Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH:19]=1)[C:7]([NH:9][C:10]1[S:11][C:12]2[O:18][CH2:17][CH2:16][CH2:15][C:13]=2[N:14]=1)=[O:8].CC(C)([O-])C.[K+].Br[CH2:29][CH2:30][CH2:31][CH3:32]>CN(C)C=O.O1CCCC1>[CH2:29]([N:14]1[C:13]2[CH2:15][CH2:16][CH2:17][O:18][C:12]=2[S:11]/[C:10]/1=[N:9]\[C:7](=[O:8])[C:6]1[CH:19]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:20][CH3:21])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCBr
Reactant: COc1ccc(Cl)cc1C(=O)Nc1nc2c(s1)OCCC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCn1c2c(s/c1=N\C(=O)c1cc(Cl)ccc1OC)OCCC2
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of the product from Example 26B (mixture) in 10 mL of N,N-dimethylformamide and tetrahydrofuran (1:4) were added potassium t-butoxide (21 mg, 0.18 mmol) and 1-bromobutane (25 mg, 0.18 mmol). After stirring at 80° C. for 16 h, the reaction mixture was cooled to room temperature and quenched with saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-50% ethyl acetate in methylene chloride) to afford 3 mg of the title compound as a single regioisomer. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.94 (t, J=7.3 Hz, 3H), 1.28-1.42 (m, 2H), 1.73 (t, 2H), 2.06 (t, 2H), 2.67 (t, J=6.3 Hz, 2H), 3.79 (s, 3H), 4.06-4.13 (m, 2H), 4.18-4.25 (m, 2H), 7.11 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 3.1 Hz, 1H), 7.71 (d, J=3.1 Hz, 1H); MS (ESI+) m/z 381 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:13]1[C:18]([N+:19]([O-])=O)=[CH:17][N:16]=[C:15]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:25][CH2:24]2)[N:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH3:2]>CO.CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:13]1[C:18]([NH2:19])=[CH:17][N:16]=[C:15]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:25][CH2:24]2)[N:14]=1)[C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1nc(NC2CCN(CCOC)CC2)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)C(C(=O)OC(C)(C)C)c1nc(NC2CCN(CCOC)CC2)ncc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
2-{2-[1-(2-Methoxy-ethyl)-piperidin-4-ylamino]-5-nitro-pyrimidin-4-yl}-malonic acid tert-butyl ester ethyl ester (5, 733 mgs, 1.6 mmol) was dissolved in a mixture of MeOH (15 mls) and EtOAc (5 mls) to which was added 10% Pd/C (137 mgs). The reaction mixture was stirred under an atmosphere of H2 at room temperature and pressure for 2 hrs, filtered through Celite with thorough washing with MeOH and the filtrate concentrated in vacuo to give 2-{5-amino-2-[1-(2-methoxy-ethyl)-piperidin-4-ylamino]-pyrimidin-4-yl}-malonic acid tert-butyl ester ethyl ester (6, 677 mgs, 99%) which was used in the next reaction without further purification. LC/MS Calcd for [M+H]+ 438, found 438.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].CCN(CC)CC.[C:16](Cl)(=[O:20])[CH:17]([CH3:19])[CH3:18]>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)C(C)C

