Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[N:12][C:7]3[O:8][CH2:9][CH2:10][NH:11][C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.[Br:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([Br:26])[C:23]=1[O:24][CH3:25])[C:18](Cl)=[O:19].C(N(CC)CC)C.Cl>ClCCl>[CH:1]1([C:4]2[CH:13]=[N:12][C:7]3[O:8][CH2:9][CH2:10][N:11]([C:18]([C:17]4[CH:21]=[C:22]([Br:26])[C:23]([O:24][CH3:25])=[C:15]([Br:14])[CH:16]=4)=[O:19])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1
Reactant: c1nc2c(cc1C1CC1)NCCO2
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(C4CC4)cc32)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.7 %

Procedure:
To a 10 ml flask, 7-cyclopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (10 mg, 0.057 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (28 mg, 0.085 mmol) were dissolved in dichloromethane (1.2 ml). After cooling to 0□, triethylamine (0.04 ml, 0.285 mmol) was added thereto and then stirred at room temperature for 3 hours. The reaction mixture was neutralized with 1N hydrochloric acid solution and extracted with dichloromethane, and then the combined organic layer was dried over anhydrous magnesium sulfate (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of ethyl acetate and n-hexane (1:1). The fractions containing the product were collected and evaporated to obtain the target compound as white solid (9.0 mg, 33%).
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]([CH3:20])([CH3:19])[CH2:15][C:16](Cl)=[O:17].C(N(CC)CC)C>ClCCl>[CH3:13][C:14]([CH3:20])([CH3:19])[CH2:15][C:16]([N:9]1[CH2:10][CH2:11][O:12][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1)=[O:17]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: c1ccc(C2CNCCO2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC(=O)N1CCOC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.8 %

Procedure:
A solution of 2-phenylmorpholine (326 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 3,3-dimethyl-butyryl chloride (336.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:4). The fractions containing the 3,3-dimethyl-1-(2-phenylmorpholin-4-yl)butan-1-one are collected and the solvent is removed in vacuo to give 438 mg of colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([CH3:20])=[N:4][CH:5]=[C:6]([C:18]=1[OH:19])[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:8].[CH3:21][O-:22].[Na+].CO>CN(C)C=O.[Cu]I>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][NH:9][C:7](=[O:8])[C:6]2[C:18]([OH:19])=[C:2]([O:22][CH3:21])[C:3]([CH3:20])=[N:4][CH:5]=2)=[CH:12][CH:13]=1
Reactant: Cc1ncc(C(=O)NCc2ccc(F)cc2)c(O)c1Br
Reactant: C[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1c(C)ncc(C(=O)NCc2ccc(F)cc2)c1O
Temperature: 105 °C
Reaction time: 1.67 h
Yield: 86.9 %

Procedure:
The compound 21 (75.2 g, 222 mmol) and copper (I) iodide (21.1 g, 111 mmol) were dissolved in dimethylformamide (750 ml), a 28% sodium methoxide-methanol solution (216 ml, 888 mmol) was added, and the mixture was stirred at 105° C. for 100 minutes. After cooling, ice-water (800 ml) was added, and unnecessary matters were filtered. To the solution was added 2 M hydrochloric acid (443 ml), and crystals were collected by filtration. N-(4-fluorobenzyl)-4-hydroxy-5-methoxy-6-methylnicotinamide 22 (56.0 g, 87%) was obtained as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12.[Br:22]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:15][C:14]1[C:3]2[C:4](=[N:5][C:6]3[C:11]([C:2]=2[Cl:1])=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1c2ccccc2nc2c1c(CBr)nn2-c1ccccn1
Temperature: 25 °C
Yield: 53.5 %

