Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[C:10]1([N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[NH:25][NH2:26])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO.C(O)(=O)C>[C:10]1([N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[NH:25][N:26]=[C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[CH3:2])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)c1ccccn1
Reactant: NNc1nc2ccccc2n1-c1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: CC(=NNc1nc2ccccc2n1-c1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2-acetyl pyridine (1.00 g, 8.26 mmol) and 1-phenyl-2-hydrazinobenzimidazole (1.85 g, 8.26 mmol) in 20 ml of methanol is stirred at room temperature for 2 days after the addition of 6 drops of glacial acetic acid. The reaction is monitored by means of thin layer chromatography (Polygram Sil G/UV254 prefabricated foils; eluting agent: CH2Cl2:MeOH (12:1)). Subsequently, the reaction mixture is diluted with distilled water until a precipitate forms and stored for 24 hours in the refrigerator at approximately 5° C. The precipitate is filtered, washed several times with 50% methanol, and dried. The product is recrystallized from a mixture of methanol and water. Yield: 1.35 g (50% of theory).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH:10]=O)[CH:8]=1)([O-:3])=[O:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[NH:19][CH2:18][CH2:17]2>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]([CH2:10][CH2:9][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[N:6]1)[CH2:18][CH2:17]2
Reactant: O=CCn1cc([N+](=O)[O-])cn1
Reactant: COc1cc2c(cc1OC)NCC2
Solvent: ClCCl
Product: COc1cc2c(cc1OC)N(CCn1cc([N+](=O)[O-])cn1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-nitro-1H-pyrazol-1-yl)acetaldehyde (942 mg, 6.08 mmol) in DCM (60.0 mL), 5,6-dimethoxyindoline (from step 1) (1.09 g, 6.08 mmol) and STAB (1.55 g, 7.29 mmol) was added. After stirring at rt for 1 h, the reaction mixture was quenched with water and extracted with DCM (2×). The combined org. layers were concentrated and purification was performed by FC (EtOAc/hex 1:4 to 1:1) to yield 5,6-dimethoxy-1-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)indoline as a brown solid. LC-MS conditions B: tR=0.65 min, [M+H]+=319.19.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH:7]([NH:17][C:18]([NH:20][CH:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:19])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].C1(N=C=O)C=CC=CC=1.[CH3:44][Sn:45]([CH3:55])([CH3:54])[C:46]1[CH:53]=[CH:52][C:49]([CH:50]=O)=[CH:48][CH:47]=1>>[C:1]([O:5][C:6](=[O:34])[CH:7]([NH:17][C:18]([NH:20][CH:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:50][C:49]1[CH:52]=[CH:53][C:46]([Sn:45]([CH3:44])([CH3:55])[CH3:54])=[CH:47][CH:48]=1)=[O:19])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)NC(CCCCN)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: C[Sn](C)(C)c1ccc(C=O)cc1
Solvent: O=C=Nc1ccccc1
Product: CC(C)(C)OC(=O)CCC(NC(=O)NC(CCCCNCc1ccc([Sn](C)(C)C)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 40 %

Procedure:
The following compounds of the general structure 8 were prepared in overall yields ranging from 20-60% by the route depicted in Scheme B. The key synthetic intermediate (4) was reacted with the appropriate phenylisocyanate at room temperature to afford the desired protected intermediates (5) in good yields. The t-butyl ester protecting groups were removed in the presence of 50% TFA in DCM for 1 hour at room temperature. Upon completion, the reactions were concentrated on a rotary evaporator purified by HPLC or recrystallization to afford the desired products (6) in 40-90% yield.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>O1CCCC1.CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=2)=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(C(C)(C)C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 23A (0.71 g, 2.28 mmol) in tetrahydrofuran (23 mL) and CH3OH (5.7 mL) was treated with 1N aqueous LiOH (5.7 mL, 5.7 mmol). After stirring overnight at room temperature, the organic solvents were removed under reduced pressure and the remaining aqueous solution was acidified to pH 1 with concentrated HCl. The acidified solution was extracted with ethyl acetate. The extracts were combined, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.06 (m, 4H), 7.69 (m, 2H), 7.38 (m, 2H), 1.29 (s, 9H); MS (ESI+) m/z 298 (M+H)+.
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1[O-])([O-])=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]2[O:21][CH2:22][CH2:23][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]([O:34][CH2:35][CH3:36])(=[O:33])[C:31]#[CH:32]>CN(C)C=O.O>[C:31]1([C:30]([O:34][CH2:35][CH3:36])=[O:33])[CH:32]=[N:14][N:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][CH2:23][C:17]=3[C:16]=12
Reactant: N[n+]1ccc2c(c1)CCO2
Reactant: C#CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn2ccc3c(c12)CCO3
Temperature: 25 °C
Reaction time: 20 h
Yield: 16.9 %

