Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C@H:5]1[CH2:9][C@@H:8]([OH:10])[CH:7]=[CH:6]1)(=O)C.[Cu]C#N.[C:14]1([Mg]Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH4+].[Cl-]>C1COCC1>[C:14]1([C@@H:5]2[CH2:9][C@@H:8]([OH:10])[CH:7]=[CH:6]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)O[C@@H]1C=C[C@H](O)C1
Reactant: Cl[Mg]c1ccccc1
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O[C@H]1C=C[C@H](c2ccccc2)C1
Reaction time: 0.17 h
Yield: 83.8 %

Procedure:
A solution of (1R,4S)-4-acetoxy-2-cyclopenten-1-ol (491 mg, 3.45 mmol), THF (10 mL), and copper(I) cyanide (93 mg, 1.04 mmol) was cooled to <−20° C. and phenylmagnesium chloride (2.0 M in THF, 5.18 mL, 10.4 mmol) was added at the same temperature. After 10 minutes, TLC (50% EtOAc/hexanes) showed complete conversion. Saturated aqueous NH4Cl (50 mL) was added, extracted with EtOAc (3×50 mL), and dried (Na2SO4) the combined organic layers. Concentrated and purified the residue by flash column chromatography (10-50% EtOAc/hexanes, gradient elution), to provide the title compound (463 mg, 2.89 mmol, 84%). MS (DCI) m/z 143 (M−OH)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][C:13]([OH:15])=O.[N:16]1([C:21]2[N:26]=[C:25]([N:27]3[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:24]=[C:23]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[N:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][C:13]([N:30]1[CH2:31][CH2:32][CH2:33][N:27]([C:25]2[CH:24]=[C:23]([N:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)[N:22]=[C:21]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[N:26]=2)[CH2:28][CH2:29]1)=[O:15]
Reactant: O=C(O)COc1ccc2ccccc2c1
Reactant: c1c(N2CCCC2)nc(N2CCCC2)nc1N1CCCNCC1
Solvent: C1CCOC1
Product: O=C(COc1ccc2ccccc2c1)N1CCCN(c2cc(N3CCCC3)nc(N3CCCC3)n2)CC1
Temperature: 25 °C
Yield: 28 %

Procedure:
To a solution of 2-(2-naphthyloxy)acetic acid (1.1 g, 5.0 mmol) in anhydrous tetrahydrofuran (25 ml) carbonyl-diimidazole (0.80 g, 5.0 mmol) was added in portions, under stirring at room temperature. After 15 minutes a solution of 1-[2,6-di(1-pyrrolidinyl)-4-pyrimidinyl]homopiperazine (1.58 g, 5.0 mmol) in anhydrous tetrahydrofuran (15 ml) was added dropwise. The mixture was stirred at room temperature for 8 hours and the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride, the solution was washed three times with water, dried over MgSO4 and concentrated. The obtained crude product was chromatographed over a silica gel column eluting with a 1:2 mixture of benzene and ethyl acetate to afford 0.7 g of the title compound, yield: 28%, mp. 103°-110° C.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([CH3:28])=[CH2:27])=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([NH:15][CH:16]2[CH2:18][CH2:17]2)=[O:14])[CH:10]=[CH:9][C:8]=1[CH3:19])=[O:5].[CH2:29](OC(OCC)OCC)C.C(O)(=O)C>C(O)C>[CH:16]1([NH:15][C:13](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([CH3:19])=[C:7]([N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:23][CH:22]=[C:21]([O:24][CH2:25][C:26]([CH3:28])=[CH2:27])[CH:20]=4)[N:1]=[CH:29]3)[CH:12]=2)[CH2:17][CH2:18]1
Reactant: C=C(C)COc1ccc(N)c(C(=O)Nc2cc(C(=O)NC3CC3)ccc2C)c1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)O
Solvent: CCO
Product: C=C(C)COc1ccc2ncn(-c3cc(C(=O)NC4CC4)ccc3C)c(=O)c2c1
Temperature: 25 °C

