Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][N:5]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[N:3]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>C1(C)C=CC=CC=1>[Br:8][C:7]1[C:2]([N:1]=[CH:24][N:25]([CH3:27])[CH3:26])=[N:3][C:4]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[N:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)c(N)n2)CC1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)ncc1Br

Procedure:
A 100 mL round bottom flask was charged with tert-butyl 4-(4-amino-5-bromopyrimidin-2-yl)piperazine-1-carboxylate (2.0 g, 5.6 mmol), N,N-dimethylformamide dimethyl acetal (0.9 g, 7.3 mmol) and toluene (60 mL). The resulting mixture was heated at reflux for 12 h. Work-up: the solvent was evaporated to dryness to afford the product, which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:28][CH3:29])=[C:7]([CH:19]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=2)[OH:20])[CH:8]=[C:9]([C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[C:1]([C:5]1[C:6]([O:28][CH3:29])=[C:7]([C:19]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=2)=[O:20])[CH:8]=[C:9]([C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ncccc1-c1cc(C(O)c2ccnc(Cl)c2)c(OC)c(C(C)(C)C)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1ncccc1-c1cc(C(=O)c2ccnc(Cl)c2)c(OC)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
step 2—To a solution of 40 (124 mg, 0.301 mmol) in DCM (10 mL) at RT was added MnO2 (528 mg, 6.073 mmol). The reaction mixture was vigorously stirred at RT overnight then the solid was filtered through a pad of CELITE. The filtrate was concentrated and the crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (5 to 10% EtOAc) to afford 106 mg (86%) of [3-tert-butyl-2-methoxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-(2-chloro-pyridin-4-yl)-methanone (42) as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][C:15]=1[Cl:26].C(N(CC)CC)C>O>[Cl:26][C:15]1[CH:16]=[C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:18]=[CH:19][C:14]=1[NH:13][C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:12]
Reactant: CCOC(=O)Cc1ccc(N)c(Cl)c1
Reactant: O=C(O)c1c[nH]c2ccccc12
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NC(=O)c2c[nH]c3ccccc23)c(Cl)c1
Temperature: 70 °C
Reaction time: 24 h
Yield: 56.4 %

Procedure:
EDC•HCL (1.78 g, 9.28 mmol) was added to a solution of indole-3-carboxylic acid (1.00 g, 6.21 mmol), ethyl 4-amino-3-chlorophenylacetate (1.33 g, 6.22 mmol) and triethylamine (1.80 mL, 12.9 mmol). The mixture was stirred at 70° C. for 24 hours. After cooling to room temperature, the reaction mixture was added with water (30 ml), followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (1:1, v/v) eluate fractions, ethyl 3-chloro-4-(3-indolylcarbonylamino)phenylacetate (1.25 g, 56%) was obtained as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)(=[O:14])=[O:13])[CH:9]=2)[NH:4][N:3]=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[F:21][C:19]1[CH:20]=[C:15]([S:12]([NH:11][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[NH:1][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:14])=[O:13])[CH:16]=[C:17]([F:22])[CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1n[nH]c2ccc(NS(=O)(=O)c3cc(F)cc(F)c3)cc12
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2ccc(NS(=O)(=O)c3cc(F)cc(F)c3)cc12)c1ccccc1

Procedure:
N-[5-(3,5-Difluorobenzenesulfonylamino)-1H-indazol-3-yl]benzamide can be obtained as described in Example 28 from 0.15 g of N-(3-amino-1H-indazol-5-yl)-3,5-difluorobenzenesulfonamide, 13.5 ml of pyridine and 0.06 ml of benzoyl chloride. 30 mg of N-[5-(3,5-difluorobenzenesulfonylamino)-1H-indazol-3-yl)benzamide are thus obtained in the form of a cream solid melting at 246° C. (analysis C20H14F2N4O3S.1.33H2O % calculated C, 56.08; H, 3.29; F, 8.87; N, 13.08; O, 11.20; S, 7.48. % found C, 56.49; H, 3.38; N, 11.90; S, 6.95).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].Br[CH2:14][CH:15]([OH:19])[CH2:16][CH2:17]Br.C(=O)([O-])[O-].[Na+].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:17][CH2:16][CH:15]([OH:19])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: OC(CBr)CCBr
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: OC1CCN(c2cc(Br)cc(C(F)(F)F)c2)C1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
3-Bromo-5-(trifluoromethyl)aniline (5.0 g) and 1,4-dibromobutan-2-ol (4.83 g) were stirred at 100° C. for 3 hr. After cooling to room temperature, to the reaction mixture was added saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10-50:50) to give the title compound (5.6 g, yield 22%) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-])=O)[C:17]([F:23])=[CH:16][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[CH:6]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:20][C:18]1[C:17]([F:23])=[CH:16][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[CH:6]=2)=[C:2]([F:1])[CH:19]=1
Reactant: CCC(=O)Nc1cc(Oc2cc(F)c([N+](=O)[O-])cc2F)ccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCC(=O)Nc1cc(Oc2cc(F)c(N)cc2F)ccn1
Temperature: 80 °C
Yield: 70.5 %