Procedure:
To a mixture of 5-amino-2,3-dihydrofuro[3,2-c]pyridin-5-ium 2,4-dinitrobenzenolate (8.00 g, 25.0 mmol) and potassium carbonate (4.84 g, 35.0 mmol) in dimethylformamide (100 mL) was added ethyl propiolate (2.80 mL, 27.6 mmol) under ice-cooling, and the mixture was stirred at room temperature for 20 hr. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (980 mg, yield 17%).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([S:18]([CH2:21][CH:22]([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH2:13]2)[C:8]([C:25]2[N:26]=[C:27]3[CH:33]=[CH:32][N:31](COCC[Si](C)(C)C)[C:28]3=[N:29][CH:30]=2)=[CH:7][N:6]=1)(=O)=O.[CH3:42][NH:43][CH3:44].CS(C)(=O)=O>>[CH3:42][N:43]([CH3:44])[C:5]1[N:10]=[C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([S:18]([CH2:21][CH:22]([CH3:23])[CH3:24])(=[O:19])=[O:20])[CH2:13]2)[C:8]([C:25]2[N:26]=[C:27]3[CH:33]=[CH:32][NH:31][C:28]3=[N:29][CH:30]=2)=[CH:7][N:6]=1
Reactant: CC(C)CS(=O)(=O)N1CCC[C@H](Nc2nc(S(C)(=O)=O)ncc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1
Reactant: CNC
Agent: CS(C)(=O)=O
Product: CC(C)CS(=O)(=O)N1CCC[C@H](Nc2nc(N(C)C)ncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
From {2-methanesulfonyl-5-[5-(2-trimethysilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-[(S)-1-(2-methyl-propane-1-sulfonyl)-piperidin-3-yl]-amine derived from Example 3, step 1, dimethylamine was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5 of Example 76 to give N*2*,N*2*-dimethyl-N*4*-[(S)-1-(2-methyl-propane-1-sulfonyl)-piperidin-3-yl]-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidine-2,4-diamine. MS (ES+): 459.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[C:3]=1[C:4](OC)=[O:5].C(O)(=O)C.[CH:20](N)=[NH:21]>COCCO>[CH3:15][O:14][C:8]1[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:21][CH:20]=[N:1]2
Reactant: COC(=O)c1c(N)cc(OC)cc1OC
Reactant: N=CN
Solvent: COCCO
Solvent: CC(=O)O
Product: COc1cc(OC)c2c(=O)[nH]cnc2c1
Yield: 92.8 %

Procedure:
A mixture of methyl 2-amino-4,6-dimethoxybenzoate (16 g), formamidine acetate (24 g) and 2-methoxyethanol (330 ml) was stirred and heated to reflux until all of the starting material had reacted. The mixture was evaporated and the residue was triturated under water (100 ml). The resultant solid was isolated, washed with water and dried under vacuum to give 5,7-dimethoxy-3,4-dihydroquinazolin-4-one (14.5 g); NMR Spectrum: (DMSOd6) 3.82 (s, 3H), 3.86 (s, 3H), 6.5 (s, 1H), 6.7 (s, 1H), 7.9 (s, 1H), 11.7 (br s, 1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:11][Si:12]([C:15]#[C:16][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)([CH3:14])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1ccc([N+](=O)[O-])cc1
Yield: 69.8 %

