Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5](=[CH:11][CH:12]([C:16]1[C:21]([CH3:22])=[C:20]([Cl:23])[CH:19]=[CH:18][N:17]=1)[CH:13]1[CH2:15][CH2:14]1)[C:6](OCC)=[O:7])[CH3:2]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Cl:23][C:20]1[CH:19]=[CH:18][N:17]2[C:16]([C:21]=1[CH3:22])=[C:12]([CH:13]1[CH2:15][CH2:14]1)[CH:11]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:24])[C:6]2=[O:7]
Reactant: CCOC(=O)C(=CC(c1nccc(Cl)c1C)C1CC1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Temperature: 25 °C
Yield: 75 %

Procedure:
A solution of 2-[2-(3-methyl-4-chloro-pyridin-2-yl)-2-cyclopropyl-ethylidene]-malonic acid diethyl ester (5.76 g, 16.4 mmol) in Dowtherm A (80 mL) was heated in a preheated oil bath at 230° C. for 15 min. The reaction mixture was cooled to room temperature and purified by flash silica column chromatography (hexane:ethyl acetate, 2:1 to 1:2) to afford the title compound as a yellow solid (3.76 g, 75%). ESI-MS m/z: 306 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ ppm: 9.34 (d, J=7.8 Hz, 1H), 8.40 (s, 1H), 7.12 (d, J=7.8 Hz, 1H), 4.41 (q, 2H), 3.00 (s, 3H), 2.28-2.33 (m, 1H), 1.42 (t, 3H), 1.03-1.08 (m, 2H), 0.71-0.76 (m, 2H).
Reaction SMILES: [K+].[C:2]([C:4]1[C:13]([F:14])=[CH:12][C:7]2[N:8]=[C:9]([S-:11])[S:10][C:6]=2[CH:5]=1)#[N:3].[K].S[C:17]1SC2C(N=1)=NC=C(C(OCC)=O)C=2>>[F:14][C:13]1[C:4]([C:2]#[N:3])=[CH:5][C:6]2[S:10][C:9]([S:11][CH3:17])=[N:8][C:7]=2[CH:12]=1
Reactant: N#Cc1cc2sc([S-])nc2cc1F
Reactant: CCOC(=O)c1cnc2nc(S)sc2c1
Agent: [K+]
Agent: [K]
Product: CSc1nc2cc(F)c(C#N)cc2s1

Procedure:
5-Fluoro-2-(methylthio)benzo[d]thiazole-6-carbonitrile was synthesized as an orange solid (1.2 g, 86%) using a procedure analogous to that described in Step 2 of Example 114, substituting 6-cyano-5-fluorobenzo[d]thiazole-2-thiolate potassium salt from the previous step for ethyl 2-mercaptothiazolo[4,5-b]pyridine-6-carboxylate potassium salt used in Example 114. 1H NMR (300 MHz, DMSO-d6) δ 8.67 (d, J=6.4 Hz, 1H), 8.01 (d, J=10.5 Hz, 1H), 2.84 (s, 3H); LCMS (ESI) m/z 225 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>C1CCCCC1.CCCCCCC.[CH-]1[C-]=[C-][C-]=[C-]1.[CH-]1[C-]=[C-][C-]=[C-]1.Cl[Ti]Cl>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:1][CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=CCCCCCC
Agent: Cl[Ti]Cl
Agent: [c-]1[c-][c-][cH-][c-]1
Solvent: CCCCCCC
Solvent: C1CCCCC1
Product: CC=CCCCCC
Product: CCCCCCCC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.12 mmoles of bis-(η5-cyclopentadienyl)titanium dichloride (Cp2TiCl2; Aldrich commercial product), 20 ml of anhydrous cyclohexane, 0.03 ml of a solution of n-dibutylglima 0.45 M in anhydrous cyclohexane and 0.54 ml of 1 molar Mg(butyl)2 in n-heptane (atomic ratio Mg/Ti=4.5), are charged into a tailed test-tube equipped with a magnetic stirrer, in an atmosphere of argon. The mixture is left under stirring for 20 hours at room temperature. 18.8 ml of 1-octene (distilled and maintained on molecular sieves) are added. At this point the solution is siphoned in an autoclave previously maintained under argon and the same procedure is carried out as described in example 1 above. At the end it is cooled to room temperature. About 14 ml of octane and 4 ml of 2-octene are obtained by distillation (GC, mass GC and NMR analyses). The results and process conditions are summarized in table 1 below.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:11].C[O-].[Na+].C[CH2:16][O:17]C(C)=O>CO>[CH3:16][O:17][C:6]1[CH:5]=[CH:4][N+:3]([O-:11])=[C:2]([CH3:1])[CH:7]=1
Reactant: CCOC(C)=O
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc[n+]([O-])c(C)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-methyl-4-nitropyridine 1-oxide (24 g, 0.155 mol) in MeOH (100 mL). Sodium methoxide (10 g, 0.187 mol, Aldrich) was added, and the reaction mixture was stirred for 2 h at 80° C. Reaction progress was monitored by TLC (50% EtOAc in petroleum ether). The reaction mixture was concentrated and water (50 mL) was added and the aqueous solution was extracted with EtOAc (4×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford the title compound as a brown liquid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (d, J=7.2 Hz, 1H), 7.14 (d, J=3.3 Hz, 1H), 6.91 (dd, J=3.6, 7.2 Hz, 1H), 3.80 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[C:17]=2[F:24])=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C[C@H]1CC[C@H](CNC2C=CC(F)=C(F)C=2F)CC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:32][C@H:29]1[CH2:30][CH2:31][C@H:26]([CH2:25][N:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[C:17]=2[F:24])[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:8][N:9]=2)[CH2:27][CH2:28]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(C[C@H]2CC[C@H](C)CC2)c2ccc(F)c(F)c2F)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: C[C@H]1CC[C@H](CNc2ccc(F)c(F)c2F)CC1
Product: C[C@H]1CC[C@H](CN(C(=O)Nc2ncc(SCC(=O)O)s2)c2ccc(F)c(F)c2F)CC1

