Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](/[CH:4]=[C:5]1\[C:6](=[O:14])[NH:7][C:8]2[C:13]\1=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:3].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)/[C:5](=[CH:4]/[N:2]([CH3:1])[CH3:3])/[C:6]1=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CN(C)/C=C1\C(=O)Nc2ccccc21
Solvent: CN(C)C=O
Product: CN(C)/C=C1\C(=O)N(Cc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (3Z)-3-[(dimethylamino)methylene]-1,3-dihydro-2H-indol-2-one (iii-a, 626 mg, 3.33 mmol) in DMF (10 mL) was added Nail (151 mg, 6.29 mmol) and the reaction was stirred at RT. After 10 min, benzyl bromide (500 μL, 4.20 mmol) was added and the mixture was stirred under an atmosphere of Ar for 22 h. The reaction was quenched with a few drops of water and poured into a separatory funnel containing EtOAc (150 mL) and was washed with water (2×100 mL), followed by brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (EtOAc/Hexane) to yield (3Z)-1-benzyl-3-[(dimethylamino)methylene]-1,3-dihydro-2H-indol-2-one as a yellow solid (iv-a, 660 mg, 71%). N′H4OAc QC conditions. DAD Retention Time=1.71 min. M+H=279.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[C:16]([N+]([O-])=O)[CH:15]=[CH:14][N:13]=1>C1COCC1.O>[CH2:3]([O:10][C:16]1[CH:15]=[CH:14][N:13]=[C:12]([Cl:11])[CH:17]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1cc(OCc2ccccc2)ccn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cooled (0° C.) slurry of washed (hexanes) sodium hydride (14.07 g, 352 mmol) in THF (650 mL) was added dropwise a solution of benzyl alcohol (35.2 mL, 337 mmol) in THF (200 mL). After stirring for 15 minutes, a solution of 2-chloro-4-nitropyridine (50 g, 306 mmol) in THF (200 mL) was added dropwise. After heating to reflux for 16 hours, the black slurry was diluted with water (200 mL) and concentrated to remove the THF. The resulting mixture was diluted with more water and filtered. The filtrate was extracted with ether and ethyl acetate. The combine organics were dried and concentrated. The residue was chromatographed (10% ethyl acetate in hexanes) to provide the product as orange solid.
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:38][CH2:39][O:40][CH3:41]>>[CH2:33]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[N:11]([CH2:38][CH2:39][O:40][CH3:41])[CH:12]=1)=[O:7])[CH2:34][CH2:35][CH3:36]
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Reactant: COCCBr
Product: CCCCN(CCCC)C(=O)c1cn(CCOC)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Yield: 79 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 274A, 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (200 mg, 0.40 mmol) and bromoethylmethylether (68 mg, 0.38 mmol) were converted to the title compound (165 mg, 74%). 1H NMR (CDCl3) δ 8.67 (d, J=1.6 Hz, 1H), 8.23 (dd, J=8.0, 2.0 Hz, 1H), 7.61 (s, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.35-7.32 (m, 3H), 7.25-7.23 (m, 2H), 5.14 (s, 2H), 3.97 (s, 3H), 3.92-3.85 (m, 2H), 3.67 (t, J=5.4 Hz, 2H), 3.45-3.41 (m, 2H), 3.60 (t, J=5.4 Hz, 2H), 3.17 (s, 3H), 1.70-1.55 (m, 4H), 1.40-1.20 (m, 4H), 0.98-0.82 (m, 6H); MS(ESI+) m/z 550.2 (M+H)+.