Procedure:
A mixture of p-bromonitrobenzene (2.02 g, 10 mmol), bis(triphenylphosphine)palladium(II) chloride (0.2 g, 0.3 mmol), and copper(I) iodide (0.05 g, 0.3 mmol) in 40 ml of N,N-diisopropylamine was degassed by freeze/pump/thaw technique (three times). Trimethylsilylacetylene (1.2 g, 12 mmol) was added and the mixture was refluxed for 12 hours. After removal of amine by rotary evaporation, the residue was dissolved in CH2Cl2 and washed with water. The organic layer was dried (Na2SO4), filtered, and rotary evaporated. The residue was purified by column chromatography (EtOAc/hexanes, 1:10) to afford 4-(trimethylsilylethynyl)nitrobenzene (1.53 g, 70%). (Procedure adapted from Takahashi, S; Kuroyama, Y; Sonogashira, K; Hagihara, N. Synthesis, 1980, 627.)
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.[CH3:17][C:18]([CH3:21])([O-])[CH3:19].[Na+].BrCC1CC1.O>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:17][CH:18]3[CH2:21][CH2:19]3)[C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Reactant: CC(C)(C)[O-]
Agent: BrCC1CC1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1C2COCCN2c2nc(Cl)ncc2N1CC1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.1 %

Procedure:
To a mixture of 2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (3 g, 12.47 mmol) in DMSO (10 mL) cooled in an ice water bath was added sodium tert-butoxide (1.32 g, 13.7 mmol). After 15 minutes stirring, the mixture was allowed to warm up to room temperature and stirred for 45 minutes. Then (bromomethyl)cyclopropane (1.27 mL, 13 mmol) was added dropwise in 12 minutes and the resulting mixture stirred at room temperature for 15 hours. Water was added and the resulting yellow precipitate was collected by vacuum filtration and washed repeatedly with water. The solid was subjected to vacuum for 4 hours to give 2-chloro-5-(cyclopropylmethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one as a yellow solid (3.57 g, 97%). MS [M+H] found 295.2.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.Cl.[CH:19]1([NH:22][C:23](=[O:37])[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[C:26]([CH3:36])[CH:25]=2)[CH2:21][CH2:20]1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C>C(#N)CC>[CH:19]1([NH:22][C:23](=[O:37])[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:31][CH2:32][N:33]([CH2:2][C:3]4[CH:12]=[N:11][C:10]5[N:9]6[CH2:13][CH2:14][CH2:15][C@H:8]6[C:7](=[O:16])[NH:6][C:5]=5[CH:4]=4)[CH2:34][CH2:35]3)=[C:26]([CH3:36])[CH:25]=2)[CH2:21][CH2:20]1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: Cc1cc(C(=O)NC2CC2)ccc1N1CCNCC1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC2CC2)ccc1N1CCN(Cc2cnc3c(c2)NC(=O)[C@@H]2CCCN32)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
To a suspension of (S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (0.1 g, 0.456 mmol), N-cyclopropyl-3-methyl-4-(piperazin-1-yl)benzamide dihydrochloride (0.179 g, 0.538 mmol), and (cyanomethyl)trimethylphosphonium iodide (0.188 g, 0.775 mmol) in Propiononitrile (Volume: 2.0 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.556 mL, 3.19 mmol) at 23° C. The reaction was stirred at 90° C. for 8 hr. The reaction mixture was cooled to room temperature, filtered, and rinsed with propiononitrile (3×1 mL). The resulting solid was reconstituted in DMSO (Volume: 3.0 mL) and purified via preparative mass trigger LCMS using a gradient eluant of 25-65% ACN: 10 mM NH4HCO3 (aq). The collected fractions were combined and the ACN was removed via rotary evaporation to furnish a suspension. The suspension was filtered, rinsed with H2O (3×10 mL), and the resulting solid was dried in vacuo to provide (S)—N-cyclopropyl-3-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (0.0624 g, 0.135 mmol, 29.7% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.50-0.59 (m, 2H) 0.60-0.70 (m, 2H) 1.86-2.00 (m, 3H) 2.14-2.20 (m, 1H) 2.25 (s, 3H) 2.47-2.50 (m, 4H) 2.76-2.93 (m, 5H) 3.34-3.44 (m, 3H) 3.55-3.63 (m, 1H) 3.93-4.02 (m, 1H) 6.96-7.04 (m, 2H) 7.56-7.67 (m, 3H) 8.22 (d, J=4.29 Hz, 1H) 10.45 (s, 1H). ESI-MS: m/z 461.4 (M+H)+. mp=226.7-233.5° C.
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].CCN(CC)CC.[CH3:12][N:13]1[C:17]([CH3:18])=[C:16]([C:19]([NH:21][C:22]2[CH:44]=[CH:43][C:25]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34](=O)[O:35]C4C=CC=CC=4)[CH:28]=3)=[CH:24][CH:23]=2)=[O:20])[C:15](=[O:45])[N:14]1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN1C(=O)CCC1>[CH2:2]([NH:4][C:34](=[O:35])[NH:33][C:29]1[CH:28]=[C:27]([O:26][C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:19]([C:16]3[C:15](=[O:45])[N:14]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[N:13]([CH3:12])[C:17]=3[CH3:18])=[O:20])=[CH:44][CH:43]=2)[CH:32]=[CH:31][N:30]=1)[CH3:3]
Reactant: CCN
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)cc2)c(=O)n(-c2ccccc2)n1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCNC(=O)Nc1cc(Oc2ccc(NC(=O)c3c(C)n(C)n(-c4ccccc4)c3=O)cc2)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.6 %

