Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH2:10]([N:14]1[C:19](=[O:20])[CH:18]=[N:17][C:16]([CH3:21])=[N:15]1)[CH2:11][CH2:12][CH3:13].[NH4+].[Cl-].C(OCC)(=O)C>CCOCC>[CH2:10]([N:14]1[C:19](=[O:20])[CH:18]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[NH:17][C:16]([CH3:21])=[N:15]1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCn1nc(C)ncc1=O
Reactant: Cc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCN1N=C(C)NC(c2ccc(C)cc2)C1=O
Yield: 86 %

Procedure:
4-Methylphenylmagnesium bromide (1.64 mL, 1.0 M in ether) was added all at once via syringe to a well-stirred solution of 1-n-butyl-3-methyl-1,2,4-triazin-6-one (178 mg, 1.06 mmol) in ether (9.85 mL) under N2 at room temperature. After stirring the resulting mixture overnight, saturated aqueous NH4Cl (10 mL) and ethyl acetate (10 mL) were added, the organic phase was separated, and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (5 g, 4:1 hexanes:ethyl acetate) to afford Compound 22 as a tan solid (236 mg, 86% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24]OS(C)(=O)=O)=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:30])[CH2:4][CH3:5])[CH3:2].[CH2:31]([CH2:33][NH2:34])[OH:32]>>[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH:34][CH2:33][CH2:31][OH:32])=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:30])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCOS(C)(=O)=O)cc3)no2)cc1C
Reactant: NCCO
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCNCCO)cc3)no2)cc1C
Yield: 13 %

Procedure:
The title compound (6 mg) is prepared in analogy to Example 160 starting from methanesulfonic acid 2-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethyl ester (50 mg, 111 μmol) and ethanolamine (34 mg, 556 μmol); LC-MS: tR=0.63 min; [M+1]+=415.07; 1H NMR (CDCl3): δ1.11 (t, J=7.0 Hz, 6H), 2.26 (s, 3H), 2.63 (q, J=7.0 Hz, 4H), 2.80-2.86 (m, 2H), 2.87-2.93 (m, 2H), 2.94-3.00 (m, 2H), 3.62-3.67 (m, 2H), 3.73 (s, 2H), 7.35 (d, J=8.0 Hz, 2H), 7.67 (s, 1H), 8.09 (d, J=8.0 Hz, 2H).
Reaction SMILES: [N:1]1([C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)[C:5]2=[N:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]2[CH2:3][CH2:2]1.Cl[C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=1>CN1C(=O)CCC1.O>[N:1]1([C:13]2[CH:19]=[CH:18][C:16]([NH:17][C:21]3[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:15][CH:14]=2)[C:5]2=[N:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]2[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccc(N2CCn3c2nc2ccccc23)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccnc1Nc1ccc(N2CCn3c2nc2ccccc23)cc1
Temperature: 140 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
A mixture of 4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)aniline (55 mg) and 2-chloro-3-nitropyridine (35 mg) in NMP (3 mL) was stirred at 140° C. overnight. After this time, the reaction mixture was cooled to ambient temperature, diluted with water (50 mL) and extracted with ethyl acetate (2×75 mL). The combined organic layers were washed with water (50 mL) then brine (50 mL), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1:9 ethyl acetate/methylene chloride) to afford N-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-3-nitropyridin-2-amine (34 mg) as a dark brown solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH:8]1[C:20]2[NH:19][C:18](=[O:21])[C:17](=[O:22])[NH:16][C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2>O1CCCC1>[N:1]1([CH:8]2[C:20]3[NH:19][C:18](=[O:21])[C:17](=[O:22])[NH:16][C:15]=3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=c1[nH]c2c([nH]c1=O)C(Cl)c1ccccc1-2
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: O=c1[nH]c2c([nH]c1=O)C(N1CCNCC1)c1ccccc1-2
Reaction time: 72 h
Yield: 35.2 %