Procedure:
A solution of 2-amino-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[(2-methylprop-2-en-1-yl)oxy]benzamide (3.6 g), triethylorthoformate (4.6 ml) and acetic acid (0.6 ml) in ethanol (50 ml) was heated at reflux for 18 hours. The reaction was cooled to room temperature and concentrated. The residue was partitioned between aqueous potassium carbonate solution (50 ml) and ethyl acetate (200 ml). The organic extracts were washed with brine (100 ml), dried (magnesium sulfate) and concentrated to give the crude N-cyclopropyl-4-methyl-3-[6-[(2-methylprop-2-en-1-yl)oxy]-4-oxoquinazolin-3(4H)-yl]benzamide as an oil (2.5 g) which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[CH2:9]Br.[Mg].[C:13]([NH:20][C:21]([CH3:25])([CH3:24])[CH:22]=O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>CCOCC>[C:13]([NH:20][C:21]([CH3:25])([CH:24]=[CH:9][CH:3]1[C:2]([CH3:11])([CH3:1])[CH2:6][CH2:5][C:4]1([CH3:8])[CH3:7])[CH3:22])([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14]
Reactant: CC1(C)CCC(C)(C)C1CBr
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(C=CC1C(C)(C)CCC1(C)C)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A solution of 2,2,5,5-Tetramethyl-1-cyclopentylmethyl bromide in ether is added slowly to magnesium turnings until the Grignard reagent begins to form. The remainder of the alkyl bromide is then added and the mixture is stirred until all of the magnesium has dissolved. At 0° C. a solution of N-Boc-2-amino-2-methylpropanal is then added and the mixture is stirred overnight. The reaction is quenched with 1M HCl, extracted with ether and the extracts are evaporated. The residue dissolves in dioxane and 2M H2SO4 is added. The mixture is heated until the alcohol is dehydrated as shown by thin layer chromatography. Water is added and the mixture extracted with ether. The organic layer is dried over MgSO4 and evaporated to give N-Boc-2-amino-2-methyl-4-(2,2,5,5-tetramethyl-1-cyclopentyl)butene.
Reaction SMILES: [OH:1][C:2](=[N:12][OH:13])[CH:3]([C:8](=[O:11])[NH:9][CH3:10])[C:4]([CH3:7])([CH3:6])[CH3:5].[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:7][C:4]([CH3:5])([CH3:6])[CH:3]([C:8](=[O:11])[NH:9][CH3:10])[C:2](=[N:12][OH:13])[O:1][S:15]([CH3:14])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)C(C(O)=NO)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CNC(=O)C(C(=NO)OS(C)(=O)=O)C(C)(C)C
Temperature: 35 °C

Procedure:
A solution of 7.5 g (0.04 mol) of 1-hydroxy-3,3-dimethyl-2-methylcarbamyloximinobutane and 5.0 g (0.044 mol) of methanesulfonyl chloride in 50 ml of benzene is treated dropwise with 4.6 g (0.044 mol) of triethylamine with cooling to keep the temperature below 35° C. After the addition, the stirred mixture is heated at 35° C. for two hours and then washed with aqueous sodium bicarbonate and with water. The organic layer is dried over magnesium sulfate, filtered, and stripped of volatiles to give 6.7 g (63%) of amber, viscous liquid residue, nD25 1.4810.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)C>[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:13][CH:12]=1
Reactant: Nc1ccc(Br)cn1
Reactant: COc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccc(-c2ccc(N)nc2)cn1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A degassed mixture of 2-amino-5-bromopyridine (3.5 g, 20.23 mmol), 6-methoxypyridin-3-ylboronic acid (3.71 g, 24.28 mmol) and bis[3-(diphenylphosphanyl)-cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethane complex (413 mg, 0.51 mmol) in 1,4-dioxane (36 mL) and a 2M aqueous potassium carbonate solution (36.4 mL) was heated at 90° C. under a nitrogen atmosphere for approximately 16 h. The reaction mixture was allowed to cool to room temperature and diluted with diethyl ether (100 mL). The organic phase was separated off, washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product was triturated with DCM (10 mL) and filtered, to afford the title compound (3.36 g, 83%) as a light brown solid. Method C LCMS: MH+ m/z 202, RT 0.60 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5].Br[CH2:34][C:35]#[N:36]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=2)[C:20]([F:23])([F:21])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:34][C:35]#[N:36])[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: N#CCBr
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCN1CCC(NC(=O)c2ccc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)cc2Br)CC1
Reaction time: 0.17 h
Yield: 47.7 %