Procedure:
To a suspension of N-(4-(2,5-difluoro-4-nitrophenoxy)pyridin-2-yl)propionamide (27.2 g, 84.2 mmol) in EtOH (750 mL) was added a solution of NH4Cl (18 g, 337 mmol) in water (188 mL) and Fe powder (97%, 325 mesh, 18.8 g, 337 mmol) in one portion at RT. The mixture was then heated at 80° C. for 1 h, cooled to ambient temp, filtered through a bed of diatomaceous earth, and washed with MeOH (1 L). The combined filtrates were concentrated to dryness and purified by silica gel chromatography (EtOAc/hexanes) to give N-(4-(4-amino-2,5-difluorophenoxy)pyridin-2-yl)propionamide (17.4 g, 70.5% yield). 1H-NMR (400 MHz, CDCl3): δ 8.07 (d, J=5.6 Hz, 1H), 8.00 (br s, 1H), 7.77 (d, J=2 Hz, 1H), 6.85 (dd, J=10.4, 7.2 Hz, 1H), 6.63-6.58 (m, 2H), 3.79 (s, 2H), 2.38 (q, J=7.6 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H); MS (ESI): m/z 294.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([C:10]([Cl:13])=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)Cl.ClCCl>[Br:15][CH2:14][C:3]1[C:2]([Cl:1])=[CH:12][CH:11]=[C:10]([Cl:13])[C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(Cl)ccc(Cl)c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(Cl)ccc(Cl)c1CBr
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A solution of 3,6-dichloro-2-methylbenzoate (253b, 120 g, 0.52 mol) and N-bromosuccinimide (147 g, 0.82 mol) in chloroform (1 L) was treated with azobisisobutyronitrile (25.3 g, 0.15 mol) and the mixture refluxed overnight. After cooling to room temperature, the mixture was diluted with dichloromethane (800 mL) and washed with water (1.2 L). The aqueous layer was extracted with dichloromethane (800 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (1.5 L), dried over sodium sulfate, and concentrated in vacuo to give ethyl 2-(bromomethyl)-3,6-dichlorobenzoate (253c, 160 g, 100% yield) which was used without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:5][C@@H:4]([CH3:17])[O:3]1.[H][H]>CCO.[Pd]>[CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5][C@@H:4]([CH3:17])[O:3]1
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)C[C@H](C)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1CN(c2ccc(N)cc2)C[C@H](C)O1