Procedure:
A solution of 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.22 g, 4.1 mmol), N-bromosuccinimide (0.87 g, 4.9 mmol) and 2,2′-azobis(isobutyronitrile) (66 mg, 0.4 mmol) in carbon tetrachloride (40 mL) was heated under reflux under an argon atmosphere for 3 hours. The solution was allowed to cool to room temperature, the insoluble solid was removed and the solution was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:chloroform:ethyl acetate=2:1:1) to give the title compound (0.82 g, 53% yield).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][N:23]2C(=O)C3=CC=CC=C3C2=O)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][NH2:5]
Reactant: O=C1c2ccccc2C(=O)N1CCOCCOCCOCCOCCOCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCOCCOCCOCCOCCOCCN
Temperature: 100 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
A solution containing 60 g of 1,17-diphthalimido-3,6,9,12,15-pentaoxaheptadecane (0.118 mol), 14.8 g of hydrazine hydrate (0.296 mol), and 500 ml of ethanol were heated with mechanical stirring in a 100° C. oil bath for three hours. The mixture was then cooled and filtered. The resultant filter cake was washed four times with 300 ml portions of ethanol. The combined filtrates were concentrated to yield 32.35 g of a yellow opaque glassy oil. The evaporative distillation at 150°-200° C. (0.01 mm) gave 22.82 g of a light yellow oil (69% yield). lit. b.p. 175°-177° C. (0.07 mm).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12][CH2:11][CH:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:9]1=[O:27]>C(Cl)Cl>[Cl:3][CH2:6][CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12][CH2:11][CH:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:9]1=[O:27]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C2CSc3ccccc3N(CCO)C2=O)cc1
Solvent: ClCCl
Product: COc1ccc(C2CSc3ccccc3N(CCCl)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.14 ml of thionyl chloride was added to a solution of 329 mg of the product of Step C in 3.3 ml of methylene chloride and the mixture was stirred for 15 minutes at ambient temperature, then evaporated to dryness under reduced pressure. The residue was taken up in 25 ml of ether at reflux, treated with activated charcoal, filtered and concentrated to 7 ml. After separation, 300 mg of the expected product melting at approx. 70° C. were obtained which was used as is for Step E. An analytical sample was prepared by dissolving 300 mg of the product in 10 ml of hot methyl ethyl ketone which was concentrated to 2 ml, then adding 2 ml of pentane. After separating, 65 mg of the desired product melting at approx. 70° C. were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1)#[N:2].[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:13]=[C:12]1[S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:20]([C:12]2[S:11][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH:13]=2)(=[O:22])=[O:21])=[C:5]([NH:10][S:20]([C:12]2[S:11][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH:13]=2)(=[O:21])=[O:22])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: N#Cc1ccc(NS(=O)(=O)c2cc3ccccc3s2)c(NS(=O)(=O)c2cc3ccccc3s2)c1
Temperature: 80 °C
Yield: 35 %