Procedure:
The title compound was prepared via {2-[3-(trans-4-methyl-cyclohexylmethyl)-3-(2,3,4-trifluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]thiazol-4-yl}-acetic acid, using trans-4-methyl-cyclohexylmethyl-(2,3,4-trifluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][NH:6][C:7]([NH:9][C:10](=[O:26])[CH:11]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:8])C.[OH-].[K+]>C(O)C.O>[CH:13]1([CH2:12][CH:11]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[C:10]([NH:9][C:7](=[O:8])[NH:6][CH2:5][C:4]([OH:27])=[O:3])=[O:26])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
A solution of {3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-acetic acid ethyl ester (prepared in Example 12B-d, 77 mg, 0.19 mmol) in ethanol (5 mL) at 25° C. was treated with a solution of potassium hydroxide (36 mg, 0.65 mmol) in water (1 mL). The reaction mixture was stirred at 25° C. for 2 h. At this time, the reaction was diluted with water (5 mL) and the ethanol was removed in vacuo. The aqueous layer was then acidified to pH=2 with a 1N aqueous hydrochloric acid solution and extracted with methylene chloride (3×15 mL). The organics were then dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 88/12 chloroform/methanol plus 1% acetic acid) afforded {3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-acetic acid (43 mg, 60%) as a white solid: mp 204.2-206.8° C.; EI-HRMS m/e calcd for C17H20Cl2N2O4 (M+) 386.0800, found 386.0795.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][CH:6]=1)=[O:4].[H-].[K+].[H][H].[CH3:20][C:21]([CH3:34])([CH3:33])[C:22]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)=[O:23]>O1CCCC1.CCCCCC>[CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:11][C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([C:22](=[O:23])[C:21]([CH3:20])([CH3:33])[CH3:34])=[CH:32][CH:31]=2)=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: [H][H]
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)C(=O)c1ccc(C(N)=O)cc1
Agent: [H-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1ccc(C(=O)NC(=O)c2ccc(C(=O)C(C)(C)C)cc2)cc1
Temperature: 0 °C