Procedure:
1-(Cis-2,6-dimethylmorpholino)-4-nitrobenzene (Method 18, 8 g) in EtOH (100 ml) was reduced with hydrogen over 10% palladium/carbon (800 mg) at 50° C. After filtering off the catalyst and washing with EtOH, evaporation of the filtrate gave the title compound as a red/brown oil, which started to solidify after several days (quantitative yield). NMR (CDCl3) 1.23 (d, 6H), 2.33 (t, 2H), 3.25 (d, 2H), 3.81 (m, 2 h), 6.65 (d, 2H), 6.79 (d, 2H); m/z 207.
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][C@@H:11]2[N:12]([CH3:24])[C:13]3[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[N:32][CH:33]=1.CC([O-])(C)C.[Na+]>>[Cl:34][C:31]1[N:32]=[CH:33][C:28]([NH:27][C:16]2[CH:15]=[C:14]([C:20]([F:23])([F:22])[F:21])[C:13]3[N:12]([CH3:24])[C@H:11]4[CH2:25][CH2:26][NH:8][CH2:9][C@H:10]4[C:18]=3[CH:17]=2)=[CH:29][CH:30]=1
Reactant: CN1c2c(cc(Br)cc2C(F)(F)F)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Reactant: Nc1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CN1c2c(cc(Nc3ccc(Cl)nc3)cc2C(F)(F)F)[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general Method A as a yellow solid (56 mg, 29%) from (4aS,9bR)-8-bromo-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 45, 217 mg, 0.5 mmol), 5-amino-2-chloro-pyridine (193 mg, 1.5 mmol) and NaOt-Bu (144 mg, 1.5 mmol). MS (ESI): 383 (base, M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:8]=1)=[O:6].[CH2:25]([C:29]1[CH:34]=[CH:33][C:32]([CH:35](Cl)[C:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH:43]([CH3:45])[CH3:44])=[CH:38][CH:37]=2)=[CH:31][CH:30]=1)[CH:26]([CH3:28])[CH3:27].C(N(C(C)C)CC)(C)C.Cl>ClCCl>[CH2:42]([C:39]1[CH:40]=[CH:41][C:36]([CH:35]([NH:1][C:2]2[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=2)[C:5]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:8]=2)=[O:6])[C:32]2[CH:33]=[CH:34][C:29]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:30][CH:31]=2)=[CH:37][CH:38]=1)[CH:43]([CH3:45])[CH3:44]
Reactant: CC(C)Cc1ccc(C(Cl)c2ccc(CC(C)C)cc2)cc1
Reactant: Nc1cccc(C(=O)c2cn(CCCC(=O)O)c3ccccc23)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)Cc1ccc(C(Nc2cccc(C(=O)c3cn(CCCC(=O)O)c4ccccc34)c2)c2ccc(CC(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 4-[3-(3-aminobenzoyl)indol-1-yl]butyric acid (880 mg), bis(4-isobutylphenyl)methyl chloride (1.03 g) and diisopropylethylamine (0.945 g) in dichloromethane (20 ml) was stirred at 25° C. overnight, and bis(4-isobutylphenyl)methyl chloride (170 mg) and diisopropylethylamine (86 mg) were added thereto. After stirring at 25° C. for 3 hours, the reaction mixture was poured into cold 1N hydrochloric acid. The organic layer was separated, washed with water, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (100 g) with a mixture of chloroform and methanol (50:1) as eluent and freeze-dried from benzene to give 4-[3-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]indol-1-yl]butyric acid (820 mg) as pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][O:20][CH3:21])=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([CH:15]=O)=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8].Cl.NO.C([N:27](CC)CC)C.C(OC(=O)C)(=O)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][O:20][CH3:21])=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([C:15]#[N:27])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8]
Reactant: CCN(CC)CC
Reactant: COCOc1ccc(Cl)cc1C(=O)c1ncccc1C=O
Agent: Cl
Agent: NO
Solvent: CC#N
Solvent: CC(=O)OC(C)=O
Product: COCOc1ccc(Cl)cc1C(=O)c1ncccc1C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.2 %

Procedure:
To a mixture of 2-(5-chloro-2-methoxymethoxybenzoyl)-3-formylpyridine (2.34 g), hydroxylamine hydrochloride (532 mg) and triethylamine (775 mg) was added acetonitrile (30 ml), which was stirred for 1.5 hour at room temperature. The reaction mixture was concentrated, which was partitioned with ethyl acetate/water. The organic layer was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate), and concentrated to give 2-(5-chloro-2-methoxymethoxybenzoyl)-3-hydroxylminomethylpyridine (2.39 g). A mixture of this compound and acetic anhydride (15 ml) was heated for one hour under reflux, followed by distilling off acetic anhydride under reduced pressure. The residue was purified by means of 10 a silica gel column chromatography (eluent: ethyl acetate/hexane) to give 2-(5-chloro-2-methoxymethoxybenzoyl)-3-cyanopyridine (1.51 g) (Compound E-12).
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[CH3:9][O:10][C:11]1[S:15][C:14]([C:16]([O:18]C)=[O:17])=[CH:13][C:12]=1[C:20]1[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=1.[OH-].[Na+]>O1CCCC1>[Cl:8][C:21]1[CH:22]=[N:23][N:24]([CH3:25])[C:20]=1[C:12]1[CH:13]=[C:14]([C:16]([OH:18])=[O:17])[S:15][C:11]=1[O:10][CH3:9]
Reactant: COC(=O)c1cc(-c2ccnn2C)c(OC)s1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Temperature: 70 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
NCS (382 mg, 2.80 mmol) was added in portions to a 50 mL sealed tube reactor containing methyl 5-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (642 mg, 2.54 mmol) [prepared according to the procedure of Example 185] in Tetrahydrofuran (THF) (12 mL) at room temperature. The mixture was heated to 70° C. for 1 hour. The reaction was cooled to room temperature, 6N NaOH (10 mL, 60.0 mmol) was added and the mixture stirred an additional 3 h at 70° C. The mixture was partitioned between CHCl3 and H2O and the aqueous layer was made acidic with 6N HCl. The organic layer was dried over Na2SO4 and concentrated affording the title compound (759 mg, 2.51 mmol, 98%) which was used without further purification: LC-MS (ES) m/z=273 (M+H)+.
Reaction SMILES: C([NH:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=1)[CH2:10]O)=[S:7])(C)(C)C.[ClH:22]>CC(C)=O>[ClH:22].[C:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][C@@H:9]1[CH2:10][S:7][C:6]([NH2:5])=[N:8]1)([OH:21])=[O:20]
Reactant: CC(C)(C)NC(=S)N[C@@H](CO)Cc1cccc(C(=O)O)c1
Agent: Cl
Solvent: CC(C)=O
Product: NC1=N[C@H](Cc2cccc(C(=O)O)c2)CS1