Reaction SMILES: [O-]S([O-])(=O)=O.[Mg+2].S(=O)(=O)(O)O.[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([I:22])[CH:21]=1)[C:16]([OH:18])=[O:17].[C:23](O)([CH3:26])([CH3:25])[CH3:24]>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([I:22])[CH:21]=1)[C:16]([O:18][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:17]
Reactant: O=C(O)c1cc(Br)cc(I)c1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(Br)cc(I)c1
Reaction time: 0.25 h

Procedure:
To a vigirously stirred suspension of poudered MgSO4 (7.36 g) in dichloromethane (50 mL) was added sulfuric acid (0.758 mL) at room temperature. After stirring for 15 minutes, to the mixture was added 3-bromo-5-iodobenzoic acid (5.00 g) followed by tert-butanol (7.31 mL). The mixture was stirred for 3 days at room temperature. The mixture was partitioned between EtOAc and water. The organic layer was washed with satd. NaHCO3 and brine, dried over MgSO4, and evaporated to give tert-butyl 3-bromo-5-iodobenzoate as pale purple crystals (4.44 g).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(=O)(O)[O-].[Na+].[CH2:14]([C:16]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH3:15]>O.CCOCC>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:24]([C:16]1([CH2:14][CH3:15])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)=[O:25])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: CCC1(C(=O)Cl)CCCCCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CNC(=O)C1(CC)CCCCCCC1

Procedure:
Glycine ethyl ester hydrochloride (0.04 mole) and sodium bicarbonate (0.08 mole) were dissolved in water (50 ml.). 1-Ethylcyclooctanecarbonyl chloride (1 g. 0.04 mole) in ether (20 ml.) was then added with stirring. The other layer was separated, dried (MgSO4) and concentrated. The residue was recrystallised from 40°-60° petroleum ether to give N-(1-ethylcyclooctanecarbonyl) glycine ethyl ester mp. 65°-7°
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:26]=[CH:27][C:28]=2[CH3:29])[CH2:11][N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@@H:13]2[CH3:25])[CH:5]=[CH:4][N:3]=1.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[CH3:29][C:28]1[CH:27]=[CH:26][C:10]([CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]2[CH3:25])=[CH:9][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[N:7]=1
Reactant: Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)cc1-c1ccnc(Cl)n1
Reactant: NCCc1ccc(O)cc1
Product: Cc1ccc(CN2CCNC[C@@H]2C)cc1-c1ccnc(NCCc2ccc(O)cc2)n1

Procedure:
Intermediate 158 from above was coupled with tyramine following procedure F. The product was deprotected by procedure G2. LC-MS showed the product had the expected M+H+ of 418. 1H NMR (Varian 300 MHz, MeOD-d6, shifts relative to the solvent peak at 3.31 ppm) δ 8.3 (d, 1H) 8.0 (d, 1H) 7.7 (d, 1H) 7.5 (d, 1H), 7.3 (d, 1H), 7.0 (d, 2H) 6.7 (d, 2H) 4.0 (t, 2H) 3.7 (m, 3H) 3.6-3.4 (m, 6H) 2.8 (t, 2H), 2.5 (s, 3H), 1.7 (d, 3H).
Reaction SMILES: [O:1]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=C2OCC1)N=CC=C3.CC1C=C(C)C=CC=1S([O-])(=O)=O.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28]1.C1(=O)CCC=C1>>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:13]2[CH2:12][CH2:7][C:6](=[O:1])[CH2:14]2)=[CH:28]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: c1cnc2ccc3c(c2c1)OCCO3
Agent: Cc1ccc(S(=O)(=O)[O-])c(C)c1
Agent: O=C1C=CCC1
Product: O=C1CCC(c2c[nH]c3ccccc23)C1
Yield: 44 %

Procedure:
This compound was prepared in similar manner as for Intermediate 14, using indole (2.34 g, 20 mmol) and 2-cyclopenten-1-one (2.0 mL, 24.0 mmol) to give 1.7 g (44%) of the desired product as a thick oil: MS (ESI) m/z 200 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH2:17]([O:19][C:20]1[CH:30]=[CH:29][C:23]([CH:24]=[CH:25][C:26](O)=O)=[CH:22][CH:21]=1)[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:30]=[CH:29][C:23](/[CH:24]=[CH:25]/[C:26]2[NH:1][C:2]3[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=3[N:8]=2)=[CH:22][CH:21]=1)[CH3:18]
Reactant: CCOc1ccc(C=CC(=O)O)cc1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OCC)cc3)nc2n(CCC)c1=O
Yield: 70.2 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.0 g (13.3 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.80 g (14.6 mmol) of 4-ethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 3.57 g (yield 70%) of Compound 47 as pale yellow needles.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9]1=[N:8][N:7]([C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:19])[CH2:6]2)=[O:4].C(N(CC)CC)C.Cl[S:39][N:40]([CH:46]([CH3:48])[CH3:47])[C:41](=[O:45])[O:42][CH2:43][CH3:44]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]12[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9]1=[N:8][N:7]([C:18]([N:20]([C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)[S:39][N:40]([CH:46]([CH3:48])[CH3:47])[C:41]([O:42][CH2:43][CH3:44])=[O:45])=[O:19])[CH2:6]2)=[O:4]
Reactant: CCOC(=O)N(SCl)C(C)C