Procedure:
To a solution of ethylamine hydrochloride (29 mg, 0.356 mmol) was in NMP (3 mL) was added Et3N (0.1 mL). The solution was stirred at rt for 10 minutes, followed by the addition of phenyl (4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)phenoxy)pyridin-2-yl)carbamate (100 mg, 0.187 mmol). The reaction was stirred at 40° C. overnight, then concentrated in vacuo at 40° C., and diluted with water (10 mL). The precipitate was collected by filtration, and then purified by a silica gel column chromatography (DCM/EtOAc/MeOH (v/v/v)=80/40/1) to give the title compound as a white solid (46 mg, 50%).
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.[Br:14][CH2:15][CH2:16][CH2:17]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Br:14][CH2:15][CH2:16][CH2:17][O:7][C:4]1[CH:3]=[CH:2][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=1
Reactant: BrCCCBr
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: BrCCCOc1ccc(-c2ccccc2)cc1
Reaction time: 24 h
Yield: 63.9 %

Procedure:
To a solution of 4-biphenylol (0.0514 g, 0.302 mmol) in acetonitrile (4 mL) was added 1,3-dibromopropane (0.310 mL, 3.05 mmol) followed by Cs2CO3 (0.154 g, 0.472 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (4 mL) and extracted with DCM (8 mL). The organic layer was dried through a phase separator and concentrated under vacuum. The residue was taken up in DMSO and purified by preparatory HPLC (without TFA) to give the title compound (0.0562 g, 64.0%). EI-MS Rt (2.62 min).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10](=O)[CH2:11][NH:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[CH:3]=1.B.[CH3:24]SC>C1COCC1.[Ni].CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][N:12]([CH3:24])[C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH:3]=1
Reactant: CSC
Reactant: Cc1cc(C)nc(NC(=O)CNc2ccc([N+](=O)[O-])cc2)c1
Agent: [Ni]
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)nc(NCCN(C)c2ccc(N)cc2)c1