Procedure:
The process is performed as in Example 2, starting with 2.31 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(3-carboxybenzyl)ethyl]thiourea in 25 cm3 of 6N hydrochloric acid for 18 hours. After concentration of the reaction mixture under reduced pressure (5 kPa) at a temperature in the region of 55° C., the residue is taken up in 20 cm3 of acetone and is then concentrated again under the above conditions. The residue obtained is purified by chromatography under a pressure of 50 kPa of argon, on a column of silica gel (particle size 40-63μ; mass of silica: 100 g), eluting with a chloroform/methanol/20% aqueous ammonia mixture (12/6/1 by volume) and collecting 30 cm3 fractions. Fractions 16 to 38 are combined and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The solid obtained is dissolved in 10 cm3 of aqueous 6N hydrochloric acid and is then concentrated as previously. After taking up the residue obtained in 10 cm3 of acetone, the resulting insoluble material is filtered off; the filtrate is concentrated as above. A solid is obtained, which is dried for 5 hours in an oven at 40° C., under reduced pressure (8 Pa). 0.650 g of (+)-(4R)-4-(3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride is obtained in the form of a beige-colored solid melting at 151° C. (αD20=+13.4±0.6 at a concentration of 0.5% in methanol).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:18][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:5])[CH3:2]
Reactant: NC1CCCCC1
Reactant: CCOC(=O)C1CCCC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCCC1NC1CCCCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (2.01 g, 12.9 mmol) in ethanol (20 mL) was treated with cyclohexylamine (1.75 mL, 12.1 mmol), sodium cyanoborohydride (1.39 g, 22.2 mmol), and glacial acetic acid (10 drops) and stirred for 16 h at 50° C. After cooling to 25° C. the solvent was removed in vacuo, the crude material was redissolved in ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was discarded and the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was discarded, 1.0 M aqueous sodium hydroxide solution (75 mL) was added and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford the desired product 2-cyclohexylamino-cyclopentanecarboxylic acid ethyl ester (2.10 g, 8.77 mmol, 86.9%), as a light yellow oil. LC-MS (ESI) calcd for C14H25NO2239.19, found 240.2 [M+H+].
Reaction SMILES: [F:1][C:2]([F:7])([F:6])C([O-])=O.[Na+].Br[C:10]1[C:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=2[C:13]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[C:12]([F:34])[CH:11]=1>[Cu]I.CN(C)C(=O)C>[CH3:19][C:17]1([CH3:20])[O:16][C:15]2[C:10]([C:2]([F:7])([F:6])[F:1])=[CH:11][C:12]([F:34])=[C:13]([N:21]3[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]3=[O:33])[C:14]=2[O:18]1
Reactant: O=C([O-])C(F)(F)F
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Br)c3c2OC(C)(C)O3)c1=O
Agent: [Cu]I
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(C(F)(F)F)c3c2OC(C)(C)O3)c1=O
Temperature: 150 °C
Reaction time: 3 h