Procedure:
10.00 g of glycine ethyl ester hydrochloride (71.6 mmol) and 21.97 ml of NEt3 (2.2 eq.) were dissolved in 200 ml of CH2Cl2 and treated between 0° and 5° dropwise with 7.81 ml of isobutyryl chloride (1.05 eq.), dissolved in 50 ml of CH2Cl2. The reaction mixture was allowed to reach ambient temperature (2.5 h) and then quenched by carefully pouring onto crashed ice/HCl/AcOEt. Separation of the layers, additional extraction of the aqueous phase with AcOEt, washing with Na2CO3 and brine, drying of the combined organic phase over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=6/4) yielded 11.74 g of the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCN(C)CC1
Temperature: 105 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A mixture of 200 mg (0.455 mmol) of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile (Reference Example 20) and 273 mg (2.73 mmol) of N-methylpiperazine in 1 mL of 1-methyl-2-pyrrolidinone was heated at 105° C. for 16 hours. The solvents are removed in vacuo. A 10 mL portion of water is added to the residue, from which a tan solid precipitates out. The solid is filtered off and washed with water. After drying in vacuo, the solid is suspended in ethyl acetate and stirred for 1 hour. The solid is filtered off, washed with ethyl acetate and dried in vacuo to provide 0.175 g of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-6-methoxy-7-(4-methypiperazin-1-yl)-quinoline-3-carbonitrile as a yellow solid, mp 270-272° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Br[CH2:18][C:19]1[N:29]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:22]2[N:23]=[C:24]([C:27]#[N:28])[N:25]=[CH:26][C:21]=2[CH:20]=1>CN(C=O)C.C1OCCOCCOCCOCCOCCOC1>[CH3:32][C:31]([CH3:34])([CH3:33])[CH2:30][N:29]1[C:22]2[N:23]=[C:24]([C:27]#[N:28])[N:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[CH2:18][N:14]1[CH2:15][CH2:16][N:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH3:3])[CH2:12][CH2:13]1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Reactant: COc1ccccc1N1CCNCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
To a suspension of NaH (0.91 mmol) in DMF (10 ml), 1-(2-methoxyphenyl)piperazine (1.04 mmol) and 18-crown-6 (0.003 mmol) are successively added at 0° C. To the mixture, 6-bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.65 mmol) is added at 0° C. and the mixture is stirred for 2 h at ambient temperature. The reaction mixture is quenched with ice-water and extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over magnesium sulfate. Chromatography on silica gel (eluent; n-hexane:AcOEt=1:1) give 227 mg of desired 7-(2,2-Dimethyl-propyl)-6-[4-(2-methoxy-phenyl)-piperazin-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 83% yield.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])=[CH:14][C:13]=2[F:25])[NH:4][CH:3]=1.C([Li])CCC.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1.C(=O)(O)[O-].[Na+]>C1COCC1.O>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:21])[F:22])=[CH:14][C:13]=2[F:25])[N:4]([S:37]([C:34]2[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=2)(=[O:39])=[O:38])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(Nc1ccc(Cc2ccnc3[nH]cc(Br)c23)c(F)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(Cc4ccc(NC(=O)C(F)(F)F)cc4F)ccnc32)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
1.70 g (4.08 mmol) of N-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl]-3-fluorophenyl}-2,2,2-trifluoroacetamide are dissolved in 50 ml of THF and cooled to −78° C. A solution of n-butyllithium (2.81 ml, 1.6M in hexane, 4.49 mmol) is added dropwise. After 15 min, a solution of 860 mg (4.49 mmol) of p-toluenesulfonyl chloride in 5 ml of THF is added dropwise. The mixture is allowed to warm to RT and stirred for 1 h. Water and saturated sodium bicarbonate solution are then added, and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography on silica gel (mobile phase dichloromethane:ethanol=50:1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([N+]([O-])=O)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:20](C1C=CC(NN)=CC=1)#[N:21]>>[NH2:19][C:7]1[N:8]([C:10]2[CH:15]=[CH:14][C:13]([C:20]#[N:21])=[CH:12][CH:11]=2)[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: N#Cc1ccc(NN)cc1
Product: CC(C)(C)c1cc(N)n(-c2ccc(C#N)cc2)n1
Yield: 85 %

Procedure:
The title compound was prepared (85% yield) in the same manner as described for 5-tert-butyl-2-(4-nitro-phenyl)-2H-pyrazol-3-ylamine, replacing 4-nitrophenylhydrazine with 4-cyanophenylhydrazine. MS LC-MS [M+H]+=241, RT=2.39 min.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([O:26]C)=[O:25])=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>O.CO>[CH2:3]([C:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([OH:26])=[O:25])=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCc1c[nH]c2cc(C(=O)OC)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCc1c[nH]c2cc(C(=O)O)ccc12
Temperature: 0 °C
Yield: 73.3 %