Procedure:
From 1-fluoro-4-nitrobenzene by heating with glycine at reflux in a mixture of aqueous sodium bicarbonate and dioxane to give (4-nitro-phenylamino)-acetic acid, followed by treatment with formaldehyde and formic acid at reflux to give [methyl-(4-nitro-phenyl)-amino]-acetic acid. Treatment with thionyl chloride and catalytic DMF to give the acid chloride followed by amide formation with 2-amino-4,6-dimethylpyridine in triethylamine and chloroform gives N-(4,6-dimethyl-pyridin-2-yl)-2-(4-nitro-phenylamino)-acetamide. The amide is the reduced with borane-dimethylsulfide in THF at reflux then catalytic hydrogenation over Raney nickel in methanol gives the required aniline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[CH:3]=1.Cl[C:10]1[C:11]2[C:18]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])=[CH:17][N:16]([CH3:27])[C:12]=2[N:13]=[CH:14][N:15]=1.FC(F)(F)C(O)=O>C(OCC)C>[NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:10]2[C:11]3[C:18]([C:19]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:20])=[CH:17][N:16]([CH3:27])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cc(C(=O)c2ccccc2)c2c(Cl)ncnc21
Reactant: Nc1cccc(N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Cn1cc(C(=O)c2ccccc2)c2c(Nc3cccc(N)c3)ncnc21

Procedure:
(4-((3-aminophenyl)amino)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(phenyl)methanone was synthesized according to general procedure A step 2 using 1,3-diaminobenzene and (4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(phenyl)methanone. A white solid was obtained. M.p: 170-173° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.53 (s, 1H), 8.12 (s, 1H), 8.06 (s, 1H), 7.86 (d, J=6.6 Hz, 2H), 7.71 (d, J=4.3 Hz, 2H), 7.68 (d, J=4.3 Hz, 2H), 7.43 (d, J=7.8 Hz, 1H), 7.13 (t, J=7.8 Hz, 1H), 6.95 (d, J=5.8 Hz, 1H), 6.69 (s, 1H), 6.57 (d, J=1.9 Hz, 1H), 3.68 (s, 3H); LCMS [M+H]: 344; Calc. C20H17N5O.1.6 trifluoroacetic acid.0.1 diethyl ether: C, 53.16; H, 3.70; N, 13.13. Found C, 50.79; H, 3.73; N, 12.93.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[CH3:10][C:11]1[CH:12]=[C:13]([C:17](=O)[CH3:18])[CH:14]=[CH:15][CH:16]=1.[C:20](#[N:24])[CH2:21][C:22]#[N:23]>C(O)(=O)C.O>[CH3:10][C:11]1[CH:12]=[C:13]([C:17](=[C:21]([C:20]#[N:24])[C:22]#[N:23])[CH3:18])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)c1cccc(C)c1
Reactant: N#CCC#N
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC(=O)O
Solvent: O
Product: CC(=C(C#N)C#N)c1cccc(C)c1
Temperature: 70 °C
Yield: 106.4 %

Procedure:
To a stirred solution of acetic acid (10 mL) was added dropwise hexamethyldisilazane (3.89 mL, 18.65 mmol) over ca. 30 min with the temperature kept below 40° C. throughout the addition. This resulting solution was subsequently added to a stirred solution of 1-(3-methylphenyl)ethanone (2.03 mL, 14.91 mmol) and malononitrile (1.88 mL, 29.8 mmol) in acetic acid (10 mL) and the mixture heated to 70° C. under nitrogen overnight. The reaction mixture was then cooled to RT, diluted with water (ca. 50 mL) and extracted with toluene (ca. 50 mL×2). The combined organic layer was passed through a phase separator and the solvent concentrated in vacuo, to give the title compound (2.89 g) which was used in next step without further purification. LCMS (A) m/z: 181 [M−1]−, Rt 1.23 min (acidic).
Reaction SMILES: Cl[O-].[Na+].[OH-].[Na+].[C:6]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:19])[CH:15]=2)[CH:10]=1)(=[O:8])C.CC1(C)CC=C(C2C=CC(C)=CC=2)C2C=C(C#CC3C=CC(C(OCC)=[O:45])=CC=3)C=CC1=2>O.O1CCOCC1>[Br:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:6]([OH:8])=[O:45])[CH:18]=[CH:17]2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Reactant: CC(=O)c1ccc2cc(Br)ccc2c1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc2cc(Br)ccc2c1
Temperature: 70 °C
Yield: 232.7 %

