Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:12])[CH2:4][S:5][CH2:6][C:7]1[O:11][CH:10]=[CH:9][CH:8]=1.[H-].[K+].Cl>CO.O>[CH2:6]([S:5][CH2:4][C:3]([OH:12])=[O:2])[C:7]1[O:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)CSCc1ccco1
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)CSCc1ccco1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 g of methyl-2-(furfurylthio)acetate was dissolved in 60 ml of methanol, and the solution prepared by dissolving 4.25 g of 85% potassium hydride in 15 ml of water was added dropwise. The mixture was stirred for 2 hours at room temperature, and pH was adjusted to 5 by adding 2N aqueous hydrochloric acid. Water and methanol were evaporated under reduced pressure. 100 ml of ethyl acetate and 100 ml of water were added to the residue and extraction was carried out. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evapoated in vacuo to obtain the captioned 2-(furfurylthio)acetic acid. Yield: 9.2 g.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[C:37]([F:38])=[CH:36][C:26]([C:27]([NH:29][C@@H:30]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31]2)=[O:28])=[C:25]([F:39])[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:19][CH2:18]3)[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[C:37]([F:38])=[CH:36][C:26]([C:27]([NH:29][C@@H:30]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31]5)=[O:28])=[C:25]([F:39])[CH:24]=4)=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1CC[C@@H](NC(=O)c2cc(F)c(N)cc2F)C1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1CC[C@@H](NC(=O)c2cc(F)c(Nc3ncc4c(n3)N(C3CCCC3)CC3(CC3)C(=O)N4C)cc2F)C1
Temperature: 100 °C
Yield: 55.8 %

Procedure:
2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 109 mg, 0.36 mmol), aniline (Intermediate 229; 83 mg, 0.324 mmol), and caesium carbonate (211 mg, 0.648 mmol) added to dioxane (3 mL) and the suspension bubbled with nitrogen for 10 minutes. Tris-dibenzylideneacetone dipalladium (II) (11 mg, 0.02 mmol) and XANTPHOS (17 mg, 0.03 mmol) were added and the mixture heated to 100° C. for 16 hours. The reaction mixture was cooled to room temperature filtered, and the filter cake washed with DCM and the filtrate evaporated. The residue was dissolved in DCM and purified on a silica column eluting with a gradient of 0-5% 2M ammonia in MeOH/DCM over 30 column volumes. Product containing fractions were combined and evaporated and the residue purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (95 mg, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[O:4][CH:5]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)[CH:6]([OH:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[H-].[Na+].[CH2:24](Br)[CH3:25]>O1CCOCC1>[CH2:24]([O:11][CH:6]([C:7]([CH3:8])([CH3:9])[CH3:10])[CH:5]([O:4][C:3]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:2]=1[Cl:1])[N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)[CH3:25]
Reactant: CCBr
Reactant: CC(C)(C)C(O)C(Oc1ccc(Cl)cc1Cl)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(C(Oc1ccc(Cl)cc1Cl)n1ccnc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
33 g (0.1 mol) of 1-(2,4-dichlorophenoxy)-3,3-dimethyl-1-imidazol-1-yl-butan-2-ol were dissolved in 150 ml of dioxane and the solution was added dropwise to 3.5 g of 80% strength sodium hydride in 150 ml of dioxane. The mixture was stirred for 3 hours at room temperature. After addition of 13.1 g (0.12 mol) of ethyl bromide, the mixture was stirred under reflux for further 17 hours. After cooling, the solvent was distilled off in vacuo, the residue was taken up in 600 ml of methylene chloride and the methylene chloride solution was washed twice with 1,000 ml of water each time, dried over sodium sulphate and distilled under a high vacuum. 10 g (28% of theory) of 2-ethoxy-1-(2,4-dichlorophenoxy)-3,3-dimethyl-1-imidazol-1-yl-butane of boiling point 170°-175° C./0.2 mm Hg were obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[O:7]1[CH2:11][CH2:10][O:9][CH:8]1[C:12]1[N:17]=C(C(=O)C)[CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[O:7]1[CH2:11][CH2:10][O:9][CH:8]1[C:12]1[CH:13]=[CH:14][CH:15]=[C:1]([C:2]([CH3:5])=[CH2:3])[N:17]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)c1cccc(C2OCCO2)n1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C(C)c1cccc(C2OCCO2)n1
Reaction time: 0.75 h