Procedure:
To a solution of 4-cyanobenzene-1,2-diamine (1 mmol) in pyridine (4 mL), benzothiophene-2-sulfonyl chloride (2.2 mmol) was added in small portions. The reaction mixture was then heated at 80° C. with stirring until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with ethyl acetate (20 mL). The organic phase was washed with 10% aqueous HCl solution (15 mL), water (15 mL) and brine (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 184 mg of N,N′-(4-cyano-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:26]C(OC(C)(C)C)=O)[C:11]([O:13][C@H:14]([CH3:25])[CH2:15][O:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[ClH:34]>O1CCOCC1>[ClH:34].[NH2:26][C@@H:10]([CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1)[C:11]([O:13][C@H:14]([CH3:25])[CH2:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18])=[O:12]
Reactant: C[C@H](COC(=O)c1ccccc1)OC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](COC(=O)c1ccccc1)OC(=O)[C@@H](N)Cc1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
(1R)-1-Methyl-2-phenylcarbonyloxyethyl (2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate (1.87 g, 4 mmol) was dissolved in 40 mL of 4M HCl in dioxane. The resulting mixture was stirred at room temperature for 30 min. Dioxane was evaporated completely under reduced pressure. The resulting white solid was dissolved in acetonitrile (5 mL), and ether added until the solution became slightly cloudy. The solution was refrigerated overnight and the product was crystallized. The white crystalline solid was collected and dried under vacuum to afford 1.5 g (93%) of the title compound. 1H NMR (400 MHz, CD3OD): δ 1.35 (d, J=6.4 Hz, 3H), 3.01 (dd, J=6.8, 14.4 Hz, 1H), 3.08 (dd, J=6.4, 14.4 Hz, 1H), 4.19 (t, J=6.4 Hz, 1H), 4.34 (dd, J=6, 12.4 Hz, 1H), 4.49 (dd, J=2.8, 12.4 Hz, 1H), 5.35 (m, 1H), 6.55 (dd, J=2, 8 Hz, 1H), 6.66 (d, J=2 Hz, 1H), 6.71 (d, J=8 Hz, 1H), 7.48 (t, J=7.2 Hz, 2H), 7.61 (t, J=7.2 Hz, 1H), 8.02 (d, J=7.6 Hz, 2H). MS (ESI) m/z 360.16 (M+H)+ and 358.13 (M−H)−.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:32])=[C:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:23][CH:22]=1)[C:10]([CH:17]1[CH2:19][CH2:18]1)=[N:11]2.[OH-].[Li+].Cl>O1CCCC1.O>[CH:17]1([C:10]2[C:9]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:25][CH:26]=3)=[C:8]([CH3:32])[C:7]3[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=3[O:5][CH2:4][C:3]([OH:33])=[O:2])[N:11]=2)[CH2:19][CH2:18]1
Reactant: COC(=O)COc1ccc(F)c2nc(C3CC3)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C2CC2)nc2c(F)ccc(OCC(=O)O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A solution of [2-cyclopropyl-8-fluoro-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.034 g) in tetrahydrofuran (0.19 mL) and water (0.19 mL) was treated with lithium hydroxide (0.037 g), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with water, cooled to 0° C. and acidified by the addition of 1.0 M aqueous hydrochloric acid. The resulting precipitate was collected by filtration and dried to afford title compound as a pale pink solid (0.022 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:32][CH3:33])[CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:27]3[C:26]4[C@@H:25]([CH2:28][C:29]([OH:31])=O)[CH2:24][CH2:23][C:22]=4[S:21][C:20]=3[N:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:40]C=2C=1.CCN=C=NCCCN(C)C.[NH4+].[Cl-]>CN(C)C1C=CN=CC=1.CN(C=O)C.O>[C:29]([CH2:28][C@H:25]1[CH2:24][CH2:23][C:22]2[S:21][C:20]3[N:19]=[CH:18][N:17]=[C:16]([O:15][CH:12]4[CH2:11][CH2:10][CH:9]([N:8]([CH2:32][CH3:33])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:14][CH2:13]4)[C:27]=3[C:26]1=2)(=[O:31])[NH2:40]
Reactant: On1nnc2ccccc21
Reactant: CCN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(=O)O)CC4)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 74.6 %

Procedure:
A 50-mL round-bottom flask was charged with a solution of 2-[(3R)-12-[(4-[[(tert-butoxy)carbonyl](ethyl)amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetic acid (310 mg, 0.65 mmol, 1.00 equiv), HOBt (132 mg), EDCI (186.9 mg), 4-dimethylaminopyridine (118 mg) and NH4Cl (209 mg, 3.91 mmol, 5.99 equiv) in distilled DMF (6 mL). The solution was stirred for 14 hrs at 25° C. under nitrogen. The resulting solution was diluted with water and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with 3×20 mL of brine, dried over sodium and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:1) to afford tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-ethylcarbamate (230 mg, 74%) as a colorless oil. MS (ES): m/z 475 [M+H]+.
Reaction SMILES: CN(C)[C:3](=[CH:9][CH:10]=[C:11]([S:23][CH3:24])[C:12]([C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.C([OH:29])C>>[CH3:21][N:20]([CH3:22])[C:17]1[CH:18]=[CH:19][C:14]([C:12](=[O:13])[C:11]([S:23][CH3:24])=[CH:10][CH:9]=[C:3]([OH:29])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:15][CH:16]=1
Reactant: CCO
Reactant: CCOC(=O)C(=CC=C(SC)C(=O)c1ccc(N(C)C)cc1)N(C)C
Agent: Cl
Product: CCOC(=O)C(O)=CC=C(SC)C(=O)c1ccc(N(C)C)cc1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
The procedure is as in Example 4, starting with ethyl 2-dimethylamino-6-(4-dimethylaminophenyl)-5-methylthio-6-oxo-2,4-hexadienoate (5.5 g), 12N aqueous hydrochloric acid solution (38 cc) and ethanol (50 cc). The mixture is heated to boiling for 5 minutes, and is then cooled to a temperature of approximately 20° C. After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (60:40 by volume), ethyl 6-(4-dimethylaminophenyl)-2-hydroxy-5-methylthio-6-oxo-2,4-hexadienoate (3.9 g) is obtained in the form of a brown oil (Rf=0.2; support: silica gel; eluent: cyclohexane/ethyl acetate 60:40 by volume).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[C:5](=[NH:8])OC)[CH3:2].[Cl:12][C:13]1[CH:14]=[C:15]([CH2:19][NH2:20])[CH:16]=[CH:17][CH:18]=1>CO>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[CH2:19][NH:20][C:5](=[NH:8])[CH:4]([O:3][CH2:1][CH3:2])[O:9][CH2:10][CH3:11]
Reactant: CCOC(OCC)C(=N)OC
Reactant: NCc1cccc(Cl)c1
Solvent: CO
Product: CCOC(OCC)C(=N)NCc1cccc(Cl)c1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
In a nitrogen-flushed sealed tube was placed methyl 2,2-diethoxyacetimidate (2 g, 12.41 mmol) in methanol (6 mL) and (3-chlorophenyl)methanamine (1.444 mL, 11.82 mmol). The tube was capped and heated to 70° C. After 18 hours, the reaction was cooled to room temperature and the reaction was concentrated to yield N-(3-chlorobenzyl)-2,2-diethoxyacetimidamidea (2.3 grams, 8.5 mmol, 71%) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=O)[CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC1C=CC(C2C=CC=C(C[NH:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)C=2)=CC=1>>[F:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][NH:32][CH2:16][C:12]2[CH:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH:15]=[CH:14][CH:13]=2)=[CH:35][CH:36]=1
Reactant: O=Cc1cccc(-c2ccc([N+](=O)[O-])cc2)c1
Reactant: Fc1ccc(CNCc2cccc(-c3ccc(Cl)cc3)c2)cc1
Product: O=[N+]([O-])c1ccc(-c2cccc(CNCc3ccc(F)cc3)c2)cc1
Yield: 71 %

