Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][NH:32][CH2:33][CH2:34][CH2:35][CH3:36]>O1CCOCC1>[CH2:33]([N:32]([CH3:31])[C:27]([NH:28][C:22]1[CH:21]=[C:20]([CH2:19][N:13]2[C:14]([CH3:18])([CH3:17])[C:15](=[O:16])[N:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:10][CH:9]=3)[C:12]2=[O:30])[CH:25]=[CH:24][N:23]=1)=[O:26])[CH2:34][CH2:35][CH3:36]
Reactant: CCCCNC
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Solvent: C1COCCO1
Product: CCCCN(C)C(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)ccn1

Procedure:
This compound may be prepared as obtained in stage c) of Example 9, but starting with 150 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9, 3 mL of dioxane and 36.9 mg of N-methylbutan-1-amine. After chromatography on a column of silica, eluting with a mixture of heptane/ethyl acetate (gradient from 100/0 to 0/100 by volume), 77.8 mg of 1-butyl-3-(4-{[3-(4-tert-butyl-phenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-1-methylurea are obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=2)[CH:3]=1.[CH3:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:23][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=2)[CH:3]=1
Reactant: Nc1cccc(Nc2cc(Cl)ncn2)n1
Reactant: Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(Oc2cc(Nc3cccc(N)n3)ncn2)c1
Temperature: 145 °C
Yield: 75.8 %

Procedure:
A mixture of 2,6-diaminopyridine (1.530 g, 14.020 mmol) and 4,6-dichloropyrimidine (2.610 g, 17.519 mmol) in 15 mL of n-butanol in a sealed vial was heated at 100° C. for 72 h. The dark brown sample was cooled and was concentrated at reduced pressure to remove most of the n-butanol. The residue was then partitioned between EtOAc and saturated. NaHCO3 solution. An emulsion formed, the sample was filtered through a pad of Celite and the layers were separated. The organic extract was washed with sat. KH2PO4 and brine solutions, dried (MgSO4), filtered and concentrated to brown oily-solid. The sample was suspended into ˜50 mL of CH2Cl2, cooled and filtered to give 1.017 g (36%) of N-(6-chloro-pyrimidin-4-yl)-pyridine-2,6-diamine as yellow-orange solid. MS: m/z 222/224 (M+1, 100/63%). To a solution of N-(6-chloro-pyrimidin-4-yl)-pyridine-2,6-diamine (100 mg, 0.45 mmol) in DMF (1 mL) was added 3-methylphenol (88 mg, 0.8 mmol) and anhydrous K2CO3 (93 mg, 0.6 mmol). The reaction mixture was heated at 145° C. for 16 h. It was then cooled and DMF was removed under reduced pressure to get a yellow gummy residue. The residue was taken in EtOAc (20 mL), was washed sequentially with water (5 mL) and brine (5 mL) and was dried over Na2SO4. Filtration followed by concentration under reduced pressure afforded a yellow gum which was further purified by column chromatography (SiO2, 60-120, EtOAc/hexane, 5/5) to give 100 mg of 2-[6-(3-methylphenoxy)-pyrimidin-4-yl]amino-6-aminopyridine (IR-12) as a pale yellow solid. MS: m/z 294 (M+H)
Reaction SMILES: [OH-].[Li+].[CH3:3][S:4]([NH:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:26]([O-:28])=[O:27])[N:14]2[C:17]([O:19]CCC(C)(C)C)=[O:18])=[CH:10][CH:9]=1)(=[O:6])=[O:5].CO.O>C1COCC1>[CH3:10][C:11]([O:19][C:17]([N:14]1[C:15]2[C:11](=[CH:10][CH:9]=[C:8]([NH:7][S:4]([CH3:3])(=[O:5])=[O:6])[CH:16]=2)[CH:12]=[C:13]1[C:26]([OH:28])=[O:27])=[O:18])([CH3:15])[CH3:12]
Reactant: CC(C)(C)CCOC(=O)n1c(C(=O)[O-])cc2ccc(NS(C)(=O)=O)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)n1c(C(=O)O)cc2ccc(NS(C)(=O)=O)cc21
Temperature: 50 °C
Yield: 79.2 %