Procedure:
4.2 grams (20.5 mmoles) of 4-(2,2-dimethyl-1-oxopropyl) benzamide is dissolved in 100 milliliters of dry tetrahydrofuran. The solution is cooled to 0° C., and 3.7 grams (22.6 mmoles) of potassium hydride (from a 24.5% mixture in mineral oil) which has been washed free of oil with hexane, is added. After hydrogen evolution has ceased, (approximately 2 hours), a solution of 4.6 grams (20.5 mmoles) of 4-(2,2-dimethyl-1-oxopropyl)-benzoyl chloride in 20 milliliters of dry tetrahydrofuran is added dropwise at 0° C. When addition is complete, the reaction mixture is concentrated in vacuo, and the residue is then dissolved in methylene dichloride and filtered to remove solids. The filtrate is purified by flash chromatography (3 inch column and 0.3% then 1% methanol/methylene chloride to elute) and crystallized from diethyl ether to yield the title product (m.p. 131°-132° C.).
Reaction SMILES: Cl.[CH2:2]([S:4][C:5]1[N:6]([C:10]2[CH:15]=[CH:14][C:13](C)=[CH:12][CH:11]=2)[CH:7]=[CH:8][N:9]=1)[CH3:3].Br.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:20]>>[CH2:2]([S:4][C:5]1[N:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:20])=[CH:12][CH:11]=2)[CH:7]=[CH:8][N:9]=1)[CH3:3]
Reactant: CCSc1nccn1-c1ccc(C)cc1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: Br
Agent: Cl
Product: CCSc1nccn1-c1ccc(O)cc1
Yield: 72.5 %

Procedure:
A mixture of 14 parts of 2-(ethylthio)-1-(4-methylphenyl)-1H-imidazole monohydrochloride and 113 parts of hydrobromic acid solution 48% in glacial acetic is stirred and refluxed for 3 hours. The reaction mixture is evaporated and the residue is dissolved in water. The solution is neutralized with sodium hydrogen carbonate. The precipitated product is filtered off and crystallized from 2-propanol, yielding 8.3 parts (72.5%) of 4-[2-(ethylthio)-1H-imidazol-1yl]phenol; mp. 165.2° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[C:10]([O-])(O)=O.[Na+]>C(O)=O.O>[CH3:1][C:2]1[C:3]2[N:9]=[CH:10][NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: Cc1cccc(N)c1N
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: Cc1cccc2[nH]cnc12

Procedure:
A solution of 3-methylbenzene-1,2-diamine (170 mg) in formic acid (2 mL) was heated at 140° C. for 5 min in a microwave reactor. The mixture was diluted with water, neutralized with sat. NaHCO3, then extracted with EtOAc. The organic phase was washed with water and brine, dried (Na2SO4), filtered through a 1″ pad of silica gel and concentrated to afford 122 mg of Intermediate 171.1 as a tan solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].F[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Reactant: N#Cc1ccc(F)cc1
Product: N#Cc1ccc(N(c2ccc(C#N)cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[(4-cyanophenyl)amino]pyrimidine and 4-fluorobenzonitrile
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[CH:20]=3)[CH:14]=[CH:15][CH:16]=2)=[C:8]([N+:33]([O-:35])=[O:34])[CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:7]2[C:8]([N+:33]([O-:35])=[O:34])=[C:9]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1
Reactant: N#C[S-]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc(N)cc3[N+](=O)[O-])c2)c1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4c3[N+](=O)[O-])c2)c1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 34.3 %

