67 (m)) and 370 mg of 2-chloro-3-(2-chloro-6-fluorophenyl)-4-(2-butylamino)-6-(pyridin-2-yl)pyridine (1H-NMR (CDCl3) δ=0.90 (m); 1.20 (m); 1.50 (m); 3.67 (broad); 3.77 (m); 7.15-7.45 (m); 7.75 (s); 7.82 (t); 8.42 (d); 8.67 (m)). The compounds are present as rotamer mixtures.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[S:9][C:10]3[N:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)=[CH:5][CH:4]=1.[H-].[Li+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:7][C:6]1[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(N=c2sc3ncccc3c(=O)n2Cc2ccccc2)cc1

Procedure:
The reaction procedure of Example 11 was followed except that 428 mg of 2-(4-methoxyanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 14 mg of lithium hydride and 0.18 ml of benzyl bromide were used. As a result, 295 mg of 3-benzyl-2-[(4-methoxyphenyl)imino]-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a low polarity substance, and 174 mg of 2-[N-benzyl-N-(4-methoxyphenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a high polarity substance.
Reaction SMILES: [H-].C([Al+]C[CH:8]([CH3:10])C)C(C)C.C(C[C:17]1([OH:27])[CH2:26][CH2:25][CH:24]2[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:18]1)(OCC)=O.S(=O)(=O)(O)[OH:29]>C1C=CC=CC=1>[OH:29][CH2:8][CH2:10][CH:18]1[CH:19]2[CH:24]([CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:25][CH2:26][CH:17]1[OH:27]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)CC1(O)CCC2CCCCC2C1
Reactant: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: c1ccccc1
Product: OCCC1C(O)CCC2CCCCC21
Yield: 72 %

Procedure:
A solution of 235 g of diisobutyl aluminium hydride in 300 ml of anhydrous benzene is added dropwise to a mixture of 120 g of 2-carbethoxymethyl-2-hydroxy-decalin and 120 ml of anhydrous benzene under nitrogen. During the addition the temperature of the reaction mass is held between 15° and 20°C. This temperature is maintained for a further two hours after the end of the addition. The mass is then cooled to 0°C and hydrolysed with 1500 ml of a 10% aqueous solution of sulphuric acid. The temperature is allowed to return to ambient, the organic layer decanted and the mother liquor extracted twice with 250 ml of benzene. The benzene extracts are then combined and washed to neutrality. After distillation of the solvent on a water bath under reduced pressure the crude product is rectified giving 72 g of 2-hydroxy-ethyl-2-hydroxy-decalin (72% yield) having b.p.1 = 147°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2=[N:9][C:10]3[C:15]([C:14](=O)[NH:13][CH2:12][N:11]=3)=[C:5]2[CH:4]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:14]1[C:15]2[C:5]3[C:6](=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:9][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(c1)=C1C(=O)NCN=C1N=2
Product: COc1ccc2[nH]c3ncnc(Cl)c3c2c1
Temperature: 90 °C
Yield: 81 %

Procedure:
A suspension of 6-methoxy-3H-indolo[2,3-d]pyrimidine-4-one (800 mg, 3.08 mmol, ~83% pure) and POCl3 (7 mL) is heated at 90° C. for 6 h. The suspension is concentrated to a solid that is evacuated at 1 mm for 1 h. The solids are cooled in a -78° C. bath then treated dropwise with cold H2O. The bath is removed and the frozen solids are allowed to gradually melt. The solids are filtered, washed well with cold H2O, and dried to leave 4-chloro-6-methoxyindolo[2,3-d]pyrimidine (733 mg, 81%) that is about 80% pure. 1H NMR (DMSO): δ12.64 (1H, br s, exchanges with D2O), 8.74 (1H, s), 7.74 (1H, d, J=2.4 Hz), 7.57 (1H, d, J=8.9 Hz), 7.28 (1H, dd, J=8.9, 2.4 Hz), 3.88 (3H, s).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[CH2:5]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1.CCN(CC)CC>[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([CH2:2][C:3]#[N:4])[CH2:14][CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: N#CCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CCN1CCN(Cc2ccccc2)CC1
Reaction time: 10 h