Reactant: COC(=O)C12CCc3ccccc3C1=NN(C(=O)Nc1ccc(C(F)(F)F)cc1)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N(SN(C(=O)N1CC2(C(=O)OC)CCc3ccccc3C2=N1)c1ccc(C(F)(F)F)cc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution of the title compound of Step B (2.0 g, 4.8 mmol) in 50 ml methylene chloride cooled to 0° C. was added triethylamine (1.0 g, 0.01 mol) and ethyl (chlorosulfenyl) (1-methylethyl)carbamate from Step D (1.4 g, 7.7 mmol). The mixture was allowed to warm to room temperature and stirred for one hour. The crude mixture was purified by silica column chromatography using ether-hexane (1:2) as eluent. The title compound (2.38 g) was obtained in about 90% purity (mp: 130°-134°). Extraction of the product with ether-hexane (2:1) gave 1.8 g of highly pure material mp: 139°-140° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH2:23](Br)[C:24]#[CH:25].O>CN(C)C=O>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([N:17]([CH2:25][C:24]#[CH:23])[C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: C#CCBr
Reactant: CC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN(C(C)=O)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
To 3.0 g of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide in 250 ml of dimethylformamide under argon was added 0.6 g of sodium hydride (50% in oil). The mixture was stirred for one hour, then 1.38 ml of propargyl bromide was added. This mixture was stirred for 12 hours then poured into 200 ml of water and extracted with 150 ml portions of dichloromethane. The extracts were combined, dried and evaporated in vacuo. The residue was chromatographed on 300 g of silica gel with dichloromethane-methanol (97:3) as the eluent. Fractions containing the desired product were collected, evaporated in vacuo and recrystallized from dichloromethanhexane to give 2.5 g of orange crystals mp 195°-198° C.
Reaction SMILES: CC1(C)OC(=O)[C:5](=[CH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[C:4](=O)[O:3]1.[F:20][C:21]([F:38])([F:37])[C:22]1[CH:23]=[C:24]([NH:28]/[C:29](/[CH3:36])=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:25]=[CH:26][CH:27]=1>COCCOCCOC.O>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([CH:9]2[CH2:5][C:4](=[O:3])[N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:37])([F:38])[F:20])[CH:23]=3)[C:29]([CH3:36])=[C:30]2[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:11][CH:12]=1)#[N:15]
Reactant: CCOC(=O)/C=C(\C)Nc1cccc(C(F)(F)F)c1
Reactant: CC1(C)OC(=O)C(=Cc2ccc(C#N)cc2)C(=O)O1
Solvent: COCCOCCOC
Solvent: O
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)CC1c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
4-[(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl]benzonitrile (Example 18A; 200 mg, 0.77 mmol) and ethyl (2E)-3-{[3-(trifluoromethyl)phenyl]amino}-2-butenoate (212.4 mg, 0.77 mmol) are dissolved in 1-methoxy-2-(2-methoxyethoxy)ethane (3 ml). The solution is stirred at reflux temperature overnight. The reaction mixture is cooled to room temperature and diluted with water (5 ml). After extraction with toluene (2×5 ml), it is dried with anhydrous sodium sulphate, filtered, and the solvent is removed in vacuo. The product is purified via preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[O:21]1[CH2:25][CH2:24][CH:23]([CH:26]=O)[CH2:22]1.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH2:26][CH:23]3[CH2:24][CH2:25][O:21][CH2:22]3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: O=CC1CCOC1
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NCC3CCOC3)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and tetrahydro-furan-3-carbaldehyde using decaborane yielded a mixture of epimers of the title compound as a colorless waxy solid. MS (ESI): m/z=363.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:22](=[O:25])[CH2:23]Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([CH2:23][C:22]([C:21]3[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:19]([O:18][CH3:17])[CH:20]=3)=[O:25])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: COc1cc(C(=O)CCl)cc(OC)c1OC
Product: COc1cc(C(=O)CN2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.1 using 2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (2 mmol) and 3,4,5-trimethoxy-phenacyl chloride (2 mmol). Chromatograph on silica gel to give the title compound. Rf =0.45 (6% methanol/dichloromethane).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14](=[O:16])[NH:13][C:12]=2[CH:17]=1)[C:4]([OH:6])=[O:5].Cl.[CH3:19]O>>[CH3:19][O:5][C:4](=[O:6])[CH:3]([NH2:2])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14](=[O:16])[NH:13][C:12]=2[CH:17]=1
Reactant: CO
Reactant: NC(Cc1ccc2oc(=O)[nH]c2c1)C(=O)O
Agent: Cl
Product: COC(=O)C(N)Cc1ccc2oc(=O)[nH]c2c1

Procedure:
The product from Example 17 is held for 6 hours at reflux in 1500 ml of methanol saturated with HCl gas. The alcoholic solution is evaporated to yield a product which is recrystallized from water or methanol: ether to yield the Example 21 title compound.