Procedure:
A solution of sodium hydroxide (15 g) in water (100 ml) was added dropwise during 30 minutes to a refluxing solution of methyl 3-(n-dodecyl)indole-6-carboxylate (12.8 g prepared as hereinbefore described in Example 85) in methanol (800 ml). The mixture was stirred and refluxed for 12 hours. The mixture was then concentrated to 500 ml volume and water (400 ml) was added. After cooling to 0° C., a solid was collected and was dissolved in hot glacial acetic acid (300 ml). The solution was then poured into water (800 ml) and a solid was collected, washed with water (4×100 ml) and dried at 60° C. Recrystallisation of the solid from methanol gave 3-(n-dodecyl)indole-6-carboxylic acid (9.0 g), in the form of a white solid, m.p. 181°-184° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C@H:11]3[CH2:15][CH2:14][CH2:13][NH:12]3)[O:10][C:5]2=[CH:4][C:3]=1[Cl:16].Cl.[CH2:18]=O>C(O)=O.CCOCC>[ClH:1].[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C@H:11]3[CH2:15][CH2:14][CH2:13][N:12]3[CH3:18])[O:10][C:5]2=[CH:4][C:3]=1[Cl:16]
Reactant: Clc1cc2oc([C@H]3CCCN3)cc2nc1Cl
Reactant: C=O
Agent: Cl
Solvent: CCOCC
Solvent: O=CO
Product: CN1CCC[C@@H]1c1cc2nc(Cl)c(Cl)cc2o1
Temperature: 60 °C
Yield: 46 %

Procedure:
5,6-Dichloro-2-(2-(R)-pyrrolidinyl)furo[3,2-b]pyridine from Example 39b (56 mg, 0.22 mmol) was dissolved in an aqueous solution of 37% formaldehyde (excess) and 88% formic acid (excess). The aqueous mixture was heated to 60° C. for 1 hour and then allowed to cool to ambient temperature. The reaction mixture was washed with Et2O, basified with 15% NaOH solution and extracted with CH2Cl2 (2×). The organic phases were combined, dried (MgSO4), concentrated and chromatographed (silica gel; CHCl3 /MeOH, 98:2) to afford a solid. The solid was dissolved in Et2O (10 mL) and a saturated solution of HCl in Et2O was added dropwise. The solvent was removed and the product recrystallized from MeOH/Et2O to afford a white solid (31 mg, 46%): mp 244-246° C.; 1H NMR (D2O, 300 MHz) δ 2.27-2.37 (m, 2H), 2.47-2.71 (m, 2H), 2.93 (s, 3H), 3.38 (m, 1H), 3.78 (m, 1H), 4.81 (m, partially buried under H2O peak, 1H), 7.27 (s, 1H), 8.26 (s, 1H); MS (CI/NH3) m/z: 271 (M+H)+ ; Anal. Calcd for C12H12Cl2N2O.HCl: C, 46.85; H, 4.26; N, 9.11. Found: C, 46.53; H, 4.21; N, 8.82.
Reaction SMILES: F[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([F:8])=[CH:6][N:7]=1.C[O-].[Na+].[C:14](OCC)(=[O:16])C.O>CO>[F:8][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2]([O:16][CH3:14])=[N:7][CH:6]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1nc(F)cnc1F
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ncc(F)nc1C#N
Temperature: 0 °C