Procedure:
1.62 g of potassium tert-butoxide (14.4 mmol) are added in portions to a suspension of 5.25 g of (methyl)triphenylphosphonium bromide (14.7 mmol) in 30 ml of tetrahydrofuran maintained under a nitrogen atmosphere. The mixture is stirred for 45 minutes and then a solution of 0.95 g of 1-(6-[1,3]dioxolan-2-yl-pyridin-2-yl)ethanone (4.92 mmol) in 5 ml of tetra-hydrofuran is introduced dropwise. The mixture is stirred for 12 hours at room temperature and then it is poured into a saturated aqueous solution of ammonium chloride. The mixture is extracted with ethyl acetate, the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is taken up in diethyl ether and the precipitate formed is removed by filtration. After evaporation of the solvent, the title product is isolated by chromatography on a silica column (eluent: hexane/ethyl acetate; 85:15). 0.67 g of a pale yellow oil is obtained.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@H:28]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@H:28]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: COC(=O)C[C@@H](CC(C)C)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(F)c(-c2cc(COc3ccc([C@@H](CC(=O)O)CC(C)C)cc3)ccc2C(C)(C)C)c1
Reaction time: 19 h
Yield: 81.2 %

Procedure:
To a stirred solution of 46.2 (0.047 g, 0.09 mmol) in THF (2.00 mL, 0.10 mmol) and EtOH (2.00 mL, 0.10 mmol) at 23° C. was added a 1 M solution of sodium hydroxide (1 mL, 1 mmol). The resulting reaction mixture was stirred for 19 hours. The resulting reaction was concentrated in vacuo. 1 N HCl was added to bring the pH to 1, and the resulting mixture was extracted EtOAc, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 46 (36 mg, 80% yield) as a colorless oil. MS ESI (neg.) m/e: 983.5 (M−H)+, 491.2 (M−H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([F:29])([CH2:14][NH:15][C:16]2[NH:17][C:18]3[CH:24]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=[CH:21][C:19]=3[N:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:30].O1CCOCC1>CO>[ClH:30].[CH3:28][O:27][C:25]([C:23]1[CH:22]=[CH:21][C:19]2[N:20]=[C:16]([NH:15][CH2:14][C:11]3([F:29])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[NH:17][C:18]=2[CH:24]=1)=[O:26]
Reactant: COC(=O)c1ccc2nc(NCC3(F)CCN(C(=O)OC(C)(C)C)CC3)[nH]c2c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(NCC3(F)CCNCC3)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 4-fluoro-4-({[5-(methoxycarbonyl)benzimidazol-2-yl]amino}methyl)piperidinecarboxylic acid tert-butyl ester (1.2 g, 2.95 mmol) in MeOH (6 ml), a 4N hydrogen chloride/1,4-dioxane solution (3.7 ml, 14.7 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to obtain 2-{[(4-fluoro-4-piperidyl)methyl]amino}benzimidazole-5-carboxylic acid methyl ester hydrochloride. The compound was identified by LC-MS.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[N:8][CH:7]=[CH:6]2.B(Br)(Br)Br.O.CCOC(C)=O>C(Cl)Cl>[N:16]1([CH2:15][CH2:14][O:13][C:9]2[C:10]3[C:5](=[CH:4][C:3]([OH:2])=[CH:12][CH:11]=3)[CH:6]=[CH:7][N:8]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1ccc2c(OCCN3CCCCC3)nccc2c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Oc1ccc2c(OCCN3CCCCC3)nccc2c1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
6-Methoxy-1-(2-(piperidin-1-yl)ethoxy)isoquinoline (0.60 g, 2.10 mmol) was dissolved in 30 mL of dry CH2Cl2 at room temperature. BBr3 (10.50 mmol, 10.50 mL of 1.0 M CH2Cl2 solution) was added dropwise with stirring via a syringe at room temperature. The reaction solution was allowed to stir overnight at room temperature. The mixture was cooled to 0° C. in an ice bath and hydrolyzed by adding water. EtOAc was added to partition the solution. The organic layer was separated; the aqueous layer was extracted with EtOAc twice. The organic layers were combined, washed with brine and dried over anhydrous MgSO4. The solvent was removed under vacuum. The residue was purified by flash column chromatography using silica-gel with CH3OH/CH2Cl2 (1/9 v/v) to give a white solid product, 40 g, 70.2% yield. MS: 273.2 [M+H]+. 1H NMR (DMSO-d6, 300 MHz) δ 10.29 (s, 1H), 8.05 (d, 1H, J=8.7 Hz), 7.32 (d, 1H, J=7.2 Hz), 6.93 (d, 1H, J=8.4 Hz), 6.87 (s, 1H), 6.43 (d, 1H, J=7.2 Hz), 4.03 (s, br, 2H), 2.62 (s, br, 2H), 2.50 (s, br, 2H), 1.49-1.39 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)[CH3:2]>C(O)C.[Pt]=O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(Oc2ccc(N)cc2)cc1
Reaction time: 1 h