Procedure:
To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.25 g, 0.43 mmol) in THF (10.0 mL) was added TEA (0.16 mL, 1.29 mmol) and the reaction was stirred for 10 min. Then 2-bromoacetonitrile (0.07, 0.65 mmol) was added and the reaction was stirred for 8 h at ambient temperature. The reaction mixture was diluted with EtOAc and washed with saturated brine solution. The combined EtOAc layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (0.125 g, 46.8%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=2)[CH2:3]1.[C:14]([O:18][C:19]([NH:21][C:22]([NH:24][CH2:25][CH3:26])=S)=[O:20])([CH3:17])([CH3:16])[CH3:15].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[C:14]([O:18][C:19]([NH:21][C:22]([NH:24][CH2:25][CH3:26])=[N:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=2)[CH2:3]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1ccnc(N2CCC(N)C2)c1
Reactant: CCNC(=S)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=NC1CCN(c2cc(C)ccn2)C1)NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
To a solution of 3-amino-1-(4-methylpyridin-2-yl)pyrrolidine (177 mg) and N-(tert-butoxycarbonyl)-N′-ethylthiourea (245 mg) in N,N-dimethylformamide (5 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (230 mg), and the mixture was stirred for 18 hours. The mixture was diluted with ethyl acetate, washed with water three times and brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, 5% methanol in dichloromethane) to give N-(tert-butoxycarbonyl)-N′-ethyl-N″-(1-(4-methylpyridin-2-yl)-pyrrolidin-3-yl)guanidine (290 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[NH2:9][NH2:10]>C(O)C>[CH:2]([C:3]1[CH:4]=[C:5]([NH2:6])[NH:10][N:9]=1)([CH3:8])[CH3:1]
Reactant: NN
Reactant: CC(C)C(=O)CC#N
Solvent: CCO
Product: CC(C)c1cc(N)[nH]n1
Temperature: 25 °C
Yield: 69.9 %

Procedure:
To a mixture of 4-methyl-3-oxopentanenitrile (0.9 g, 0.008 mole) in ethyl alcohol (5 mL) was added hydrazine (0.25 mL, 0.008 mole). The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The reaction mixture was concentrated and the residue was dissolved in MeOH (2 mL). The crude product was loaded on a sulfuric acid bound resin (AG 50W-X2, hydrogen form, 100-200 mesh, BioRad), washed with MeOH (50 mL), then washed with 2N NH3 in methanol (10 mL). The ammonia washes were combined and concentrated to afford the desired product (700 mg, 68%). 1HNMR (400 MHz, MeOD) δ 5.44 (s, 1H), 2.84-2.90 (m, 1H), 1.24 (d, J=6.4 Hz).
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([N+:20]([O-])=O)[CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H][H]>[Pd].O1CCCC1>[CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([NH2:20])[CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1ccc(O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1ccc(O)c(N)c1
Yield: 99.5 %