Procedure:
4′-Nitrobiphenyl-3-carbaldehyde (0.73 g, 3.2 mmol) was converted to the desired compound (0.82 g, 71%) in a manner similar to the preparation of 1-(4′-chlorobiphenyl-3-yl)-N-(4-fluorobenzyl)methanamine (Compound A of Example 207). 1H NMR (CDCl3) δ 8.34-8.30 (m, 2H), 7.80-7.74 (m, 2H), 7.64 (bs, 1H), 7.58-7.42 (m, 3H), 7.38-7.30 (m, 2H), 7.09-7.00 (m, 2H), 3.91 (s, 2H), 3.84 (s, 2H). MS (ESI): 337.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[CH3:11][C:12]1[S:29][C:15]2=[N:16][C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:18]([C@@H:20]([NH2:22])[CH3:21])[CH:19]=[C:14]2[CH:13]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:11][C:12]1[S:29][C:15]2=[N:16][C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:18]([C@@H:20]([NH:22][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)[CH3:21])[CH:19]=[C:14]2[CH:13]=1
Reactant: Cc1cc2cc([C@H](C)N)c(-c3ccccn3)nc2s1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2cc([C@H](C)Nc3ncnc4[nH]cnc34)c(-c3ccccn3)nc2s1
Temperature: 120 °C

Procedure:
6-Chloropurine (26.4 mg, 0.171 mmol), (S)-1-(2-methyl-6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethanamine (40 mg, 0.148 mmol) and hunig's base (38.9 μL, 0.223 mmol) was dissolved in 2 mL of n-butanol and heated to 120° C. overnight. The reaction was cooled to rt and purified by reverse phase chromatography to afford (S)—N-(1-(2-methyl-6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethyl)-9H-purin-6-amine. 1H NMR (400 MHz, CDCl3) δ 12.5 (br s, 1H), 8.78 (br m, 1H), 8.55-7.80 (series of m, 6H), 7.60-7.30 (br m, 1H), 7.26 (m, 1H), 6.89 (br s, 1H), 6.40-6.00 (br m, 1H), 2.60 (br s, 3H), 1.60-1.25 (series of M, 3H). LC/MS (M+1, found=388.1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:15])=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1)=O.CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:2][CH2:3][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:15])=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc2c(Cl)ccnc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1ccc2c(Cl)ccnc2c1
Temperature: -45 °C