Procedure:
In 25 mL of methanol was dissolved 2.5 g of 3,6-difluoro-2-pyrazinecarbonitrile. Then, 2.4 g of 28% methanolic solution of sodium methoxide was dropwise added at 5-15° C., and the mixture thus formed was stirred at an ice-cooled temperature for 2 hours. The reaction mixture was poured into a mixture of 50 mL of ethyl acetate and 50 mL of water, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=10:1] to obtain 0.45 g of 6-fluoro-3-methoxy-2-pyrazinecarbonitrile as a colorless oily product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[C:17]2[S:18][C:19]3[CH2:20][CH2:21][O:22][C:23]4[CH:30]=[C:29]([C:31]5[CH:32]=[N:33][N:34]([CH2:36][C:37]([OH:40])([CH3:39])[CH3:38])[CH:35]=5)[CH:28]=[CH:27][C:24]=4[C:25]=3[N:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.[Cl:46]N1C(=O)CCC1=O.Cl>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([N:12]2[C:16]([Cl:46])=[CH:15][N:14]=[C:13]2[C:17]2[S:18][C:19]3[CH2:20][CH2:21][O:22][C:23]4[CH:30]=[C:29]([C:31]5[CH:32]=[N:33][N:34]([CH2:36][C:37]([OH:40])([CH3:39])[CH3:38])[CH:35]=5)[CH:28]=[CH:27][C:24]=4[C:25]=3[N:26]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4nccn4C4CN(C(=O)OC(C)(C)C)C4)nc2-3)cn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncc(Cl)n4C4CN(C(=O)OC(C)(C)C)C4)nc2-3)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To a solution of 3-(2-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-imidazol-1-yl)-azetidine-1-carboxylic acid tert-butyl ester (90.0 mg, 0.179 mmol) in N,N-Dimethylformamide (3.35 mL, 43.3 mmol) was added N-Chlorosuccinimide (19 mg, 0.14 mmol) and 1.00 M of Hydrogen chloride in Water (0.018 mL). The reaction was stirred at rt 4 h. the reaction was quenched with water then extracted with EtOAc 3×. The organic layer was dried Na2SO4, concentrated. The crude product was purified by isco column to give 3-(5-Chloro-2-{8-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-imidazol-1-yl)-azetidine-1-carboxylic acid tert-butyl ester (EtOAc/Hep eluted at 75%). MS: (ESI+)=483.1
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[Br:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1.C([O-])(O)=O.[Na+]>C(OCC)C>[Br:11][C:12]1[CH:13]=[C:14]([S:18]([O:5][C:4]2[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=2)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.8 %

Procedure:
To a solution of 534 mg (4.30 mmol) of orcinol monohydrate and 1.00 g (3.91 mmol) of 3-bromobenzenesulfonyl chloride in 25 mL of diethyl ether was added 25 mL of saturated aqueous NaHCO3 and the biphasic mixture was stirred vigorously at ambient temperature for 3 days. The layers were separated and the aqueous layer extracted with 2×30 mL of ethyl acetate. The combined organic layers were washed with 50 mL of brine, dried (Na2SO4) and concentrated to 1.4 g of an amber-colored resin. Chromatography on 65 g of silica gel with 3% ethyl acetate-dichloromethane afforded 870 mg (65%) of the desired product as a colorless syrup: 1H-NMR (300 MHz; CDCl3) δ 8.02 (t, 1H, J=1.8 Hz), 7.79 (m, 2H), 7.41 (t, 1H, J=7.9 Hz), 6.57 (m, 1H), 6.40 (m, 1H), 6.33 (t, 1H, J=2.2 Hz) and 2.24 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([F:10])[CH:3]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)=[C:4]([F:10])[CH:3]=1
Reactant: C1=COCCC1
Reactant: OCc1ccc(Br)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: Fc1cc(Br)ccc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.4 %

Procedure:
Mix under nitrogen atmosphere 4-bromo-2-fluorobenzyl alcohol, (4.1 g, 20 mmol), dihydropyran (2 g, 24 mmol), p-toluenesulfonic acid monohydrate (100 mg, 0.52 mmol), and anhydrous DCM (70 mL). Stir for 16 h at ambient temperature. Dilute with DCM, wash sequentially with saturated aqueous NaHCO3 then brine. Separate the organic layer, dry over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain the desired intermediate as a clear oil (4.36 g, 75%). MS (ES+) m/z: 312 (M+Na)+.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:9]=[O:10])=[C:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)c1cccc(OCc2ccccc2)c1
Reactant: CN(C=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1cc(OCc2ccccc2)ccc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104 %