Procedure:
Lithium hydroxide (0.068 g, 2.85 mmol) was added to a solution of 1-(1,1-dimethylethyl)2-ethyl 6-[(methylsulfonyl)amino]-1H-indole-1,2-dicarboxylate (0.109 g, 0.285 mmol) in THF:methanol:water/3:1:1 (3 mL). The mixture was heated at 50° C. for 2 hrs. The solvent was evaporated and the residue was dissolved in water, acidified with 1N aqueous HCl and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated to give the title compound (0.040 g, 55%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.92 (br. s., 1H), 11.41-11.79 (m, 1H), 9.32-9.73 (m, 1H), 7.48-7.57 (m, 1H), 7.31 (s, 1H), 6.94-7.00 (m, 1H), 6.88-6.94 (m, 1H), 2.88 (s, 3H). ES MS: m/z 253 (M−1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:16]1([CH2:22][C:23](=O)[C:24](O)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH2:22]([C:23]1[C:24](=[O:25])[N:8]([C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc(Nc2ncccc2N)c1
Reactant: O=C(O)C(=O)Cc1ccccc1
Solvent: CCO
Product: Cc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Yield: 53.8 %

Procedure:
A mixture of 3-amino-2-[(m-tolyl)amino]pyridine (299 mg) and phenylpyruvic acid (246 mg) in ethanol (5 ml) was refluxed for 2 hours. The mixture was cooled and the precipitates were collected and washed with ethanol to give 2-benzyl-3-oxo-4-(m-tolyl)-3,4-dihydropyrido[2,3-b]pyrazine (264 mg).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH:6]=[C:7]([C:13]([O:15]C)=[O:14])[NH:8]3)=[CH:4][C:3]=2[O:2]1.[OH-].[K+]>>[CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH:6]=[C:7]([C:13]([OH:15])=[O:14])[NH:8]3)=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)c1cc2cc3c(cc2[nH]1)OCO3
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1cc2cc3c(cc2[nH]1)OCO3

Procedure:
Following the general procedure of PREPARATION 63 and making non-critical variations but starting with methyl 5,6-methylenedioxyindole-2-carboxylate (PREPARATION 78, 4.77 g), potassium hydroxide (1.47 g), the title compound is obtained, C,H,N analysis calcd. for C10H7NO4C, 58.54; H, 3.44; N, 6.83; found: C, 58.27; H, 3.18; N, 6.95.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13](O)=[O:14])=[CH:12][C:7]=2[S:6][C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[NH:3]1.S(Cl)([Cl:22])=O>>[Cl:22][C:13]([C:11]1[CH:10]=[CH:9][C:8]2[C:2](=[O:1])[NH:3][C:4]3[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=3[S:6][C:7]=2[CH:12]=1)=[O:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1NC2=O
Product: O=C(Cl)c1ccc2c(c1)Sc1ccccc1NC2=O