Procedure:
Piperazine (1.1 g, 12.8 mmol) was suspended in 15 ml of dry tetrahydrofuran at -20° C. 9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione (1.5 g, 6.4 mmol) was added over 25 min. and the temperature was slowly rised to room temperature while stirring. After 20 hours another portion of piperazine (0.55 g, 6.4 mmol) was added and stirring was continued for 72 hours. The reaction mixture was evaporated in vacuo to dryness and the remanence was suspended in 10 ml 6M HCl. The product was filtered off and washed with 1M HCl and dried to give 1.7 g of the crude product, which was purified by dissolving in aqueous sodium hydroxide and precipitated by adding to hydrochloric acid. The procedure was repeated and the product was finally washed with ethanol and dried to give 0.64 g (27%) of the title compound as a hydrochloride. M.p. 259°-263° C. 1H-NMR (DMSO-d6, δ): 2.65-3.15 (m, 8H), 4.7 (s, 1H), 7.17 (t, 1H), 7.34 (t, 1H), 7.45 (d, 1H), 7.57 (d, 1H), 8.93 (s, 2H), 11.8 (s, 1H), 12.3 (s, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:8][CH:9]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Oc1ccc(Cc2ccc(O)cc2)cc1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc(Cc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 3.36 g of sodium hydride (in mineral oil) in 50 ml of dimethylformamide is added dropwise at room temperature a solution of 15 g bis-(p-hydroxyphenyl)-methane in 50 ml dimethylformamide. The resulting solution is stirred at room temperature for one hour. Ten grams of benzyl chloride is added dropwise and the stirring is continued at room temperature overnight. After evaporation of the solvent under reduced pressure, the residue is treated with 100 ml of water and extracted twice with diethyl ether. The combined ether extracts are combined, dried over anhydrous magnesium sulfate, evaporated to dryness, and the resulting oil dissolved in hot ethanol. Bis(p-(benzyloxy)phenyl)methane crystallizes upon cooling and is collected by filtration. The mother liquors are evaporated to dryness and the crystalline mono-addition product is obtained by chromatography on silica gel with chloroform. After separation, the mono-benzyl ether is recrystallized from isopropyl ether, m.p. 95°-96°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([O:10][CH3:11])=[C:5]([CH3:12])[C:4]=1[CH3:13].[Br:14]Br>C(O)(=O)C>[Br:14][C:8]1[C:7]([CH3:9])=[C:6]([O:10][CH3:11])[C:5]([CH3:12])=[C:4]([CH3:13])[C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1cc(C)c(OC)c(C)c1C
Solvent: CC(=O)O
Product: COc1c(C)c(C)c(OC)c(Br)c1C
Temperature: 0 °C
Yield: 83.6 %

Procedure:
A stirred solution of 1,4-dimethoxy-2,3,5-trimethylbenzene (61.2 g) was dissolved into 350 mL acetic acid (1.0 M) and treated with a solution of Br2 (17.7 mL, 55.1 g) in 115 mL acetic acid over 1 h. The reaction was stirred for an additional hour and poured over 1.5 l ice. The cloudy solution was filtered and the solids washed 2×200 mL H2O and dried under high vacuum. The product was azeotroped twice from toluene to remove residual acetic acid to give 73.6 g of 1-bromo-2,5-dimethoxy-3,4,6-trimethylbenzene as a red-brown solid; Mp 57.2-62.8° C.; 1H NMR (400 MHz, CDCl3) δ=3.75 (s, 3H), 3.66 (s, 3H), 2.35 (s, 3H), 2.22 (s, 3H), 2.17 (s, 3H) ppm.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH:15][C:18](=[O:20])[CH3:19])=[N:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Product: CC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1

Procedure:
introducing an acyl group at the N4 position of 1-β-D-arabinofuranosyl cytosine with an acylating agent, for example using acetic anhydride under conditions suitable for obtaining 1-β-D-arabinofuranosyl-N4-acetyl cytosine,
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].I[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH2:10]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCI
Reactant: OCC1CCCCN1
Product: CCCCCCN1CCCCC1CO
Yield: 102.7 %