Procedure:
To a solution of potassium thiocyanate (18.6 g, 192 mmol) in acetic acid (1.0 L) was added N-[3-(4-amino-2-nitrophenoxy)phenyl]-3-(1-cyano-1-methylethyl)benzamide (20 g, 48 mmol), and the mixture was stirred at 50° C. for 10 min. The obtained solution was cooled to room temperature, a solution of bromine (8.05 g, 50.4 mmol) in acetic acid (200 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 16 hr. Then, a solution of potassium thiocyanate (9.3 g, 96 mmol) and bromine (4.02 g, 25.2 mmol) in acetic acid (100 mL) was added, and the mixture was further stirred at room temperature for 4 hr. The resulting yellow insoluble material was filtered off and washed with acetic acid. The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (600 mL), water (300 mL) was added, and the mixture was neutralized with 8N aqueous sodium hydroxide solution. The organic layer was washed successively with 5% aqueous sodium hydrogen carbonate solution (300 mL) and saturated brine (300 mL×2) and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was purified by basic silica gel column chromatography (eluate: ethyl acetate). The obtained solution was concentrated under reduced pressure to give the title compound (7.8 g, 34%) as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][CH:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30]O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][O:17][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1)([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Nc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCCC1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1COC(c1cccc(N)c1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-(3-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (1.30 g), 2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.04 g), PPh3 (2.64 g) and molecular sieves 4 Å in THF (100 mL) was added DEAD (1.55 mL) slowly. The reaction was stirred at RT for 4 h and at reflux overnight. After filtration to remove solids, the filtrate was concentrated and the residue was taken up into Et2O. The organic phase was washed with saturated NaHCO3 and brine. The organic layer was dried over MgSO4 and evaporated to give a very viscous brown oil, which was purified by chromatography through silica gel (500 g, 30% to 50% EtOAc in hexanes) to afford 2-[1-(3-amino-phenyl)-2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a light brown oil.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15](OCC)[C:16](=[O:18])[OH:17])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)#[N:2].[CH3:22][O:23][CH2:24][C@H:25]1[CH2:29]OC(=O)O1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:22][O:23][CH2:24][C@@H:25]1[O:17][C:16](=[O:18])[N:15]([C:12]2[CH:11]=[CH:10][C:9]([C@H:6]3[CH2:5][CH2:4][C@H:3]([C:1]#[N:2])[CH2:8][CH2:7]3)=[CH:14][CH:13]=2)[CH2:29]1
Reactant: COC[C@H]1COC(=O)O1
Reactant: CCON(C(=O)O)c1ccc([C@H]2CC[C@H](C#N)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC[C@H]1CN(c2ccc([C@H]3CC[C@H](C#N)CC3)cc2)C(=O)O1
Reaction time: 16 h

Procedure:
A suspension of 500 mg (1.84 mmol) of trans-[4-(4-cyano-cyclohexyl)-phenyl]-ethoxycarbamic acid, 365 mg (2.8 mmol) of (S)-4-methoxymethyl-1,3-dioxolan-2-one and 185 mg of potassium carbonate was stirred at 160° for 16 hours. The reaction mixture was chromatographed over silica gel with ethyl acetate/hexane 1:1 and the yellow crystals obtained were recrystallized from ethyl acetate. 165 mg (29%) were obtained as white crystals with m.p. 174°.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:8][C:9]2[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=2)[N:11]=1.Cl.Cl.[NH2:21][CH:22]1[CH2:29][CH:28]2[N:30]([CH3:31])[CH:24]([CH2:25][CH2:26][CH2:27]2)[CH2:23]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:31][N:30]1[CH:24]2[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:29][CH:22]([NH:21][C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:3]4[S:4][CH:5]=[CH:6][C:2]=4[Cl:1])=[N:11][C:10]=13)=[O:18])[CH2:23]2
Reactant: O=C(O)c1cccc2oc(-c3sccc3Cl)nc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4sccc4Cl)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.5 %

Procedure:
A mixture of 2-(3-chlorothiophen-2-yl)benzoxazole-4-carboxylic acid (59 mg, 0.21 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (57 mg, 0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (80 mg, 0.42 mmol) and 1-hydroxybenzotriazole (57 mg, 0.42 mmol) in DMF (2 mL) was stirred at at room temperature for 10 min, then triethylamine (0.15 mL, 1.05 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (30 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×30 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) and semi-preparative HPLC to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(3-chlorothiophen-2-yl)benzoxazole-4-carboxamide (45 mg, 51%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.11 (d, J=7.0 Hz, 1H), 8.22 (dd, J=8.0, 1.0 Hz, 1H), 7.69 (dd, J=8.0, 1.0 Hz, 1H), 7.59 (d, J=5.5 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.16 (d, J=5.5 Hz, 1H), 4.65-4.55 (m, 1H), 3.18-3.09 (m, 2H), 2.68-2.60 (m, 2H) 2.56 (s, 3H), 2.12-1.95 (m, 3H), 1.62-1.44 (m, 4H), 1.21-1.10 (m, 1H); MS (ESI+) m/z 416 (M+H); HPLC>99% (AUC), tR=12.97 min.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:24][O:25][C:26]([CH:28]1[CH2:32][C:31]2([S:37][CH2:36][CH2:35][CH2:34][S:33]2)[CH2:30][N:29]1C(=O)C(N)C(C)(C)C)=[O:27]>C(Cl)Cl>[CH3:24][O:25][C:26]([CH:28]1[CH2:32][C:31]2([S:33][CH2:34][CH2:35][CH2:36][S:37]2)[CH2:30][NH:29]1)=[O:27]
Reactant: COC(=O)C1CC2(CN1C(=O)C(N)C(C)(C)C)SCCCS2
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)C1CC2(CN1)SCCCS2
Reaction time: 2 h