Reaction SMILES: [C:1]1([C:7]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][NH:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:43]([O:45][C:46]([C:48]1[C:49](Cl)=[N:50][C:51]([CH3:54])=[N:52][CH:53]=1)=[O:47])[CH3:44]>C1COCC1.C(N(CC)CC)C>[CH3:54][C:51]1[N:50]=[C:49]([N:26]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:25][C:22]2[CH:23]=[CH:24][C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[N:8]([C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:9]=[N:10][N:11]=3)=[CH:20][CH:21]=2)[C:48]([C:46]([O:45][CH2:43][CH3:44])=[O:47])=[CH:53][N:52]=1
Reactant: CCCCNCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1cnc(C)nc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)c1nc(C)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Example 1A was dissolved in 15 ml of THF containing 4.6 ml of triethylamine. A solution of 1.94 g (9.7 mmoles) of ethyl-2-methyl-4-chloropyrimidine-5-carboxylate (E. Peters, et al., J. Org. Chem. 25 2137 (1960)) in 2 ml of THF was added and the resulting solution was stirred at room temperature for 2 hours. The solution was then concentrated and the resulting residue was dissolved in toluene. The toluene solution was extracted with potassium bicarbonate, dried over sodium sulfate and concentrated. The crude product was chromatographed on silica gel eluting with 12% ethyl acetate/88%toluene to provide 4.97 g of the desired product, which was crystallized from ether/hexane (1:1). M.p. 130°-132° C.
Reaction SMILES: [C:1]12([O:11][C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([F:19])[CH:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:21][CH2:22][CH2:23][CH2:24]Br.C([O-])([O-])=O.[K+].[K+]>C(O)C>[C:1]12([O:11][C:12]3[CH:18]=[CH:17][C:15]([N:16]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[C:14]([F:19])[CH:13]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: Nc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Fc1cc(OC23CC4CC(CC(C4)C2)C3)ccc1N1CCCC1

Procedure:
A mixture of 2.3 g (8.8 mmoles) of 4-(1-adamantyloxy)-2-fluoroaniline, 1.90 g (8.80 mmoles) of 1,4-dibromobutane, and 2.68 g (19.4 mmoles) of K2CO3 in deaerated absolute ethanol (25 ml) is refluxed for twenty-four hours. The solvent is evaporated, and the residue taken up in methylene chloride (125 ml) and water (125 ml). The methylene chloride layer is washed with 2×125 ml of water, and the combined aqueous portions are extracted with methylene chloride (50 ml). The combined methylene chloride layers are dried and concentrated. The crude product is chromatographed by high pressure liquid chromatography on a 2.54 × 109 cm column at approximately 40 psi, eluting with 0.5% acetone in methylene chloride and collecting 200 ml fractions. Fraction 3 contains 1.5 g of tan solid, m.p. 99.0°-105.9° C.
