Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH2:25])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:26][C:27](=[CH2:30])[CH2:28]I>O.[OH-].[Li+].C(O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:28][C:27]([CH3:30])=[CH2:26])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Sc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Reactant: C=C(C)CI
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=C(C)CNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Sc1ccc(NC(C)=O)cc1

Procedure:
The starting material is prepared as follows: To the solution of 3.81 g of 4-(4-acetamidophenylmercapto)-3-amino-5-sulfamoylbenzoic acid in 25 ml of water and about 2 ml of 4 N aqueous lithium hydroxide (to adjust the pH to 7.2), the solution of 2 g of 2-methylallyliodide in 2 ml of ethanol is added at room temperature while stirring and maintaining the pH between 6.7 and 7.0 with lithium hydroxide, and diluting the mixture with 10 ml of ethanol. After 23 hours (and the consumption of about 65% of the theoretical amount of lithium hydroxide) the mixture is washed with diethyl ether and acidified with hydrochloric acid. The precipitate formed is filtered off and recrystallized from aqueous ethanol, to yield the 4-(4-acetamidophenylmercapto)-3-(2-methylallylamino)-5-sulfamoylbenzoic acid melting at 193°-195°.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][N:30]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)=[CH:12][C:11]=1[F:28])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:28][C:11]1[CH:12]=[C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)[CH:14]=[CH:15][C:10]=1[S:7]([NH:6][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][N:30]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 107 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.27 g, 0.47 mmol) prepared in Example 29b, triethylsilane (0.38 mL, 2.36 mmol), trifluoroacetic acid (0.47 g, 0.44 mmol) and dichloromethane (5.0 mL), to yield the title compound (0.21 g, 22%) as a colorless solid.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([Li])CCC.CN(C)P(=O)(N(C)C)N(C)C.[CH3:24][O:25][CH:26]([O:29][CH3:30])[CH2:27]Br>C1COCC1>[CH3:24][O:25][CH:26]([O:29][CH3:30])[CH2:27][C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: COC(CBr)OC
Reactant: C#CCCCCC
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCCCCC#CCC(OC)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
1-Heptyne (50 ml, 381 mmole) is dissolved in 360 ml dry THF in a flame dried 2000 ml 3-neck round bottom flask under nitrogen. The solution is cooled to 0° C. and treated with n-butyllithium (232 ml, 360 mmole) dropwise over 40 minutes via a dropping funnel. The reaction mixture is stirred 30 minutes at 0° C., treated with hexamethylphosphoric triamide (68 ml, 391 mmole), and stirred an additional 30 minutes at 0° C. 1,1-Dimethoxy-2-bromoethane (43 ml, 364 mmole) is added dropwise to the reaction mixture over 10 minutes at 0° C. The reaction mixture is stirred 3 hours at 0° C. and an additional 72 hours at room temperature. The mixture is subsequently quenched with 5 ml water and the THF removed in vacuo. The amber oily residue is dissolved in 200 ml diethyl ether and poured into 100 ml 50% saturated sodium chloride. The aqueous layer is extracted with 3×75 ml diethyl ether. The organics are combined, washed with 6×50 ml 50% saturated sodium chloride, and dried over anhydrous magnesium sulfate. The diethyl ether is removed in vacuo and the red oily residue distilled under reduced pressure. After a 5 ml forerun, the fraction boiling at 65°-67° C. (0.5 mm) is collected to provide 42 g of the title compound as a colorless oil. Following the above procedure gives the title compound having the physical characteristic described below:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]1([C:12]2[CH2:13][CH2:14][C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([C:22](OCC)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=[CH:8]1.O>C1COCC1>[N:7]1([C:12]2[CH2:13][CH2:14][C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([CH2:22][OH:23])=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: CCOC(=O)c1ccc2c(c1)C=C(n1ccnc1)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc2c(c1)C=C(n1ccnc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a suspension of LiAlH4 (202 mg) in dry THF (2.4 ml) a solution of 1,2-dihydro-3-(1-imidazolyl)-6-ethoxycarbonyl-naphthalene (2.8 g) in dry THF (22 ml) was added dropwise at 0° C. under nitrogen atmosphere. The reaction mixture was refluxed for 1 day and then stirred overnight at room temperature. H2O (40 ml) was added and the precipitate formed filtered off. The filtrate was concentrated, extracted with CHCl3, dried (Na2SO4) and evaporated under vacuum to give 1,2-dihydro-3-(1-imidazolyl)-6-hydroxymethyl-naphthalene (2 g), m.p. 88°-91° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13](O)[CH2:14][CH2:15][OH:16]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:16][CH2:15][CH2:14][CH2:13][O:7]2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: OCCCO
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(C2OCCCO2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
A mixture of 4-hydroxy-3-nitro-benzaldehyde (5.0 g, 29.9 mmol), 1,3-propanediol (3.4 g, 44.9 mmol) and 0.1 g of p-toluene sulfonic acid in 100 mL of toluene is warmed to reflux. The water generated is removed by a Dean-Stark trap. After 2 hours, the reaction mixture is cooled to room temperature and extracted with 2×100 mL of saturated sodium bicarbonate followed by 100 mL of brine. Drying over sodium sulfate and evaporation of the solvent gives 5.6 g (83% yield) of 2-[4-hydroxy-3-nitro-phenyl]-1,3-dioxane oil.
Reaction SMILES: [C:1]([NH:22][C@@H:23]([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=1)[C:24]([O:26]C)=[O:25])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].[OH-].[Na+].Cl>C1COCC1>[C:1]([NH:22][C@@H:23]([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=1)[C:24]([OH:26])=[O:25])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)N[C@@H](CCCCNC(=O)c1cccnc1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)N[C@@H](CCCCNC(=O)c1cccnc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
(S)-methyl 2-((5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenamido)-6-(nicotinamido)hexanoate (140 mg, 0.225 mmol) was taken up in 2 mL of THF along with an aqueous solution of NaOH (35 mg in 2 mL of H2O). The resulting reaction mixture was stirred at room temperature for 2 h. It was then acidified to pH 4 with 2 N HCl and then extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford 31 mg of (S)-2-((5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenamido)-6-(nicotinamido)hexanoic acid. MS calculated for C34H47N3O4: 561.36. found: [M+H]+ 562. MS calculated for C32H45N3O4: 535.34. found: [M+H]+ 536.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12]C(C)(C)C)=[O:11].[CH2:18](Cl)Cl>CN(C)C1C=CN=CC=1.C(O)C>[CH3:1][C:2]1([CH3:17])[CH:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH3:18])=[O:8])[CH:3]1[C:10]([OH:12])=[O:11]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C
Agent: CN(C)c1ccncc1
Solvent: CCO
Product: COC(=O)/C=C\C1C(C(=O)O)C1(C)C
Temperature: 20 °C
Reaction time: 16 h