Procedure:
2-Piperidine methanol (2.30 g, 20 mmol) and 1-iodohexane (1.5 mL, 10 mmol) were converted to product by the procedure of Preparation 1 to yield 2.048 g (51%) of the title compound. 3H NMR consistent with desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:66]=[CH:65][C:6]([CH2:7][O:8][C:9]([C:11]2[N:12]3[C@H:15]([S:16][CH2:17][C:18]=2[CH2:19]Cl)[C@H:14]([NH:21][C:22](=[O:63])/[C:23](/[C:57]2[N:58]=[C:59]([NH2:62])[S:60][CH:61]=2)=[N:24]\[O:25][C@H:26]([C:41]([O:43][CH:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])[C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34](=[O:36])[CH3:35])=[C:29]([O:37][C:38](=[O:40])[CH3:39])[CH:28]=2)[C:13]3=[O:64])=[O:10])=[CH:5][CH:4]=1.[I-:67].[Na+].O>CC(C)=O>[CH3:1][O:2][C:3]1[CH:66]=[CH:65][C:6]([CH2:7][O:8][C:9]([C:11]2[N:12]3[C@H:15]([S:16][CH2:17][C:18]=2[CH2:19][I:67])[C@H:14]([NH:21][C:22](=[O:63])/[C:23](/[C:57]2[N:58]=[C:59]([NH2:62])[S:60][CH:61]=2)=[N:24]\[O:25][C@H:26]([C:41]([O:43][CH:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])[C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34](=[O:36])[CH3:35])=[C:29]([O:37][C:38](=[O:40])[CH3:39])[CH:28]=2)[C:13]3=[O:64])=[O:10])=[CH:5][CH:4]=1
Reactant: [I-]
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)/C(=N\O[C@H](C(=O)OC(c4ccccc4)c4ccccc4)c4ccc(OC(C)=O)c(OC(C)=O)c4)c4csc(N)n4)C(=O)N23)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(COC(=O)C2=C(CI)CS[C@@H]3[C@H](NC(=O)/C(=N\O[C@H](C(=O)OC(c4ccccc4)c4ccccc4)c4ccc(OC(C)=O)c(OC(C)=O)c4)c4csc(N)n4)C(=O)N23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of the product obtained in Step 6 (14 g) in acetone (210 ml) was added sodium iodide (4.85 g) in total darkness and the mixture was stirred at room temperature for one hour. The reaction mixture was then poured into water (300 ml) and extracted twice with ethyl acetate (500 ml). The combined organic layer was washed with 5% sodium thiosulfate solution (200 ml) and brine (200 ml), and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure, giving 15.1 g of the objective compound as yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][CH2:11][C:12](=[O:28])[NH:13][C:14]1[C:18]([C:19]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[N:20]=2)=[N:17][O:16][N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:36]([O:43][C:44](=[O:56])[NH:45][C:46]1[CH:51]=[CH:50][C:49]([C:52](=[O:55])[CH2:53]Br)=[CH:48][CH:47]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:36]([O:43][C:44](=[O:56])[NH:45][C:46]1[CH:47]=[CH:48][C:49]([C:52](=[O:55])[CH2:53][N:20]2[C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=[C:19]2[C:18]2[C:14]([NH:13][C:12](=[O:28])[CH2:11][NH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:29])=[N:15][O:16][N:17]=2)=[CH:50][CH:51]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(Nc1ccc(C(=O)CBr)cc1)OCc1ccccc1
Reactant: O=C(CNC(=O)OCc1ccccc1)Nc1nonc1-c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CNC(=O)OCc1ccccc1)Nc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.3 %

Procedure:
To a stirred solution of 0.4 g of {[4-(1H-benzoimidazol-2-yl)-furazan-3-ylcarbamoyl]-methyl}-carbamic acid benzyl ester (0.97 mmol, 1 eq.) in 6 mL of N,N′-dimethylformamide are added 0.2 g of potassium carbonate (1.4 mmol; 1.45 eq.) at room temperature followed by the addition of 0.41 g of [4-(2-bromo-acetyl)-phenyl]-carbamic acid benzyl ester (CAS 157014-41-0) (1.16 mmol; 1.2 eq.). The reaction mixture is stirred for 2 h at room temperature and is then diluted with 20 mL of ethyl acetate. The solution is washed with water (2×10 mL) and brine (2×10 mL), dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue is then dissolved in hot ethyl acetate (2 mL) and the solution is placed in an ice-bath. After 0.5 h, the resulting suspension is filtered and the solid is washed with cold ethyl acetate (1 mL) to afford 0.2 g of the desired product as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13][CH2:12]1)[C:5](Cl)=[O:6].[Cl:19][C:20]1[CH:31]=[CH:30][C:23]2[NH:24][C:25]([C@@H:27]([NH2:29])[CH3:28])=[N:26][C:22]=2[CH:21]=1>C1COCC1>[Cl:19][C:20]1[CH:31]=[CH:30][C:23]2[NH:24][C:25]([C@@H:27]([NH:29][C:5](=[O:6])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13][CH2:12]4)=[C:2]([CH3:1])[CH:3]=3)[CH3:28])=[N:26][C:22]=2[CH:21]=1
Reactant: Cc1cc(C(=O)Cl)ccc1N1CCCN(C)CC1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCCN(C)CC1