Procedure:
To a solution of 6.0 g (0.044 mole) of sodium trifluoroacetate, 4.18 g (0.022 mole) of copper(I)iodide, and 40 mL of N,N-dimethylacetamide under a nitrogen atmosphere at 140 ° C is added 4.83 g (0.011 mole) of 3-(7-bromo-2,2-dimethyl-5-fluoro- 1,3-benzodioxol-4-yl)- 1 -methyl-6-trifluoromethyluracil (Example 3). The temperature is then raised to 150° C. at which the reaction mixture is stirred for three hours. After being cooled to ambient temperature, the reaction mixture is poured into ice and then extracted with diethyl ether. The combined extracts are dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure, leaving a residue which is purified using column chromatography on silica gel. The product-containing fractions are combined and the solvent evaporated under reduced pressure, leaving 3-(2,2-dimethyl-5-fluoro-7-trifluoromethyl- 1,3-benzodioxol-4-yi)- 1 -methyl-6-trifluoromethyluracil as a residue.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH:12]=[C:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:17]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].CCN=C=NCCCN(C)C.O>ClCCl>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([NH:25][C:14]([C:11]2[CH2:10][CH2:9][N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:13][CH:12]=2)=[O:16])=[CH:26][CH:27]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: O=C(O)C1=CCN(c2ncccc2Cl)CC1
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc(NC(=O)C2=CCN(c3ncccc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3′-Chloro-3,6-dihydro-2H-1,2′-bipyridine-4-carboxylic acid (120 mg, 0.35 mmol), 4-tert-butylaniline (90.0 mg, 0.6 mmol), and EDCI (145 mg, 0.75 mmol) were combined in dichloromethane (3 mL) under N2 and stirred at room temperature overnight. The mixture was treated with water and the layers were separated. The organic layer was concentrated and the residue was purified via column chromatography (SiO2, ethyl acetate:hexanes, 1:4) to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 8.18 (dd, 1H), 7.61 (dd, 1H), 7.46 (d, 2H), 7.38 (s(br), 1H), 7.35 (d, 2H), 6.85 (dd, 1H), 6.75 (m, 1H), 4.10 (dd, 2H), 3.58 (dd, 2H), 2.68 (m, 2H), 1.30 (s, 9H); MS (ESI) 370 (M+H)+.
Reaction SMILES: [C:1]([CH2:9][C:10]([CH3:12])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Br[CH2:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=1)[O:23][Si:24]([CH3:30])([CH3:29])[C:25]([CH3:28])([CH3:27])[CH3:26].[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH3:30][Si:24]([CH3:29])([C:25]([CH3:27])([CH3:26])[CH3:28])[O:23][C:22]1[CH:21]=[C:20]([CH2:19][CH2:12][C:10](=[O:11])[CH2:9][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CBr)c1
Reactant: CC(=O)CC(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(CCC(=O)CC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
Sodium hydride (2.13 g of a 50% dispersion in mineral oil, 44 mmol) was washed twice with hexanes, covered with dry THF (150 mL) and 1-benzoylacetone (6.00 g, 37 mmol) added portionwise. The mixture was stirred at room temperature under an atmosphere of nitrogen for 10 minutes to give a slurry which was cooled to -20° C. n-Butyllithium (2.60 g, 40 mmol) in hexane (16.3 mL) was added dropwise to provide a solution which was stirred for 20 minutes prior to the dropwise addition of [3-(bromomethyl)phenoxy]dimethyl(1,1-dimethylethyl)silane (11.17 g, 37 mmol). After 15 minutes, the mixture was poured onto saturated ammonium chloride solution and extracted with CH2Cl2. The combined extracts were dried over sodium sulfate, concentrated in vacuo and the residual oil chromatographed on a column of silica gel. Elution with a mixture of hexanes and diethyl ether (9:1) gave 5-[3-[dimethyl(1,1-dimethylethyl)siloxy]phenyl]-1-phenyl- 1,3-pentanedione (9.00 g, 63%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1>>[N+:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][CH2:2][NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)([O-:12])=[O:11]
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1ccccc1CCBr
Product: O=[N+]([O-])c1ccccc1CCNC1CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 17 h
Yield: 81 %

Procedure:
1-(2-Bromoethyl)-2-nitrobenzene (1.5 g, 6.52 mmol) and 4-amino-1-benzylpiperidine (3.0 ml, 14.71 mmol) were combined. Mixture was heated neat at 100° C. and held with stirring for 17 hours. Mixture was cooled to room temperature. Residue was triturated in 30 mL diethyl ether. Solids were filtered off, washed with diethyl ether and discarded. Filtrate was concentrated. Silica gel chromatography on the residue eluting 2M ammonia in methanol-dichloromethane afforded the title compound as brown oil in 81% yield. MS (M+H)+=340.4.