Procedure:
4 g of the product of Step A, 3.4 g of dicyclohexylcarbodiiumide and 6 mg of 4-dimethylamino-pyridine were added to 30 ml of methylene chloride followed by the addition of 1.5 ml of ethanol and the mixture was stirred at 20° C. for 16 hours. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 9-1 cyclohexane-ethyl acetate mixture to obtain 4.25 g of tert.butyl (1R, cis) 2,2-dimethyl-3-(ethoxycarbonyl-ethynyl)-cyclopropane-carboxylate.
Reaction SMILES: [CH2:1]([SH:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[H-].[Na+].Cl[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[N:11]=1>O1CCCC1>[C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([S:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[N:11]=1)#[N:17]
Reactant: N#Cc1cccc(Cl)n1
Reactant: CC(C)CCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CCSc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
Isopentyl mercaptan (0.83 g, 7.9 mmol) was dissolved in tetrahydrofuran (100 ml) and added dropwise to sodium hydride (60% oil, 0.35 g, 8.7 mmol). The reaction mixture was stirred at room temperature for 1 hr. A solution of 2-chloro-6-cyanopyridine (1.00 g, 7.2 mmol) in tetrahydrofuran (10 ml) was added to the mixture, and the mixture was stirred at room temperature for 18 hrs. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure to give the titled compound (1.48 g, ca. 100%) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:37][CH2:36]1)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:4][CH:3]=3)=[CH:40][CH:39]=2)[CH2:36][CH2:37]1)=[O:34])[CH3:31]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(CCc1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(CCc4ccccc4)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1,3-diphenyl-propyl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1.[Cl:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][N:28]([CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:21])[C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)[CH2:6][CH2:5]2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:25][CH:24]=1
Reactant: O=C(NC1CCN(CCCl)CC1)c1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccc(CNc2ccccn2)cc1
Product: O=C(NC1CCN(CCN(Cc2ccc(Cl)cc2)c2ccccn2)CC1)c1ccc([N+](=O)[O-])cc1