Procedure:
Heat a solution of 5 gm. of 10,11-dihydro-11-oxodibenzo[b,f][1,4]thiazepin-3-carboxylic acid and 40 ml of thionyl chloride under reflux for 20 minutes. Evaporate the reaction mixture under vacuum to dryness. Repeat the evaporation with two 30 ml portions of carbon tetrachloride. Crystallize the residue from diisopropyl ether to obtain the title product.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32].[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1.[C:38](=O)([O-])[O-:39].[K+].[K+].O>CN(C)C=O>[N:33]1([C:38]([CH2:2][CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([O:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=4[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:24])=[CH:10][CH:11]=[N:12]3)=[CH:7][C:6]=2[O:31][CH3:32])=[O:39])[CH:37]=[CH:36][N:35]=[CH:34]1
Reactant: c1c[nH]cn1
Reactant: O=C([O-])[O-]
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCC(=O)n1ccnc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (50 mg), imidazole (22 mg), and potassium carbonate (76 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (33 mg, yield 63%).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23]C(=O)OC(C)(C)C)[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:39]>>[ClH:39].[NH2:23][C@@H:19]1[CH2:20][CH2:21][CH2:22][N:17]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])[C:4]=23)[CH2:18]1
Reactant: ClCCl
Reactant: CCNC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](N)C3)c12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-(3-ethylureido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.130 g, 0.270 mmol) was placed in DCM (3 mL) at room temperature. TFA (1 mL) was then added. The reaction was stirred at room temperature for 1 hour and concentrated to dryness. The residue was then purified by reverse phase chromatography (Biotage SP4, C-18 12M+, 0-50% ACN in water). The resulting product was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (R)-1-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-ethylurea hydrochloride (0.100 g, 81.5% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.27 (s, 1H), 7.27 (s, 1H), 3.86-3.83 (m, 1H), 3.56-3.54 (m, 1H), 3.48-3.45 (m, 1H), 3.26-3.21 (m, 2H), 3.04-2.99 (m, 2H), 2.09-2.06 (m, 1H), 1.81-1.70 (m, 2H), 1.57-1.55 (m, 1H), 0.94-0.90 (m, 3H). LCMS (APCI+) m/z 381, 383 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:15](=[O:25])[C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:15](=[O:25])[C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccccc2Cc2cc(Cl)ccc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)N2Cc3ccccc3Cc3cc(Cl)ccc32)cc1
Yield: 73.9 %

Procedure:
A solution of 2.1 g of 2-chloro-5-(4-nitrobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine in 400 ml of ethyl acetate-ethanol (1:1) and 0.25 g of palladium-on-carbon is hydrogenated in a Parr hydrogenator under 38 pounds per square inch of hydrogen. The mixture is filtered through diatomaceous earth and the filtrate concentrated to dryness. The solid (1.94 g) is dissolved in dichloromethane and the solution filtered through a thin pad of hydrous magnesium silicate. The filter pad is washed with dichloromethane and the filtrate concentrated. The residue is crystallized from dichloromethane-hexane to give 1.43 g of crystals, m.p. 211-214° C.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[C:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20])=[O:15])([O-])=O.C(O)C.O>C(O)(=O)C.[Fe]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[C:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20])=[O:15]
Reactant: N#Cc1cccc(C(=O)c2ccc3ccccc3c2[N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: N#Cc1cccc(C(=O)c2ccc3ccccc3c2N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
3-(1-nitro-2-naphthoyl)benzonitrile (6.22 g, 20.6 mmol) was dissolved at 65° C. in acetic acid (150 mL), ethanol (150 mL) and water (15 mL). After cooled to room temperature, to the solution was added iron powder (6.67 g, 119 mmol). To the mixture was stirred at 65° C. for 1 hour, and cooled to room temperature. The resultant mixture was added silica gel (100 g), filtered, and the residue was washed with ethyl acetate. The filtrate and washings were combined, washed with a saturated aqueous sodium bicarbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform), to give the titled compound as a yellow crystal (5.40 g, yield 96%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.O.[C-:11]#[N:12].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:11]#[N:12]
Reactant: [C-]#N
Reactant: BrCc1ccccc1Br
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccccc1Br
Temperature: 0 °C
Yield: 96.4 %