Procedure:
A mixture of N-methylformanilide (9.92 g) and phosphoryl chloride (11.3 g) was stirred at room temperature for 30 minutes, and benzyloxy-3-isopropylbenzene (16.6 g) was added to the mixture. After being stirred at room temperature overnight, ice was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford 4-benzyloxy-2-isopropylbenzaldehyde (19.4 g) as a crude product. An aqueous solution (200 mL) of sodium chlorite (33.2 g) was added dropwise to an ice-cooled suspension of the crude 4-benzyloxy-2-isopropylbenzaldehyde and potassium dihydrogenphosphate (50.0 g) in tert-butylalcohol (200 mL)/2-methyl-2-butene (100 mL) with stirring. The mixture was stirred at room temperature for 3 hrs. To the resulting mixture was added water, and the insoluble materials were removed by filtration. The filtrate was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford 4-benzyloxy-2-isopropylbenzoic acid (23.3 g) as a crude product. A suspension of the crude 4-benzyloxy-2-isopropylbenzoic acid, ethyl iodide (13.7 g) and potassium carbonate (15.2 g) in N,N-dimethylformamide (300 mL) was stirred at room temperature for30 minutes. The reaction mixture was partitioned between diethyl ether and water. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to afford ethyl 4-benzyloxy-2-isopropylbenzoate (16.8 g). A suspension of ethyl 4-benzyloxy-2-isopropylbenzoate and 10% palladium-carbon (0.1 g) in ethanol (100 mL) was stirred at room temperature for 30 minutes under an atmosphere of hydrogen. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to afford the title compound (1.1 g).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[NH2:23][CH2:24][C:25]([CH3:29])([OH:28])[CH:26]=[CH2:27]>C(Cl)Cl>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:23][CH2:24][C:25]([CH3:29])([OH:28])[CH:26]=[CH2:27])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: C=CC(C)(O)CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(C)(O)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12

Procedure:
Triethyl amine (6.2 mL, 0.045 mole) was added to a solution of 2,4-dichloro-3-nitroquinoline (10.9 g 0.045 mole) in methylene chloride (60 mL). 4-Amino-3-methyl-1-butene-3-ol was added and the reaction mixture was heated at reflux for several hours before being concentrated under vacuum. The residue was chilled in an ice bath to give a solid. The solid was recrystallized from toluene to provide 17.1 g of the desired product as a yellow solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][N:8]2[C:13]([C:15]1[N:20]=[CH:19][N:18]=[C:17]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[C:35]4[C:30](=[N:31][CH:32]=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:36])[CH2:23][CH2:22]2)[CH:16]=1)=[O:14])([O-])=O.CO.[H][H]>[Pd].C1COCC1>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][N:8]2[C:13]([C:15]1[N:20]=[CH:19][N:18]=[C:17]([N:21]2[CH2:22][CH2:23][CH:24]([N:27]3[C:35]4[C:30](=[N:31][CH:32]=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:36])[CH2:25][CH2:26]2)[CH:16]=1)=[O:14]
Reactant: [H][H]
Reactant: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CCc2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cccc2c1CCN2C(=O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1

Procedure:
Under a hydrogen atmosphere 130 mg (0.27 mmol) 1-{1-[6-(4-nitro-2,3-dihydroindole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 25 mg palladium on charcoal (10%) were hydrogenated in a 1:1 mixture methanol:THF (15 mL of each) at RT and 3 bar hydrogen pressure. Then the catalyst was eliminated by suction filtering and the residue was washed with 50 mL DMF. The filtrate was evaporated down i. vac., the residue was stirred with methanol and suction filtered. The solid was dried at 50° C. in the CAD.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:21][C:22]=2[CH3:23])[CH2:13][CH2:12]1.[CH3:30]C1N=C(C2C=C(C)C=CC=2)NC=1C=O.CC1N=C(C2C=CC=CC=2)NC=1C=O>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][CH:25]=3)[NH:21][C:22]=2[CH3:23])[CH2:13][CH2:12]1
Reactant: Cc1[nH]c(-c2ccccc2)nc1CN1CCC(Nc2nc3ccccc3o2)CC1
Reactant: Cc1cccc(-c2nc(C)c(C=O)[nH]2)c1
Agent: Cc1nc(-c2ccccc2)[nH]c1C=O
Product: Cc1cccc(-c2nc(CN3CCC(Nc4nc5ccccc5o4)CC3)c(C)[nH]2)c1

Procedure:
The title compound was prepared according to the procedure described for the synthesis of example 325 (benzooxazol-2-yl-[1-(5-methyl-2-phenyl-1H-imidazol-4-ylmethyl)-piperidin-4-yl]-amine) using 5-methyl-2-m-tolyl-3H-imidazole-4-carbaldehyde ([CAS RN 68283-20-5] prepared as described in U.S. Pat. No. 4,107,307 (American Cyanamid Company)) instead of 5-methyl-2-phenyl-3H-imidazole-4-carbaldehyde. MS (ESI): 402.5 [M+H]+.