Procedure:
The title compound is prepared in a manner similar to Example 11 using 1-(2-chloroethyl)-4-(p-nitrobenzamido)piperidine and 2-(p-chlorobenzyl)aminopyridine.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH3:15])=[CH:10][CH:9]=1.[CH:17]1[C:22]([O:23][C:24](Cl)=[O:25])=[CH:21][CH:20]=[C:19]([Cl:27])[CH:18]=1>O1CCOCC1.C([O-])(O)=O.[Na+]>[Cl:27][C:19]1[CH:20]=[CH:21][C:22]([O:23][C:24](=[O:25])[N:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]#[C:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:16])[CH3:1])=[CH:9][CH:10]=2)[CH3:15])=[CH:17][CH:18]=1
Reactant: CNc1ccc(C#CCCCN(C)C)cc1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C)CCCC#Cc1ccc(N(C)C(=O)Oc2ccc(Cl)cc2)cc1
Yield: 54.9 %

Procedure:
A solution of 59 mg (0.27 mmol) of [4-(5-Dimethylamino-pent-1-ynyl)-phenyl]-methyl-amine in 0.3 ml dioxane was treated with 0.07 ml (0.55 mmol; 2 equivalents) Hünigsbase and dropwise with a solution of 0.05 ml (0.27 mmol) 4-chlorophenylchloroformate in 0.45 ml dioxane. The mixture was then immediately dissolved in aqueous saturated NaHCO3 IEt2O (3×). The organic phase was dried over Na2SO4 and evaporated. Flash column chromatography on silica gel with CH2Cl2/MeOH (95:5) yielded 55 mg (54%) of [4-(5-Dimethylamino-pent-1-ynyl)-phenyl]-methyl-carbamic acid 4-chloro-phenyl ester, MS: 371 (MH+, 1Cl).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.N.[Li].C(O)C>CCOCC>[CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH:6]1[C:14]2[CH2:13][CH:12]=[CH:11][CH2:10][C:9]=2[CH2:8][CH2:7]1
Reactant: CNCCCC1C=Cc2ccccc21
Agent: N
Agent: [Li]
Solvent: CCO
Solvent: CCOCC
Product: CNCCCC1CCC2=C1CC=CC2
Yield: 97.9 %

Procedure:
A solution of 40 g of 1-[3-(methylamino)propyl]indene in 200 ml of absolute ether is added to 2.5 liters of liquid ammonia at -33°C. Lithium ribbon (35 g) is added over 1.5 hours. The bronze mixture is stirred for 1 hour, and treated with absolute ethanol over 2 hours until the blue color is discharged. The ammonia is evaporated overnight, whereupon water and ether are added with cooling in an ice bath. The layers are separated, the aqueous layer reextracted, and the organic layers are dried (potassium carbonate) and evaporated to give 40 g of 4,7-dihydro-1-[3-(methylamino)propyl]indan as an oil. The crude diene is taken up in 400 ml of toluene and treated with 24 g of phenoxypropylbromide in 100 ml of toluene. The mixture is refluxed for 18 hours, cooled, diluted with ether, and washed several times with water. The organic layers are then shaken with excess 10% hydrochloric acid. The bottom colorless aqueous phase of the 3-phase mixture is drawn off, the toluene-ether layer is decanted, and the isolated middle layer washed with distilled water. The oily hydrochloride is then shaken with excess 10% sodium hydroxide and ether and the organic phase is separated and dried (potassium carbonate). Evaporation gives 25 g of N-methyl-N-phenoxypropylaminopropyl-4,7-dihydroindan.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19](=[O:20])[CH2:18][CH:17]([C:21]([OH:23])=O)[CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][NH2:25]>>[CH3:24][NH:25][C:21]([CH:17]1[CH2:18][C:19](=[O:20])[N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH2:16]1)=[O:23]
Reactant: O=C(O)C1CC(=O)N(c2ccc(OCc3ccccc3)cc2)C1
Reactant: CN
Product: CNC(=O)C1CC(=O)N(c2ccc(OCc3ccccc3)cc2)C1
Yield: 73 %