Procedure:
489 mg (1.61 mmol) 3-methyl-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzoic acid chloride are placed together with 400 mg (3.96 mmol) TEA in 10 ml THF at ambient temperature and a solution of 433 mg (1.61 mmol) (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl amine is added dropwise with stirring. After 16 hours stirring at ambient temperature the mixture is evaporated down i. vac., the residue is combined with water and extracted with ethyl acetate. The combined organic phases are washed with sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac. The residue is purified by chromatography on aluminium oxide (eluant: dichloromethane/methanol 100:1). The fractions evaporated down are treated with ethereal hydrochloric acid, after total concentration evaporated twice with ethyl acetate and diethyl ether and dried i. vac. at 70° C.
Reaction SMILES: ClS([N:5]=C=O)(=O)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13](O)=O.CN(C)C=O>ClCCl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]#[N:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COc1cc(C(=O)O)ccc1C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C#N)ccc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A solution of chlorosulphonyl isocyanate (5.35 ml.) in dichloromethane (3 ml.) was added over 45 minutes to a stirred suspension of 3-methoxy-4-methylbenzoic acid (9.97 g.) in dichloromethane (18 ml.) at reflux under an atmosphere of nitrogen. The resulting bright-red homogeneous solution was heated under reflux for 45 minutes, chilled in an ice-bath, and treated dropwise with N,N-dimethylformamide (9.5 ml.), over 15 minutes. After stirring for 30 minutes at 0° C., the orange solution was poured onto ice. The organic layer was separated, washed with water (5×20 ml.), dried (MgSO4) and evaporated. The residue was purified by preparative HPLC (SiO2, 10:90 v/v hexane: toluene) to give 3-methoxy-4-methylbenzonitrile (5.28 g., 60%) as a white solid, m.p. 51°-52.5° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]#[C:12][CH2:13][CH2:14][OH:15])=[CH:3][N:2]=1>C(O)C.[Pd]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:12]/[CH2:13][CH2:14][OH:15])=[CH:3][N:2]=1
Reactant: OCCC#Cc1cncc2ccccc12
Agent: [Pd]
Solvent: CCO
Product: OCC/C=C/c1cncc2ccccc12
Reaction time: 5 h
Yield: 96.1 %

Procedure:
A solution of 3.4 g of 4-(4-isoquinolinyl)-3-butyn-1-ol in 35 mL of ethanol was hydrogenated over 0.35 g of 10% Pd/C at room temperature and atmospheric pressure for 5 hours. The catalyst was removed by filtration and the filtrate was evaporated to yield 3.3 g of (E)-4-(4-isoquinolinyl)-3- buten-1-ol as an oil.
Reaction SMILES: [CH3:1][Li].[CH3:3][CH:4]1[CH2:9][C:8](=[O:10])[CH:7]=[CH:6][O:5]1.[NH4+].[Cl-]>C(OCC)C.[Cu]I>[CH3:3][CH:4]1[CH2:9][C:8](=[O:10])[CH2:7][CH:6]([CH3:1])[O:5]1
Reactant: CC1CC(=O)C=CO1
Reactant: [Li]C
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1CC(=O)CC(C)O1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 1.6M methyllithium in diethyl ether (20.9 mL, 33.4 mmol) was added to a stirred slurry of copper(I) iodide (4.25 g, 22.30 mmol) in diethyl ether (30 mL) at 0° C. and under nitrogen. The reaction was stirred at 0° C. for 20 min and then racemic 2-methyl-2H-pyran-4(3H)-one (1.25 g, 11.2 mmol) in diethyl ether (12.0 mL) was added over 10 min. The reaction was allowed to warm to RT and stirred 2 h. The reaction mixture was poured into sat NH4Cl (aq) and stirred 20 min. The solution was extracted with diethyl ether (4×60 mL) and the combined organics were washed with brine (˜80 mL), dried (MgSO4), filtered and concentrated to yield racemic (2R,6R)-2,6-dimethyldihydro-2H-pyran-4(3H)-one (Cap-2, step b) (1.34 g) as an orange oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.28-4.39 (m, 2H), 2.55 (ddd, J=14.1, 4.8, 1.5 Hz, 2H), 2.24 (ddd, J=14.1, 6.5, 1.5 Hz, 2H), 1.28 (d, J=6.3 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14][C:15]1[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=1>>[Br:14][C:15]1[CH:16]=[C:17]([NH:21][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Product: O=C(Nc1cccc(Br)c1)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with 3-Bromo-phenylamine to produce N-(3-Bromo-phenyl)-4-chloro-3-nitro-benzamide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 22A and 22B to provide the title product.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]2([C:19]#[N:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=1)=[O:4].O>CO>[OH:4][CH2:3][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]2([C:19]#[N:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=1
Reactant: N#CC1(n2cc(C=O)c3cccnc32)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CC1(n2cc(CO)c3cccnc32)CCCC1
Reaction time: 2 h