Procedure:
A mixture of 7.5 g of ethyl[ p-(p-nitrophenoxy)phenyl]acetate and 200 mg of platinum oxide in 200 ml of ethanol is shaken under 45 lbs of hydrogen for one hour and then filtered through diatomaceous earth which is washed with 20 ml of ethanol. The combined filtrate and washings are concentrated to a yellow oil. Bulb-to-bulb distillation affords a pale yellow opaque oil, b.p. 176° at 0.1 mm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH3:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=1B1OC(C)(C)C(C)(C)O1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:21][C:20]1[CH:19]=[CH:18][C:17]([CH3:16])=[C:23]([C:2]2[CH:3]=[C:4]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[CH:22]=1
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cn1cc(Br)cc(N2CCOCC2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1ccc(N)cc1-c1cc(N2CCOCC2)c(=O)n(C)c1
Temperature: 120 °C
Yield: 31 %

Procedure:
To a solution of 5-bromo-1-methyl-3-morpholinopyridin-2(1H)-one (1.0 equiv.) and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.2 equiv.) in DME and 2M sodium carbonate (3:1, 0.14 M) was added PdCl2(dppf)-DCM adduct (0.1 equiv.) in a microwave vial equipped with a stir bar. The reaction was heated to 120° C. for 15 min in the microwave. The solution was partitioned between water and ethyl acetate, the organic phase was dried with sodium sulfate, filtered and concentrated. The crude material was purified via silica gel column chromatography eluting with 100% ethyl acetate followed by 10% methanol in ethyl acetate. The pure fractions were concentrated and dried under vacuo to afford 5-(5-amino-2-methylphenyl)-1-methyl-3-morpholinopyridin-2(1H)-one in 31% yield. LCMS (m/z) (M+H)=300.2, Rt=0.41 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([N+:13]([O-])=O)[CH:5]=1)([O-])=O.[N+](C1C=C(C=C([N+]([O-])=O)C=1)N)([O-])=O.NC1C=C([N+]([O-])=O)C=C(N)C=1.[H][H]>>[NH2:1][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[C:6]([NH2:13])[CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: Nc1cc(N)cc([N+](=O)[O-])c1
Agent: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Product: Nc1cc(N)cc(N)c1