Procedure:
The title compound is prepared in analogy to Example 20d) from (RS)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid and methylamine. Yield: 73% of a slightly yellow solid. MS: m/e=325.4 (M+H)+.
Reaction SMILES: [Na].[C:2]1([N:8]=[N+:9]=[N-:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12]>C(O)C.O>[NH2:12][C:11]1[N:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=[N:10][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CC#N
Reactant: [N-]=[N+]=Nc1ccccc1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1nnn(-c2ccccc2)c1N
Temperature: 45 °C
Reaction time: 0.08 h

Procedure:
A solution of sodium (2.04 g; 0.089 mole) in ethanol (50 ml) was added to a mixture of phenyl azide (11.9 g; 0.1 mole) and ethyl cyanoacetate (11.3 g; 0.1 mole) and the product gently warmed to 45° C. with stirring for 5 mins. After stirring at ambient temperature for a further 15 minutes the flask was immersed in water at room temperature for 3 hrs. A white solid separated which was filtered off after dilution of the mixture with water and washed with water. Recrystallisation from ethanol gave 18.4 g. (79%) of material of mp 124.5-125.5° C. (lit mp 126°; B. R. Brown, D. L. Hammick and S. G. Heritage J. Chem. Soc. 3820 [1953]).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][CH:16]([CH2:21][CH:22]=O)[C:17]2=O)=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[CH2:14][CH2:15][C:16]3[CH:21]=[CH:22][N:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:17]=3[C:18]=2[CH:19]=1
Reactant: CC(=O)NCCN
Reactant: COc1ccc2c(c1)C(=O)C(CC=O)CC2
Solvent: ClCCl
Product: COc1ccc2c(c1)-c1c(ccn1CCNC(C)=O)CC2
Yield: 80.8 %

Procedure:
N-Acetylethylenediamine (14.5 g) was dissolved in 250 ml of methylene chloride under argon, treated in succession with 250 g of molecular sieve 4 Å and a solution of 28.1 g of 1,2,3,4-tetrahydro-7-methoxy-1-oxo-2-naphthaleneacetaldehyde in 190 ml of methylene chloride and refluxed for 21 hours while stirring. The reaction mixture was cooled, filtered over a Celite® pad and the filtrate was freed from solvent. The crude product, 35.3 g of brown, amorphous material, was chromatographed on 600 g of silica gel with ethyl acetate as the eluent. There were obtained 29.6 g (81%) of N-[2-(4,5-dihydro-8-methoxy-1H-benzo[g]indol-1-yl)-ethyl]acetamide which was processed without further purification.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Ni]>[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(CN2CCCCC2)cc1

Procedure:
37.0 g of 4-(piperidin-1-yl-methyl)-nitrobenzene are dissolved in 300 ml of methanol, 8.0 g of Raney nickel are added and the mixture is hydrogenated for 85 minutes with 3 bars of hydrogen at room temperature. The catalyst is filtered off and the filtrate is evaporated down.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([NH2:19])[C:13]4[CH:14]=[N:15][NH:16][C:17]=4[CH:18]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:20]1(=O)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22](=[O:29])[O:21]1.CN(C=O)C>ClCCl>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:18]=[C:17]4[C:13]([CH:14]=[N:15][NH:16]4)=[C:12]([N:19]4[C:20](=[O:21])[C:24]5[C:23](=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:22]4=[O:29])[CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1c1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 63.1 %