Procedure:
To a solution of sodium hypochlorite (62 ml, 5.25% in water (w/w), 3.6 g, 48.18 mmol) and sodium hydroxide (6.4 g, 160.6 mmol) in 50 ml of water was added a solution of 2-acetyl-6-bromonaphthalene (Compound L) 4 g, (1 6.06 mmol) in 50 ml of 1,4-dioxane. The yellow solution was heated to 70° C. in an oil bath for 2 hours, cooled to ambient temperature, and extracted with ethyl ether (2×50 ml). The aqueous layers were diluted with NaHSO3 solution (until KI indicator solution remained colorless) and then acidified (pH <2) with 1N sulfuric acid to give a white precipitate. The mixture was extracted with ethyl ether, and the combined organic phase washed with saturated aqueous NaCl, dried (MgSO4) and concentrated to give 3.54 g (88%) of the title compound as a solid. 1H NMR (DMSO-d6): δ8.63 (1H, br s), 8.32 (1H, d, J=2.0 Hz), 8.10 (1H, d, J=8.8 Hz), 8.00-8.05 (2H, m), 7.74 (1H, dd, J=2.0, 8.8 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:12])[CH2:9][CH2:10][NH2:11])[CH2:4][CH:3]=1.S(=O)(=O)(O)O.C#[N:19]>>[NH2:19][C:2]1([CH3:1])[CH2:7][CH2:6][CH:5]([CH:8]([CH2:9][CH2:10][NH2:11])[CH3:12])[CH2:4][CH2:3]1
Reactant: CC1=CCC(C(C)CCN)CC1
Reactant: C#N
Agent: O=S(=O)(O)O
Product: CC(CCN)C1CCC(C)(N)CC1
Temperature: 45 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
660 g of this amine were added dropwise to 1200 g of 70% sulphuric acid at 5 to 10° C. 170 ml of hydrocyanic acid were then added dropwise at 30 to 35° C., the mixture was stirred for a further 4 hours at 45° C. and the excess hydrocyanic acid was distilled off under vacuum. 300 ml of water were then added and the mixture was heated for 3 hours to reflux, rendered alkaline with 1400 ml of 45% sodium hydroxide solution and decanted from the precipitated salt. The phases were separated, the salts and the aqueous phase were extracted twice with toluene and the mixture was distilled under vacuum. 656 g (90%) of 1-amino-1-methyl-4-(4-aminobut-2-yl)cyclohexane, b.p.10 135 to 137° C. were obtained.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].C([C:10](=[CH2:14])[C:11]([NH2:13])=[O:12])CCC.[CH:15]([C:17]1C=CC=C[C:18]=1C=C)=[CH2:16].O>C(O)C>[C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH2:16]([NH:13][C:11](=[O:12])[CH:10]=[CH2:14])[CH2:15][CH2:17][CH3:18]
Reactant: C=C(CCCC)C(N)=O
Reactant: C=Cc1ccccc1C=C
Agent: C=CC(N)=O
Solvent: CCO
Solvent: O
Product: C=CC(=O)NCCCC

Procedure:
Polystyrenesulfonate (15.0 mmoles, 2.612 g), acrylamide (7.2 mmoles, 0.512 g), n-butylacrylamide (7.2 mmoles, 0.916 g) and divinylbenzene (0.6 mmoles, 85.5 microL) were dissolved in 5 mL ethanol and 15 mL water in a 40 mL vial fitted with a septum cap. The solution was degassed by bubbling nitrogen through and 1 mole % AIBN was added as a solution. The polymerization solution was further degassed and the placed in a heated reaction block at 60° C. for 18 h. A clear, colorless gel formed.