Procedure:
5.80 g of the 4-dodecyl-2-nitrophenol obtained in (2) above was mixed with 500 mg of 5% active carbonsupported palladium, and 150 ml of tetrahydrofuran and the resulting mixture was contacted with hydrogen at room temperature for 7 hours to reduce the nitro group. The reaction mixture was filtered, and then the solvent was distilled off to obtain 5.21 g of 4-dodecyl-2-aminophenol.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:27])[NH:23][CH:24]([CH3:26])[CH3:25])[CH:17]=2)=[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.C1(CCNC2C=C(C=CC=2)C(NC(C)C)=O)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:29]1([CH2:28][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:27])[NH:23][CH:24]([CH3:25])[CH3:26])[CH:17]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:34])=[O:3])=[CH:8][N:9]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(C(=O)NC(C)C)c2)s1
Agent: CC(C)NC(=O)c1cccc(NCCC2CCCC2)c1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: CC(C)NC(=O)c1cccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-isopropylcarbamoyl-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 3-(cyclopentylethyl-amino)-N-isopropyl-benzamide and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=2[CH:26]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].Br[C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31].[OH-].[Na+].Cl>CC(N(C)C)=O.O>[CH2:33]([O:32][C:30](=[O:31])[C:29]([O:8][C:6]1[CH:5]=[CH:4][C:3]([CH:9]([CH3:27])[C:10]([OH:15])([C:16]2[CH:17]=[CH:18][C:19]3[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=3[CH:26]=2)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=1)([CH3:36])[CH3:35])[CH3:34]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: CCOC(=O)C(C)(C)Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(C(C)C(O)(c2ccc3oc(=O)n(C)c3c2)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5-[2-(2-Chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (80 mg, obtained in Example 172) and ethyl 2-bromoisobutyrate (0.2 mL) were dissolved in dimethylacetamide (2 mL). Powdered sodium hydroxide (54 mg) was added to this solution and the mixture was allowed to stir at r.t. for 12 hours. The mixture was poured into water and ice and was acidified to pH 3 with 2N HCl. The aqueous phase was extracted with ethyl acetate two times and the organic extracts were washed with brine, dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate:hexanes=4:1) to provide the title compound 2-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl)-propyl]-phenoxy}-2-methyl-propionic acid ethyl ester as a colorless foam (113 mg). MS (m/e, ISP neg. ion)=514.1 [M−H+].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]([CH3:15])[CH3:14])[C:6]=2[N:16]=1.[CH3:17]N(C)C(=O)C.IC.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:17])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]([CH3:14])[CH3:15])[C:6]=2[N:16]=1
Reactant: CC(C)N1CCC(=O)Nc2cnc(Cl)nc21
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC(C)N1CCC(=O)N(C)c2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.096 g (0.0004 mole) of 2-chloro-9-isopropyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-43), 1 mL of N,N-dimethylacetamide and 0.037 mL (0.0006 mole) of iodomethane at 0 degrees was added 0.024 g (0.0006 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.088 g of 2-chloro-9-isopropyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-43) as an yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12])=[O:4].C([O-])([O-])=O.[Ca+2].CN(C=O)C>C1COCC1>[CH3:14][O:13][C:11]([CH:6]1[CH2:7][C:8](=[O:10])[CH:9]=[C:5]1[C:3]([O:2][CH3:1])=[O:4])=[O:12]
Reactant: COC(=O)[C@H]1CC(=O)C[C@H]1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)C1=CC(=O)CC1C(=O)OC
Temperature: 90 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
(1R,2S)-4-oxo-cyclopentane-1,2-dicarboxylic acid dimethyl ester (4.8 g, 23.8 mmol) and CuBr2 (11.9 g, 53.2 mmol) were dissolved in dry THF (70 ml) and the mixture was refluxed for two hours at 90° C. The formed CuBr was filtrated off and the organic phase was concentrated. CaCO3 (2.7 g, 27.2 mmol) and DMF (70 mL) were added and the mixture was held at 100° C. for one hour. The dark brown mixture was poured over ice (35 g) and the formed precipitate was filtrated off. The aqueous layer was extracted with ethyl acetate (1×300 ml+3×150 ml). The organic phases were dried, filtrated and concentrated. Purification by flash chromatography (toluene/EtOAc 9:1) gave the title compound (2.1 g, 45%) as yellow crystals
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10][C:11](=[O:22])[C:12]1[C:17]([O:18]C)=[CH:16][CH:15]=[CH:14][C:13]=1[O:20][CH3:21])[CH3:3].B(Br)(Br)[Br:24].O>ClCCl>[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10][C:11](=[O:22])[C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([Br:24])[C:13]=1[O:20][CH3:21])[CH3:3]
Reactant: BrB(Br)Br
Reactant: CCN1CCCC1CNC(=O)c1c(OC)cccc1OC
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCN1CCCC1CNC(=O)c1c(O)ccc(Br)c1OC
Yield: 80 %

Procedure:
To a solution of N-ethyl-2-(2,6-dimethoxybenzamidomethyl)pyrrolidine hydrochloride (23.0 g, 0.07 mole) in 300 ml of dry dichloromethane was added dropwise with stirring a solution of boron tribromide (17.5 g, 0.07 mole) in 25 ml of dry dichloromethane at 0° C. After the addition was completed the solution was allowed to reach room temperature over night. Water was added and pH adjusted to 7. The organic layer was washed with water and dried (MgSO4). The solvent was evaporated in vacuo affording the title compound as a viscous oil (20 g) which was judged by TLC and GC analysis to be sufficiently pure for use in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[N:8][CH:9]=1)=[O:4].Br[CH2:11][C:12]1[CH:16]=[C:15]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[O:14][N:13]=1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:11][C:12]2[CH:16]=[C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[O:14][N:13]=2)[CH:7]=[N:8][CH:9]=1)=[O:4]
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: COC(=O)c1cnc[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cncn1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 250 mg 3H-Imidazole-4-carboxylic acid methyl ester in 2 ml DMF 273 mg potassium carbonate and 607 mg 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001), 460 pp. WO 0107436 A2] were added and the mixture was stirred for 2 h at RT. After addition of 5 ml water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent saponification reaction without further purification. Yield: 288 mg
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH2:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>S([O-])([O-])(=O)=O.[Cu+2]>[CH2:11]([CH:10]1[CH2:9][CH:3]1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=CCCCCCCCC
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Product: CCCCCCCCC1CC1C(=O)OCC
Reaction time: 2 h