Procedure:
7-Methyloxycarbonyl-4-chloroquinoline (2.1 g, 9.5 mmol) is dissolved in anhydrous THF (25 mL) and anhydrous ether (200 mL). The solution is cooled in a dry ice/acetone bath and treated 1 M lithium aluminum hydride in THF (11.0 mL, 11 mmol). The solution is warmed (approximately −45° C.) for 20 min. and quenched with ethyl acetate. The solution is diluted with ether (100 mL) and treated with water (36 mL), 15% NaOH (36 mL) and water (3×36 mL) in succession. The mixture is filtered and evaporated to yield the title compound as a residue (2.0 g, 9.7 mmol) which is dried under vacuum and used without further purification. MS m/z: M+=193; 1H NMR (CDCl3, 300 MHz) δ0.00, 8.65 (d, 1H), 8.15 (d, 1H), 8.0 (d, 1H), 7.6 (d, 1H), 7.45 (d, 1H), 4.8 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.C(N([CH2:30][CH3:31])CC)C>ClCCl.C(OCC)(=O)C>[CH:19]1[C:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][CH2:14][N:8]([C:6]([C:5]3[CH:23]=[CH:24][C:2]([NH:1][C:6](=[O:7])[C:5]4[CH:4]=[CH:3][CH:2]=[CH:24][C:30]=4[CH3:31])=[CH:3][CH:4]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2CCc3ccccc3-c3ccccc32)cc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 130.8 %

Procedure:
A mixture of 0.10 g of 5-(4-aminobenzoyl)-6,7-dihydro-5H-dibenz[b,d]azepine, 0.10 g of triethylamine in 1 ml of dichloromethane is stirred at room temperature for 6 hours. The mixture is diluted with 6 ml of ethyl acetate and the solution washed with 1N HCl, 1N KaOH, brine and dried (Na2SO4). The solvent is removed and the solid purified by chromatography on thick layer silica gel plates with the solvent ethyl acetate-hexane (1:1) to give 90 mg of a pale yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][C:10]([CH3:14])([CH3:13])[O:11][CH2:12][C:7]=2[CH:6]=1)=[O:4].[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.CCOC(C)=O>[N:17]([CH2:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][C:10]([CH3:14])([CH3:13])[O:11][CH2:12][C:7]=2[CH:6]=1)=[O:4])=[N+:18]=[N-:19]
Reactant: CC1(C)OCc2cc(C(=O)CBr)ccc2O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc(C(=O)CN=[N+]=[N-])ccc2O1
Temperature: 20 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone (Glaxo DE 3513885, 1985) (52 g) in DMF (300 ml) was treated with sodium azide (12.24 g) and the mixture was stirred for 2 h at 20° C. The reaction mixture was diluted with EtOAc and washed with water and dried (MgSO4). The solvent was removed under reduced pressure to give the title compound (39.11 g). TSP+ve 248(MH)+.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>C(O)C>[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[N:16]1[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]1=[O:11]
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Nc1ccccc1F
Solvent: CCO
Product: O=C(O)C1CCN(c2ccccc2F)C1=O
Yield: 77.9 %

Procedure:
A mixture of 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.500 g; 2.94 mmol) and 2-fluoroaniline (0.851 mL; 8.82 mmol) in ethanol (3 mL) was irradiated in a microwave oven for 3 minutes at 100° C. The mixture was concentrated under reduced pressure and the residue was dissolved in a solution of sodium hydroxide 6N, washed with dichloromethane, acidified with a solution of hydrochloric acid 6N to pH=2, extracted with ethyl acetate dried and concentrated under reduced pressure to yield 0.511 g (78%) of a yellow solid, which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1([CH2:7][C:8](OC(C)(C)C)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:9][CH2:8][CH2:7][C:2]1([OH:1])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)CC1(O)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC1(O)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.4 %

Procedure:
To a solution of tert-butyl 2-(1-hydroxycyclopentyl)acetate (0.5 g, 2.5 mmol) in THF (10 mL) was added lithium aluminium hydride (0.28 g, 7.5 mmol) portionwise at 0° C. The reaction was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether/ethyl acetate (1:1) to give 1-(2-hydroxyethyl)cyclopentanol (0.33 g, 100%) as a yellow oil.