Procedure:
An excess of chloroacetonitrile (7 ml) was added in to a solution of benzylpiperazine (2 g, 10.5 mmol) in THF (100 ml) and Et3N (10 ml). The reaction was stirred for 10 hours before quenched with saturated aqueous NaHCO3 (100 ml). The aqueous phase was extracted with EtOAc (3×100 ml). The combined organic layer was dried over MgSO4 and concentrated to a residue, which was used in the further reactions without any purification.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[H-].[Na+].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][OH:18].CN(C=O)C>C1(C)C=CC=CC=1.O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][O:18][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: OCc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(OCc2cccc(Cl)c2)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 142.1 %

Procedure:
6-chloronicotinic acid (1.0 g, 6.3 mmol)) was added portion-wise over 30 min to a stirred suspension of sodium hydride (60%, 0.76 g, 19 mmol) in toluene (10 mL. The mixture was stirred for 30 min then cooled to 0° C. A solution of 3-chloro-benzyl alcohol (0.69 g, 6.4 mmol) in toluene (5 mL) was added drop-wise over 10 min. The mixture was warmed to room temperature, DMF (20 mL) was added and the mixture was heated to 95° C. and stirred for 18 h. The mixture was cooled to room temperature then poured into water (30 mL). The aqueous mixture was acidified to pH 2 and extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with water and brine, then dried over sodium sulfate and concentrated in vacuo to give a yellow solid (2.36 g). The residue was re-crystallised [2-propanol-water, (2:1)] to give the product as a white solid (0.85 g, 51%), m.p. 158° C. (dec.). 1H-NMR (400 MHz, CDCl3): 8.93 (1H, d, J=2.5 Hz), 8.24 (1H, dd, J=2.5, 8.5 Hz), 7.46 (1H, s), 7.35–7.29 (3H, m), 6.87 (1H, dd, J=1, 8.5 Hz) and 5.45 (2H, s).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(N(CC)CC)C>O1CCCC1.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:10]([C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1)#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=Cc1cccc(Br)n1
Reactant: C#CCCCCCCCCCCCCCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCC#Cc1cccc(C=O)n1
Temperature: 25 °C
Yield: 53.1 %

Procedure:
A solution of 6-bromo-2-pyridinecarboxaldehyde (12.3 g), 1-hexadecyne (16.1 g), triethylamine (20.0 g), bis(triphenylphosphine)palladium(II)chloride (0.92 g), and. copper(I)iodide (0.13 g) in dry tetrahydrofuran (55 ml) was heated at 50° C. for 29 hrs, under nitrogen. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate. The filtrate was evaporated and the residue was taken up in ethyl acetate (100 ml). The mixture was washed with 1:1-water:saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. Theresidue was flash chromatographed on silica gel, eluting with 1% ethyl acetate:hexanes. The appropriate fractions were collected and evaporated. The residue was dissolved in ethyl acetate and the solution was washed with half-saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to give 11.5 g (53.5%) of product, mp 38.5-40° C.
Reaction SMILES: [Cl:1][C:2]1[C:33]([C:34]2([C:37]#[N:38])[CH2:36][CH2:35]2)=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[N:19]=[C:18]3[S:20][C:21]([NH:23][C:24]([CH:26]4[CH2:28][CH2:27]4)=[O:25])=[N:22][C:17]3=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:8]=1[F:29])=[O:5].[CH:39]1([C:42](Cl)=[O:43])[CH2:41][CH2:40]1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:33]([C:34]2([C:37]#[N:38])[CH2:36][CH2:35]2)=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([N:6]([C:42]([CH:39]1[CH2:41][CH2:40]1)=[O:43])[C:7]1[CH:12]=[C:11]([O:13][C:14]2[N:19]=[C:18]3[S:20][C:21]([NH:23][C:24]([CH:26]4[CH2:28][CH2:27]4)=[O:25])=[N:22][C:17]3=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:8]=1[F:29])=[O:5]
Reactant: O=C(Cl)C1CC1
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(NC(=O)C6CC6)sc5n4)ccc3F)c2Cl)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: N#CC1(c2cccc(C(=O)N(C(=O)C3CC3)c3cc(Oc4ccc5nc(NC(=O)C6CC6)sc5n4)ccc3F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.7 %