Procedure:
A mixture of 6-(1H-indol-4-yl)-1H-indazol-4-amine (500 mg, 2.014 mmol), 2-benzofuran-1,3-dione (298 mg, 2.014 mmol) and DMF (2.5 ml) was placed in a Biotage vial (2-5 ml) equipped with a magnetic stirrer bar. The vial was placed in a Biotage Initiator microwave and heated at 150° C. for 30 min then again at 150° C. for a further 15 min. The reaction mixture was evaporated to dryness to give a brown oil which was dissolved in dichloromethane and applied to a 100 g silica SPE cartridge. The cartridge was eluted on a Flashmaster (II) instrument using a gradient of 0-100% ethyl acetate in cyclohexane over 40 min followed by 0-20% methanol in cyclohexane over 15 min. Appropriate fractions were combined and evaporated to give the title compound (481 mg) as a pale yellow foam.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([CH:7]=[C:8]([C:16](=O)[CH3:17])[C:9]([O:11][CH2:12][CH2:13][C:14]#[N:15])=[O:10])=[C:5]([O:21][CH3:22])[CH:4]=1)#[N:2].[NH2:23][C:24]1[CH:29]=[C:28]([CH3:30])[NH:27][C:26](=[O:31])[CH:25]=1>CC(O)C>[C:1]([C:3]1[CH:20]=[CH:19][C:6]([CH:7]2[C:25]3[C:26](=[O:31])[NH:27][C:28]([CH3:30])=[CH:29][C:24]=3[NH:23][C:16]([CH3:17])=[C:8]2[C:9]([O:11][CH2:12][CH2:13][C:14]#[N:15])=[O:10])=[C:5]([O:21][CH3:22])[CH:4]=1)#[N:2]
Reactant: Cc1cc(N)cc(=O)[nH]1
Reactant: COc1cc(C#N)ccc1C=C(C(C)=O)C(=O)OCCC#N
Solvent: CC(C)O
Product: COc1cc(C#N)ccc1C1C(C(=O)OCCC#N)=C(C)Nc2cc(C)[nH]c(=O)c21
Reaction time: 8 h

Procedure:
1.49 g (5.00 mmol) of the compound from Example 24A are introduced into 30 ml of 2-propanol, mixed with 620 mg (5.00 mmol) of 4-amino-6-methylpyridin-2(1H)-one [Bisagni, E., Hung, N. C., Synthesis, 765-766 (1984)] and then stirred at the reflux temperature overnight. After cooling, the precipitate is filtered off, washed with diethyl ether and dried under high vacuum. 1.53 g (76% of theory) of the title compound are obtained.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:7]([CH2:8][OH:9])[O:6][N:5]=[C:4]1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[O:16]COC>C(Cl)Cl.FC(F)(F)C(O)=O>[OH:1][CH2:2][CH:3]1[CH:7]([CH2:8][OH:9])[O:6][N:5]=[C:4]1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[OH:16]
Reactant: COCOc1cnccc1C1=NOC(CO)C1CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OCC1ON=C(c2ccncc2O)C1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 150.4 %

Procedure:
To a solution of intermediate compound 12 (3.8 g, 0.0142 mol) in 100 ml of DCM, 25 ml of triflouroacetic acid were added portionwise at room temperature. The reaction was stirred overnight at room temperature. The solvent was evaporated and the residue was co-evaporated with ethanol. Yielding 4.79 g (100, crude product) of 4-(4,5-bis-hydroxymethyl-4,5-dihydro-isoxazol-3-yl)-pyridin-3-ol (intermediate compound 13).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]1[CH3:17])[N:7]=[C:6]([C:18]1[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=1)[N:5]=2.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CN1CCCC1=O>[CH2:25]([N:3]1[C:2]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:10][C:9]2[C:4]1=[N:5][C:6]([C:18]1[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=1)=[N:7][C:8]=2[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]1[CH3:17])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)Cn1c(Cl)nc2c(N3CCOC[C@@H]3C)nc(-c3cnc(N)nc3)nc21
Reactant: C1CNCCN1
Solvent: CN1CCCC1=O
Product: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOC[C@@H]3C)nc(-c3cnc(N)nc3)nc21
Yield: 71.2 %

Procedure:
An N-methyl-2-pyrrolidone (2 ml) solution of 5-{8-chloro-9-isobutyl-6-[(3S)-3-methylmorpholin-4-yl]-9H-purin-2-yl}pyrimidin-2-amine (307 mg, 0.76 mmol) and piperazine (328 mg, 3.81 mmol) was stirred at 150° C. for 90 minutes and returned to room temperature. The reaction mixture was purified by flash silica gel column chromatography (chloroform:methanol=95:5 to 85:15) to give the title compound (245 mg, 71%) as a solid.