Procedure:
25 g (100 mmol) of 2-bromobenzyl bromide is mixed in 100 ml of N,N-dimethylformamide and 64 ml of water with 9.75 g (150 mmol) of potassium cyanide and stirred overnight at room temperature. The reaction mixture is poured into ice water. After 3× extraction with methyl-tert butyl ether, the combined organic extracts are washed with brine, dried, and the solvent is spun off. The residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 18.9 g (96.4%) of the desired compound is obtained.
Reaction SMILES: [C:1]([CH:5]1[CH2:17][CH2:16][C:8]2([O:12][N:11]=[C:10]([C:13]([OH:15])=O)[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].N[CH2:19][C:20]1[CH:25]=CC(NS(C)(=O)=O)=C(F)[CH:21]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.[N:46]1(OC(N(C)C)=[N+](C)C)[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=2N=N1>CN(C=O)C>[C:20]([C:53]1[CH:52]=[CH:51][C:50]([NH:46][C:13]([C:10]2[CH2:9][C:8]3([CH2:7][CH2:6][CH:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:17][CH2:16]3)[O:12][N:11]=2)=[O:15])=[CH:49][CH:54]=1)([CH3:25])([CH3:21])[CH3:19]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: CC(C)(C)C1CCC2(CC1)CC(C(=O)O)=NO2
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(NC(=O)C2=NOC3(CCC(C(C)(C)C)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound 8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid (120 mg, 0.51 mmol), N-(4-aminomethyl-2-fluorophenyl)methanesulphonamide (110 mg, 0.51 mmol), 4-methylmorpholine (101 mg, 1.02 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (288 mg, 0.65 mmol) (HBTU) were dissolved in DMF (10 ml) and stirred overnight under a nitrogen atmosphere at RT. The solvent was removed under vacuum, the residue taken up in EtOAc and sat. aq. NaHCO3 solution and the phases were separated. The aqueous phase was extracted several times with EtOAc and the combined organic phases were dried over magnesium sulphate and the solvent was removed under vacuum. After purification by column chromatography (silica gel, hexane/EtOAc 2:1), the desired product 8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid-(4-tert-butylphenyl)amide was obtained as a trans isomer (30 mg, 13% of the theoretical amount) and cis isomer (100 mg, 45% of the theoretical amount).
Reaction SMILES: Cl.[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.CC(OC([NH:20][C:21]1[S:25][C:24]2[CH:26]=[C:27]([C:30](O)=[O:31])[CH:28]=[CH:29][C:23]=2[N:22]=1)=O)(C)C.ClCCl.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:30]([C:27]3[CH:28]=[CH:29][C:23]4[N:22]=[C:21]([NH2:20])[S:25][C:24]=4[CH:26]=3)=[O:31])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(C(=O)O)cc2s1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc2ccc(C(=O)NC3C4CC5CC3CN(C5)C4)cc2s1
Reaction time: 8 h

Procedure:
The protected amide [6-(1-azatricyclo[3.3.1.13,7]dec-4-ylcarbamoyl)-benzothiazol-2-yl)-carbamic acid tert-butyl ester] was prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 2-N-Boc-amino-4-benzothiazole-6-carboxylic acid (Astatech) according to method A. The resulting material was dissolved in dichloromethane (4 mL), treated with dichloromethane-trifluoroacetic acid (4 mL, 1:1), and stirred overnight. After concentrating the reaction mixture under a nitrogen stream, the residue was triturated with ether, and washed with ether and ethyl acetate to afford the title compound; yield 20 mg, 0.03 mmol (43%): 1H NMR (300 MHz, methanol-d4) δ 2.05-2.31 (m, 5H), 2.46 (s, 2H), 3.41-3.61 (m, 4H), 3.83 (d, J=13 Hz, 2H), 4.27 (s, 1H), 7.47 (d, J=8 Hz, 1H), 7.88 (d, J=8 Hz, 1H), 8.23 (s, 1H); MS (DCI/NH3) m/z 329 (M+H)+; Anal. C17H20N4OS.2C2HF3O2: C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:16](N)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O[N:25]1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C=O)C>[CH2:16]([C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[C:9]([OH:15])[C:10]([C:12]([NH2:25])=[O:14])=[CH:11][C:2]=2[Cl:1])[N:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: On1nnc2cccnc21
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cc(Cl)c2cccnc2c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Cl)c2ccc(Cc3ccccc3)nc2c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-8-hydroxyquinoline-7-carboxylic acid (0.50 g, 2.24 mmol), benzylamine (0.29 g, 2.68 mmol), 1-hydroxy-7-azabenzotriazole (0.36 g, 2.68 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.51 g, 2.68 mmol), and triethylamine (0.62 mL, 4.47 mmol) in DMF (15 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. The residue was dissolved in DMSO and subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provide the title compound as yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1.C(=O)([O-])[O-:17].[K+].[K+]>O>[OH:17][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(CBr)cc1C(F)(F)F
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(CO)cc1C(F)(F)F
Temperature: 95 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a suspension of 4-bromomethyl-2-trifluoromethyl-benzoic acid (Example I7) (13.03 g) in water (200 ml) was added potassium carbonate (31.1 g). The reaction mixture was stirred at 95° C. for 1 hour. The reaction mixture was then allowed to cool to ambient temperature and was quenched by addition of aqueous hydrochloric acid (5M) (250 ml). The mixture was extracted with ethyl acetate (3×150 ml). The extracts were dried over sodium sulfate and concentrated. The residue was crystallized from ethyl acetate and heptane to give 4-hydroxymethyl-2-trifluoromethyl-benzoic acid (9.07 g) as a white crystalline powder. 1H-NMR (DMSO-d6, 400 MHz): 13.5 (br s, 1H), 7.81-7.66 (m, 3H), 5.53 (s, 1H), 4.62 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=C([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])C#N.[OH-:21].[Na+].Cl.[CH2:24]([OH:26])[CH3:25]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[C:25]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:24]([OH:21])=[O:26]
Reactant: CCO
Reactant: [OH-]
Reactant: N#Cc1ccc([N+](=O)[O-])c(Nc2ccc(F)cc2F)c1
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1ccc([N+](=O)[O-])c(Nc2ccc(F)cc2F)c1
Temperature: 0 °C