Procedure:
0.45 g of sodium borohydride is added in small portions at between 20° and 25° C. to a solution of 4.6 g of compound of stage 1 above in 80 ml of methanol. The mixture is stirred for 2 hours, 2 ml of water are then added, the resulting mixture is evaporated, the residue is taken up with dichloromethane, the dichloromethane solution is washed with water, dried over Na2SO4, filtered and evaporated and the residue is chromatographed on silica gel(eluant: ethyl acetate/hexane, 8:2).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15]2[CH:16]=[N:17][CH:18]=[C:19]([O:20][CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[C:14]=2[C:13]2[CH:34]=[C:35]([Br:38])[CH:36]=[N:37][C:12]1=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.ClCCl>[CH2:1]([O:8][C:9]([N:11]1[C:15]2[CH:16]=[N:17][CH:18]=[C:19]([O:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:14]=2[C:13]2[CH:34]=[C:35]([Br:38])[CH:36]=[N:37][C:12]1=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cncc3c2c2cc(Br)cnc2n3C(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)n1c2cncc(OC3CCNCC3)c2c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.6 %

Procedure:
A solution of 3-bromo-5-(1-tert-butoxycarbonyl-piperidin-4-yloxy)dipyrido[2,3-b;4′,3′-d]pyrrole-9-carboxylic acid benzyl ester (0.34 g, 0.59 mmol) in triflouroacetic acid (2 mL) and dichloromethane (4 mL) was allowed to stir at ambient temperature for 15 minutes. The solvent was evaporated and the resultant residue was treated with saturated sodium hydrogen carbonate solution (20 mL) and extracted with dichloromethane (3×30 mL). The combined organic phase was dried (Na2SO4), filtered and evaporated to afford a residue. The resultant residue was purified by flash chromatography (silica, 12 g cartridge, ISCO, 0-10% methanol in dichloromethane then 10% 2M NH3 in methanol in dichloromethane). The appropriate fractions were combined and evaporated to afford the title compound as a yellow solid (118 mg, 42%). LCMS (Method B): RT=3.13 min, M+H+=481/483. 1H NMR (400 MHz, CDCl3): 9.22 (s, 1H), 8.77 (d, J=2.3 Hz, 1H), 8.62 (d, J=2.4 Hz, 1H), 8.31 (s, 1H), 7.60-7.59 (m, 2H), 7.40-7.40 (m, 3H), 5.63 (s, 2H), 4.86-4.82 (m, 1H), 3.26-3.25 (m, 2H), 2.95-2.94 (m, 2H), 2.29-2.25 (m, 2H), 1.99-1.97 (m, 2H).
Reaction SMILES: [NH2:1][P:2]([NH2:16])([NH:4][C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)=[O:3].[H][H]>[Pd].CN(C)C=O>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]([NH:4][P:2]([NH2:16])([NH2:1])=[O:3])=[O:15])=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: NP(N)(=O)NC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)NP(N)(N)=O)cc1
Reaction time: 60 h

Procedure:
30 g (0.12 mole) of N-[diaminophosphinyl]-4-nitrobenzamide in 800 ml of absolute alcohol was reduced using 4.0 g of 5% Pd/C containing 50% water. A hydrogen uptake of 19.9 psi. was recorded after 60 hr. (theoretical 24 psi.). Added 2000 ml of absolute alcohol and 2000 ml of dimethylformamide to dissolve. The catalyst was removed by filtration and the filtrate flash-evaporated down to 125 ml. Chilled to 0°, filtered and washed with anhydrous ethyl ether to yield 12.4 g (48%), m.p. darkens 168°-172°, softens 290°, decomposes 340°.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH2:19])[CH3:18])=[C:8]([C:11]3[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=3)[CH:9]=2)[CH:4]=[CH:3]1.[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([F:28])=[CH:23][N:22]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[Cl:20][C:21]1[N:26]=[C:25]([NH:19][C@H:17]([C:7]2[N:6]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:10]3=[CH:9][C:8]=2[C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)[CH3:18])[C:24]([F:28])=[CH:23][N:22]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H](Nc1nc(Cl)ncc1F)c1nc2ccn(C)c2cc1-c1ccnn1C
Temperature: 120 °C
Yield: 99.9 %

Procedure:
(S)-1-(1-Methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (90 mg, 0.353 mmol), 2,4-dichloro-5-fluoropyrimidine (88 mg, 0.529 mmol), and N-ethyl-N-isopropylpropan-2-amine (190 μL, 1.058 mmol) were combined in acetonitrile (500 μL). The reaction mixture was heated to 120° C. in a microwave reactor for 1 hour. After removal of solvent, the residue was diluted with MeOH and dichloromethane, and was purified by preparative HPLC, eluting with a gradient of 15-25% ACN in H2O with 0.35% TFA. The fractions were collected and solvent was removed in vacuo to give the title compound (136 mg, 100%). ESI-MS m/z [M+H]+ calc'd for C18H17ClFN7, 386; found 386.