Reaction SMILES: Br[N:2]1[C:6](=O)[CH2:5][CH2:4][C:3]1=[O:8].O1C=CCC1.[NH2:14][C:15](N)=[S:16]>O>[NH2:14][C:15]1[S:16][C:5]([CH2:4][CH2:3][OH:8])=[CH:6][N:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: NC(N)=S
Agent: C1=COCC1
Solvent: O
Product: Nc1ncc(CCO)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold suspension of 118.2 g of N-bromosuccinimide in 750 ml of water under a nitrogen atmosphere is added dropwise 75 ml of 2,3-dihydrofuran. The resulting solution is stirred at 0° C. for one hour. Thiourea, 50.5 g, is added and the solution refluxed under a nitrogen atmosphere overnight. The acidic solution is continuously extracted with ethyl acetate for 24 hours The ethyl acetate extract contains mostly succinimide. The aqueous phase is basified with concentrated ammonium hydroxide to a pH of 10-11 and continuously extracted with ethyl acetate for 72 hours. The ethyl acetate extract is cooled and acidified with ethereal hydrogen chloride. The hydrochloride salt oils out of solution and is crystallized from an ethanol-acetonitrile mixture to give 60.1 g of 2-amino-5-thiazoleethanol as the monohydrochloride salt; mp 125°-127° C. (lit. (a) mp 126°-127° C.) lit. (a) Farmaco. Ed. Sci., Vol. 41, pages 483-498 (1986).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.C(N(C(C)C)CC)(C)C.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[C:21]([N:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1CCCNC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.6 %

Procedure:
Commercially available ethyl nipecotate (1.48 ml; 9.53 mmol) was dissolved in dichloromethane (20 ml), and diisopropylethylamine (1.82 ml; 10.45 mmol) was added. Benzoyl chloride (1.1 ml; 9.53 mmol) was then added slowly to control any rise in reaction temperature. After addition was complete the mixture was allowed to stir at ambient temperature for approximately 1-4 hours. The mixture was then diluted with fresh dichloromethane and washed with 1 N HCl. The dichloromethane solution was dried with anhydrous potassium carbonate and evaporated at ambient temperature under reduced pressure. The crude material was purified by high-vacuum distillation at approximately 200° C./0.1 torr giving ethyl 1-benzoyl-3-piperidinecarboxylate (2.38 g) as a colorless oil. (The temperatures given for distillations in these examples are oven temperatures and represent approximations. Similarly, the vacuum levels given for distillations are also approximates.) MS m/z (positive ion) 545 (dimer+; 25), 284 (M+Na+; 90), 262 (MH+; 100), 216 (25).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:9][C:10]2[N:15]=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[N:13]=[C:12]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)[N:11]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37]C(=O)OC(C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:27]([C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:12]2[N:13]=[C:14]([O:16][CH2:17][C:18]([F:20])([F:21])[F:19])[N:15]=[C:10]([NH:9][C:6]3([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:8][CH2:7]3)[N:11]=2)=[CH:31][CH:30]=1)=[O:28]
Reactant: CCOC(=O)C1(Nc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)CC1
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Nc2nc(Nc3ccc(C(=O)NCCCCN)cc3)nc(OCC(F)(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
To a solution of 4-(4-(1-(ethoxycarbonyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (100 mg) in DMF (5 mL) was added tert-butyl 4-aminobutylcarbamate (64.0 mg), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (109 mg) and iPr2NEt (0.119 mL). The mixture was stirred at r.t. for 16 hours before all the solvents were removed under vacuum. The residue was dissolved in dichloromethane (5.00 mL) and 2 mL of TFA. The mixture was stirred at r.t. for 3 hours. All solvents were removed under vacuum and the residue was purified by prep. HPLC to give ethyl 1-(4-(4-(4-aminobutylcarbamoyl)phenylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)cyclopropanecarboxylate (80 mg).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([Si@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16]Br)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Mg].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>[Cu](I)I.C(OP(OCC)(OCC)=O)C.C1COCC1>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([Si@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:24][C:23]3[CH:26]=[CH:27][C:20]([F:19])=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H]([Si@H]2CC[C@H](CBr)CC2)CC1
Reactant: Fc1ccc(CBr)cc1
Agent: I[Cu]I
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOP(=O)(OCC)OCC
Product: CCC[C@H]1CC[C@H]([Si@H]2CC[C@H](CCc3ccc(F)cc3)CC2)CC1

Procedure:
6.3 g (20 mmol) of trans-1-(trans-4-n-propylcyclohexyl)-4-bromomethyl-1-silacyclohexane was dripped into a mixture of 0.5 g (21 mmol) of magnesium and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 50 mg of triethylphosphate, 10 mg of copper iodide (I) and 3.9 g (20 mmol) of p-fluorobenzyl bromide. After a conventional after treatment, 6.1 g (yield 85%) of trans-1-(trans-4-n-propylcyclohexyl)-4-(2-(4-fluorophenyl) ethyl)-1-silacyclohexane was obtained.