Procedure:
To a solution of 2-chloro-3-(1-cyanocyclopropyl)-N-[5-({2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-2-fluorophenyl]benzamide (3.5 g, 6.39 mmol) produced in Example C127(x) in pyridine (35 mL) were added N,N-dimethylpyridine-4-amine (3.87 g, 31.7 mmol) and cyclopropanecarbonyl chloride (3.0 mL, 33.1 mmol) at 10° C., and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was poured into ice water (70 mL), and the mixture was extracted with ethyl acetate (80 mL×3). The organic layers were combined, washed successively with water (50 mL) and saturated brine (30 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5→20/80). The obtained residue was recrystallized from ethyl acetate to give the title compound (2.47 g, 63%) as white crystals.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.O=P(Cl)(Cl)Cl.[CH3:16][O:17][CH2:18][CH2:19][O:20][C:21]1[C:34]2[C:25](=[CH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[CH:23][CH:22]=1.O>C(Cl)Cl>[CH3:16][O:17][CH2:18][CH2:19][O:20][C:21]1[C:34]2[C:25](=[CH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24]([CH:9]=[O:10])=[CH:23][CH:22]=1
Reactant: COCCOc1cccc2cc3ccccc3cc12
Reactant: CN(C=O)c1ccccc1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COCCOc1ccc(C=O)c2cc3ccccc3cc12
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To a 1 L 3-necked RB flask equipped with overhead stirrer, condenser, addition funnel and N2 inlet line with bubbler was added N-methylformanilide (Aldrich, 72 g, 0.53 mol, 65.75 mL) and CH2Cl2 (150 mL). After cooling to 0°, POCl3 (Aldrich, 69.0 g, 0.44 mol, 42 mL) was added dropwise (maintaining the reaction mixture at 0°) over 20 min. The solution was allowed to warm to RT and a solution of 1-[(2-methoxy)ethoxy]anthracene (1B, 60.0 g, 0.24 mol) in CH2Cl2 (200 mL) added dropwise over 10 min. The solution warmed and turned a deep red color during this addition. The reaction mixture was refluxed for 5 h, cooled and hydrolyzed by the dropwise addition of H2O (50 mL) over 1 h. The H2O was then removed and the volume of the solution reduced to 200 mL. the solution was applied to a plug of SiO2 (1 kg) and chromatographed using CH2Cl2 followed by EtOAc as the eluting solvents. The appropriate fractions were combined and the solvent removed by rotary evaporation to give a yellow oil which solidified upon cooling. Recrystallization (abs. EtOH) gave 40.87 g (60.7%) of yellow 4-[2-(methoxy)ethoxy]-1-anthracenecarbaldehyde, m.p. 72°-74°, (C,H).
Reaction SMILES: C[N:2]([C:24](OCC1C=CC=CC=1)=O)[N:3]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)C(OCC1C=CC=CC=1)=O.[CH2:34]([NH2:40])[C:35]1[O:39][CH:38]=[CH:37][CH:36]=1.N1C=CC=CC=1.C1C=CC=CC=1>CO.[C].[Pd]>[CH2:34]([NH:40][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:3][NH:2][CH3:24])=[CH:23][CH:22]=1)[C:35]1[O:39][CH:38]=[CH:37][CH:36]=1
Reactant: CN(C(=O)OCc1ccccc1)N(Cc1ccc(C(=O)Cl)cc1)C(=O)OCc1ccccc1
Reactant: NCc1ccco1
Agent: [Pd]
Solvent: c1ccncc1
Solvent: CO
Solvent: c1ccccc1
Product: CNNCc1ccc(C(=O)NCc2ccco2)cc1

Procedure:
By reaction of 23.4 g. of 4-[(2-methyl-1,2-dicarbobenzoxyhydrazino)-methyl]-benzoyl chloride with 4.85 g. of furfurylamine in a mixture of 8 ml. pyridine and 50 ml. of benzene according to the procedure of Example 4 above, followed by hydrogenolysis of the condensation product with palladium-carbon in methanol, there was obtained 4-[(2-methyl-hydrazino)-methyl]-benzoic acid furfurylamide, the oxalate of which melted at 170°-171° (dec.).