Procedure:
L-Boc-cyclohexyl glycine (154 mg, Bachem), EDC (115 mg), HOBt (81 mg), and DIEA (284 mg) in CH2Cl2 (1 mL) was treated with amine salt 29 (189 mg) in CH2Cl2 (2 mL) and the mixture stirred for 2 hours. The mixture was partitioned between ethyl acetate and 1.0 N HCl, the organics washed with sodium bicarbonate, 1.0 N glycine sodium salt solution, 10% potassium carbonate solution and brine then dried over sodium sulfate, filtered, and concentrated in vacuo. Purification on a plug of silica gel eluting with 30% EtOAc/hexanes afforded 221 mg (70%) of 2-[2-tert-butoxycarbonylamino-2-cyclohexyl-acetylamino)-3,3-dimethyl-butyryl]-6,10-dithia-2-aza-spiro[4.5]decane-3-carboxylic acid methyl ester 30 as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH:36]=2)=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[NH:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH:36]=2)=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Product: COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1OCCCN1CCOCC1
Yield: 58 %

Procedure:
Using an analogous procedure to that described in Example 26, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline was reacted with N-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide to give the title compound in 58% yield; NMR: 1.96 (m, 2H), 2.13 (s, 3H), 3.29 (m, 4H), 3.5 (m, 4H), 3.59 (m, 4H), 3.69 (m, 4H), 3.92 (s, 3H), 4.18 (m, 2H), 7.08 (m, 1H), 7.13 (s, 1H), 7.22 (s, 1H), 7.28 (m, 1H), 7.58 (m, 1H), 7.75 (m, 1H), 7.81 (s, 1H), 8.27 (m, 2H), 9.39 (s, 1H), 10.29 (s, 1H); M/s: M+H+ 614.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([OH:16])=O)=[C:9]2[CH3:17])=[CH:4][CH:3]=1.N=C=N.Cl.[NH2:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[NH:29])=[CH:26][CH:25]=1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CS(C)=O>[C:28]([C:27]1[CH:31]=[CH:32][C:24]([CH2:23][NH:22][C:14]([C:10]2[CH:11]=[C:12]([CH3:13])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9]=2[CH3:17])=[O:16])=[CH:25][CH:26]=1)(=[NH:29])[NH2:30]
Reactant: Cc1cc(C(=O)O)c(C)n1-c1ccc(F)cc1
Reactant: N=C(N)c1ccc(CN)cc1
Agent: Cl
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(C(=O)NCc2ccc(C(=N)N)cc2)c(C)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
808 mg (4 mmol) of 1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carboxylic acid (Enamine, Kiev, Ukraine) was dissolved in 100 ml methylene chloride and 30 ml dimethyl sulfoxide, and added with stirring to 4 g of PS-carbodiimide (Biotage, Charlotte, N.C., USA), substituted at 1.33 mmol/g, wetted with 40 ml methylene chloride. 892 mg (4 mmol) of 4-(aminomethyl)benzamidine hydrochloride (Astatech, Bristol, Pa., USA), and 540 mg of HOBt were dissolved in 50 ml dimethyl sulfoxide, added to the stirred mixture, followed by 1.4 ml of diisopropylethylamine (Sigma-Aldrich). The mixture was stirred for seven days at room temperature, followed by filtration to remove the consumed resin. 50 ml of water was added to 150 ml of the filtrate, stirred vigorously for 10 minutes, then allowed to settle for 20 minutes to separate aqueous phase from the methylene chloride. The aqueous phase was carefully removed, neutralized by adding Tris base to 20 mM final concentration, then applied to a 20 ml bed volume CM-Sepharose (Sigma-Aldrich) cation-exchange column equilibriated with 20 mM Tris-HCl, pH 8. The column was washed with 40 ml of methanol and then eluted with 40 ml of 5% formic acid in methanol. The target compound was recovered as a yellowish oily solid following removal of the solvent by evaporation. The mass of the compound was verified by LC-MS/MS.