Procedure:
The compounds of the formula (I) can be synthesized e.g. by hydrogenation of 1,3,5-trinitrobenzene, 3,5-dinitroaniline or 1,3-diamino-5-nitrobenzene with hydrogen and an appropriate metal catalyst in an appropriate organic solvent. The thus obtained 1,3,5-triaminobenzene can be isolated or optionally transferred into the corresponding hydrochloride and can be purified in both forms by recrystallization from an appropriate solvent. It is also possible to use the solution of the crude trisamine or the isolated crude trisamine (with or without removal of the water formed in the hydrogenation) for the subsequent acylation reaction. Possible catalysts are e.g. Pd. PtO2, Raney-Nickel etc., preferably the commercially available versions on carbon support. The hydrogenation can be carried out under normal pressure or under pressure at temperatures between 20 and 120° C. (Safety checks are highly recommended before scale up). Appropriate solvents for the hydrogenation are e.g. tetrahydrofuran (THF), THF/methanol, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP). An alternative procedure is reduction with Raney-Nickel and hydrazine as hydrogen source (see e.g. Organikum, chapter 8.1, Reduktion von Nitroverbindungen und Nitresoverbindung, Berlin, 1970) or other known standard reductions. Recrystallization can be carried out e.g. with methanol, ethanol or other alcohols. The free amine (or the amine obtained from the hydrochloride and an appropriate base) can be acylated with a stoichiometric amount or an excess of the corresponding acid chloride, preferably in the presence of an organic or inorganic non-interacting base e.g. triethylamine, tributylamine, pyridine; another method uses a stoichiometric amount or an excess of the anhydride of the carboxylic acid as acylating agent; in this case no base is required. The reaction is carried out in the absence or preferably in the presence of a solvent. The ideal reaction temperature depends on the nature of the acylating agents (e.g. 0°-100° C.). Isolation/purification of the final product is carried out by precipitation/recrystallization/washing with an appropriate mixture of water/organic solvent or organic solvent/organic solvent or with a pure solvent, e.g. DMF/water, NMP/water, ethanol, methanol etc.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1.[NH3:22]>>[F:1][C:2]([F:21])([F:20])[CH2:3][N:4]=[C:5]([NH2:22])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1
Reactant: N
Reactant: N#CCCCSc1nccc(NC(=S)NCC(F)(F)F)n1
Product: N#CCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4-[4-(3-[2,2,2-trifluoroethyl]thioureido)pyrimid-2-ylthio]butyronitrile (0.32 g.), saturated ethanolic ammonia (20 ml.) and yellow mercuric oxide (0.5 g.) was stirred at room temperature for 20 hours and then filtered and the filtrate evaporated to dryness. The residue was recrystallised from a mixture of acetone and petroleum ether (b.p. 60°-80°) to give 4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyronitrile (0.29 g.), m.p. 137°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].Br[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][CH:18]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2(C)CC=CC=C2C2C=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][CH:18]=2)[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(P(C2CCCCC2)C2CCCCC2)CC=CC=C1c1ccccc1
Solvent: Cc1ccccc1
Product: CCOc1ccc(N2CCC(CNC(=O)OC(C)(C)C)CC2)cc1
Temperature: 70 °C
Yield: 61.7 %

Procedure:
A suspension of piperidin-4-ylmethyl-carbamic acid tert-butyl ester (1.0 g; 4.67 mmol), 1-bromo-4-ethoxy-benzene (1.87 g; 9.33 mmol), tris(dibenzylideneacetone)dipalladium (174 mg; 0.19 mmol), sodium tert-butoxide (524 mg; 4.67 mmol) and 2-(dicyclohexylphosphino)-2-methylbiphenyl (135 mg; 0.37 mmol) in toluene (30 mL) is thoroughly flushed with argon. The reaction mixture is then heated at 70° C. for 17 hours. After dilution with ethyl acetate (50 mL), the suspension is filtered over Celite and the filtrate is washed with aq. sat ammonium chloride (2×25 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue obtained is then further purified by flash column chromatography on silica gel (Ethyl acetate:heptane 25:75) to afford the desired product (963 mg; 2.88 mmol).
Reaction SMILES: C([C:3]([OH:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]1[N:8]([CH3:9])[C:7]([CH2:10][C:11]([O:13]C)=[O:12])=[CH:6][CH:5]=1)#N.Cl>[OH-].[Na+]>[C:3]([C:4]1[N:8]([CH3:9])[C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1ccc(C(O)(C#N)c2ccccc2)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CC(=O)O)ccc1C(=O)c1ccccc1
Yield: 71.3 %