Procedure:
A mixture of 3-(2,4-difluorophenylamino)-4-nitrobenzonitrile (6.9 g) and 24% sodium hydroxide solution (50 ml) in ethanol (50 ml) was refluxed for 2 hours. The mixture was poured into ice-water (400 ml) and acidified with hydrochloric acid. The precipitate was filtered and washed with water to give red brown needles of 3-(2,4-difluorophenylamino)-4-nitrobenzoic acid (7.1 g).
Reaction SMILES: Cl.[CH:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[C:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24][NH2:25])[CH2:19][CH2:18]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[CH:13]1[C:9]2[CH:10]=[CH:11][C:12]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=3[C:7](=[C:17]3[CH2:18][CH2:19][N:20]([C:23](=[O:26])[CH2:24][NH:25][C:40]([N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:41])[CH2:21][CH2:22]3)[C:8]=2[CH:16]=[CH:15][CH:14]=1
Reactant: NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reactant: O=C(Cl)N1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CNC(=O)N1CCCCC1)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
200 mg (0.545 mmol) of 2-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-2-oxoethanamine hydrochloride was suspended in 2 ml of dichloromethane. 0.19 ml of triethylamine was added to the obtained suspension. A solution of 96.5 mg (0.654 mmol) of 1-piperidinecarbonyl chloride in 3 ml of dichloromethane was added dropwise to the resultant mixture under cooling with ice, and they were stirred at room temperature for 30 minutes. Dichloromethane was concentrated under reduced pressure. Ethyl acetate was added to the residue. The resultant mixture was washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the basic silica gel chromatography (hexane:ethyl acetate=4:1 to 1:4) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:10][C:11]([CH3:14])([O-:13])[CH3:12].[Na+].I[CH2:17][CH2:18][CH2:19][CH3:20].C([O-])(O)=O.[Na+]>CC(N(C)C)=O.O>[C:11]([O:13][C:6]1[C:7]([NH:8][CH2:17][CH2:18][CH2:19][CH3:20])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1)([CH3:14])([CH3:12])[CH3:10]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: CC(C)(C)[O-]
Reactant: CCCCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCCNc1c(Cl)ncnc1OC(C)(C)C
Temperature: 50 °C
Yield: 7.8 %

Procedure:
A mixture of 4,6-dichloropyrimidin-5-amine (1.64 g, 10 mmol), sodium tert-butoxide (1.92 g, 20 mmol) and 1-iodobutane (2.02 g, 11 mmol) in DMA (30 mL) was heated at 50° C. for 12 hours. The mixture was poured into water, treated with saturated aqueous NaHCO3 and extracted with ethyl acetate. The acetate layer was washed with water, brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (hexane-EtOAc 1:1) to afford 200 mg of the title compound. MS (ESI) m/z 258 (M+H)+.