Procedure:
A mixture of 60 g of ethyl diazoacetate and 100 g of decene was added drop-by-drop to a stirred suspension of 4 g of anhydrous copper sulfate in 700 g of decene, at 105° C. The addition required 1.5 hours. The mixture was stirred for an additional 2 hours, then filtered, and the filtrate was distilled, to give 1, as a liquid, bp: 107°-110° C. (0.1 Torr.).
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:23]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:24]=2[C:25]([OH:27])=O)[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2].C(N(CC)CC)C.F[B-](F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.[CH:63]([NH:65][NH2:66])=[O:64]>CN(C)C=O>[CH:63]([N:65]([C:25](=[O:27])[C:24]1[CH:28]=[C:29]([C:32]#[N:33])[CH:30]=[CH:31][C:23]=1[CH:5]1[C:4]([C:1](=[O:3])[CH3:2])=[C:9]([CH3:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)[C:7](=[O:21])[N:6]1[CH3:22])[NH2:66])=[O:64]
Reactant: NNC=O
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)N(N)C=O
Reaction time: 0.08 h

Procedure:
2-[5-Acetyl-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidin-4-yl]-5-cyano-benzoic acid (intermediate 6) (75.0 mg, 0.16 mmol)) and triethylamine (57.1 μL, 0.41 mmol) are suspended in N,N-dimethylformamide (2 mL), stirred for 5 min and N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (63.2 mg, 0.20 mmol) is added. The mixture is stirred for 10 min and formic acid hydrazide (10.8 mg, 0.18 mmol) is added. The mixture is stirred overnight at room temperature. Another equivalent of formic acid hydrazide is added to bring the reaction to completion. The crude product is purified by reversed phase HPLC. Yield 30 mg; ESI mass spectrum [M+H]+=500; Retention time HPLC: 0.94 min (HPLC method Z018_S04).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([NH:12][CH:13]2[CH2:19][CH:18]3[N:20]([CH3:21])[CH:15]([CH2:16][CH2:17]3)[CH2:14]2)[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:22][O:23][C:24]1[N:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].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>>[CH3:22][O:23][C:24]1[N:25]=[CH:26][C:27]([NH:30][C:2]2[CH:11]=[C:10]([NH:12][CH:13]3[CH2:19][CH:18]4[N:20]([CH3:21])[CH:15]([CH2:16][CH2:17]4)[CH2:14]3)[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)=[N:28][CH:29]=1
Reactant: COC(=O)c1cnc(Cl)cc1NC1CC2CCC(C1)N2C
Reactant: COc1cnc(N)cn1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1cnc(Nc2cnc(OC)cn2)cc1NC1CC2CCC(C1)N2C
Temperature: 130 °C
Yield: 14.9 %

Procedure:
Methyl 6-chloro-4-(8-methyl-8-azabicyclo[3.2.1]octan-3-ylamino)nicotinate (26 mg, 0.084 mmol, prepared as described in Synthesis 62 and 63), 5-methoxypyrazin-2-amine (16 mg, 0.127 mmol), cesium carbonate (55 mg, 0.169 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.9 mg, 7 mol %), and tris(dibenzylideneacetone)dipalladium chloroform complex (3.5 mg, 3.5 mol %) were added to a vial which was flushed with nitrogen and sealed. Anhydrous toluene (0.3 mL) and DMF (0.1 mL) were added and nitrogen was bubbled through the stirred solution for 10 minutes. The mixture was heated by microwave irradiation at 130° C. for 30 minutes. The cooled solution was diluted with methanol and adsorbed onto an Isolute SCX-II column. The column was washed with methanol, then with 2M ammonia in methanol. The basic fractions concentrated. Preparative TLC, eluting with ethyl acetate-methanol-concentrated ammonia 10:1:0.2, gave methyl 6-(5-methoxypyrazin-2-ylamino)-4-(8-methyl-8-azabicyclo[3.2.1]octan-3-ylamino)nicotinate (5 mg, 15%) as an oil.