Procedure:
A suspension of 1.0 g of methyl 5-(cyanohydroxyphenylmethyl)-1-methylpyrrole-2-acetate in 20 ml of 5 percent sodium hydroxide solution was heated under reflux for 30 minutes. The solution was acidified with 3 N hydrochloric acid solution. The solid was collected and recrystallized from acetonitrile to give 0.61 g (77 percent yield) of white crystalline 5-benzoyl-1-methylpyrrole-2-acetic acid, mp 145°-6°, undepressed by admixture with authentic product.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=3)[CH:15]=[CH:16][C:17]=1[Cl:18])[N:5]=2.[Cl:33][CH2:34][C:35](Cl)=[O:36]>CN(C)C(=O)C.C(OCC)(=O)C>[Cl:18][C:17]1[CH:16]=[CH:15][C:14]([NH:19][C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:28])[CH3:29])[CH:22]=2)=[CH:13][C:12]=1[O:11][C:6]1[N:5]=[C:4]2[S:3][C:2]([NH:1][C:35](=[O:36])[CH2:34][Cl:33])=[N:10][C:9]2=[CH:8][CH:7]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Cl)c(Oc3ccc4nc(N)sc4n3)c2)c1
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Cl)c(Oc3ccc4nc(NC(=O)CCl)sc4n3)c2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chlorophenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.431 mmol) produced in Example C50(v) in N,N-dimethylacetamide (3.0 mL) was added chloroacetyl chloride (75.4 μL, 0.948 mmol), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate (20 mL), washed with 5% aqueous sodium hydrogen carbonate solution (20 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give N-[4-chloro-3-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)phenyl]-3-(1-cyano-1-methylethyl)benzamide as an oily residue.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28](Br)=[CH:27][N:26]=4)=[O:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1>[F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28]([N:38]5[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]5)=[CH:27][N:26]=4)=[O:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NC1CCC(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)CC1)c1ccc(Br)cn1
Reactant: CN1CCNCC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCN(c2ccc(C(=O)NC3CCC(CCN4CCC(C(=O)c5ccc(F)cc5)CC4)CC3)nc2)CC1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
5-Bromo-pyridine-2-carboxylic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide (80 mg, 0.15 mmol) and 1-methylpiperazine (31 μl, 0.28 mmol) were dissolved in 2 ml dioxane. 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9 mg, 0.016 mmol), cesium carbonate (76 mg, 0.23 mmol), water (1 μl, 0.078 mmol) and tri(dibenzylideneacetone)dipalladium chloroform complex (8 mg, 0.008 mmol) were added and the reaction mixture was stirred for 16 hrs at 110° C. The reaction mixture was then evaporated and purified by flash chromatography on silica gel (dichloromethane/methanol 100:0->90:10 gradient). The desired product was obtained as a light red solid (33 mg, 40%), MS: m/e=536.0 (M+H+).
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)([O-:3])=[O:2].[BH4-].[Na+]>C1COCC1.CO>[N+:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1ccc2c(C=C[N+](=O)[O-])c[nH]c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(CC[N+](=O)[O-])c[nH]c2c1
Reaction time: 1.5 h

Procedure:
Combine 3-(2-nitrovinyl)-6-ethoxycarbonyl-1H-indole (4.0 g, 15.37 mmol) and NaBH4 (726.7 mg, 19.21 mmol) in 100 ml of THF/Methanol (9:1) and stir at ambient temperature. After 1.5 hours, concentrate to residue. Partition the residue between brine and ethyl acetate, wash with brine, combine the organic layers, dry (Na2SO4), then evaporate to give the title compound as a yellow powder: mp 124–127° C. MS (ACPI): m/e 263.0 (M+1). Analysis for C13H14N2O4: Calcd: C, 59.54; H, 5.38; N, 10.68; found: C, 59.40; H, 5.36; N, 10.53.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH:36]([CH2:39][OH:40])[CH2:37][OH:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH:36]([CH2:39][OH:40])[CH2:37][OH:38])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Reactant: NC(CO)CO
Product: O=C(NC(CO)CO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-amino-1,3-propanediol using methods similar to Example 563 to provide a white solid: ES+ MS: 513 (M+H+).