Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:20][C:21]([CH3:44])([CH3:43])[C:22](=[O:42])[O:23][CH2:24][O:25][P:26]([CH2:38][C:39](O)=[O:40])([CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:27]>CN(C)C=O>[CH3:20][C:21]([CH3:44])([CH3:43])[C:22](=[O:42])[O:23][CH2:24][O:25][P:26]([CH2:38][C:39]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:40])([CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:27]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)(C)C(=O)OCOP(=O)(CCCCc1ccccc1)CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCOP(=O)(CCCCc1ccccc1)CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
L-Phenylalanine (1.65 g, 10 mmol), triethylamine (2.8 ml, 20 mmol) and [[(2,2-dimethyl-1-oxopropoxy)methoxy]-(4-phenylbutyl)phosphinyl]acetic acid, N-hydroxy succinimide ester (4.67 g, 10 mmol) are dissolved in 50 ml of dry dimethylformamide and stirred overnight under argon at room temperature. The reaction mixture is partitioned between dichloromethane and 5% KHSO4, and the organic layer is washed with water and brine and then dried and evaporated to yield the desired product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH2:17][C:18]([OH:20])=O)[CH:15]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25]>>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH:25][C:18](=[O:20])[CH2:17][CH2:16][N:14]1[CH:15]=[C:11]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[NH:8][CH:7]=2)[CH:12]=[N:13]1
Reactant: CN(C)CCN
Reactant: O=C(O)CCn1cc(-c2c[nH]c3cc(F)ccc23)cn1
Product: CN(C)CCNC(=O)CCn1cc(-c2c[nH]c3cc(F)ccc23)cn1
Yield: 14.6 %

Procedure:
Following the general method as outlined in Example 39, starting from 3-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)propanoic acid (Example 24; 110 mg; 0.40 mmol) and N,N-dimethylethylenediamine (0.08 mL; 0.8 mmol), 20 mg (15%) of the title product was obtained as a yellow solid purified by preparative HPLC.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[N:6]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:13][C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([N:17]3[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]3)[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1cccc(-c2csc(Br)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(F)c3)cs2)CC1
Yield: 69.3 %

Procedure:
A solution of 2-bromo-4-(3-fluorophenyl)-1,3-thiazole (800 mg, 3.10 mmol), tert-butyl piperazine-1-carboxylate (1.15 g, 6.20 mmol) and potassium carbonate (428 mg, 3.10 mmol) in dimethylformamide (10 ml) was stirred at 120° C. for 12 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 781 mg (69.4%) of the desired product as an oil.
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([CH3:34])([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][CH:8]=1)C.[H-].[Na+].Br[CH2:39][C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=1>CN(C=O)C.CCOCC.Cl>[CH3:34][C:5]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=1)([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:39][C:40]3[CH:49]=[CH:48][C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:41]=3)[C:18](=[O:21])[N:17]2[CH3:22])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:35]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN1C(=O)N(Cc2ccc3ccccc3c2)CC1CCOc1ccc(CC(C)(Oc2ccc(C(F)(F)F)cc2)C(=O)O)cc1
Reaction time: 0.33 h
Yield: 52 %

Procedure:
To a mixture of 80 mg of 2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester in 5 mL of dry DMF at 0° C. under an atmosphere of nitrogen, 16 mg of NaH (0.40 mmol) is added. The resulting solution is allowed to stand at r.t. for 20 minute Then 89 mg of 2-bromomethyl naphthalene is added and resulting mixture is allowed to stand at r.t. for overnight. Reaction mixture is diluted with Et2O and 1N HCl. Organic layer is then washed with 1N HCl (2×10 mL), brine (2×10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude material is in 5 mL of EtOH and 0.5 mL of 5N NaOH. The mixture is heated to reflux for 1 h. The organic solvent is then removed under vacuum and residue is dissolved in CH2Cl2 and 1N HCl. Aqueous layer is washed with CH2Cl2 (2×10 mL). Combined organic layer is dried over Na2SO4, filtered and concentrated under vacuum. The crude material is purified by MS/LC to give 51 mg (51%) of the title product. 1H NMR (400 MHz, CDCl3): δ 7.81-7.77 (m, 3H), 7.66 (s, 1H), 7.48-7.45 (m, 4H), 7.35 (dd, 1H, J=8.8, 1.6 Hz), 7.12 (d, 2H, J=8.8 Hz), 6.92 (d, 2H, J=8.4 Hz), 6.69 (d, 2H, J=8.4 Hz), 6.20 (bs, 1H), 4.51 (s, 2H), 3.92-3.90 (m, 2H), 3.72-3.64 (m, 1H), 3.41 (t, 1H, J=8.8 Hz), 3.29, 3.13 (ABq, 2H, J=13.8 Hz), 3.03 (t, 1H, J=8.8 Hz), 2.86 (s, 3H), 2.22-2.15 (m, 1H), 1.93-1.84 (m, 1H), 1.46 (s, 3H). HRMS (ES+) m/z exact mass calcd for C34H34N2O5F3 (m+1) 6072420, found 6072417.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][NH:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8]2)[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]=1.[H][H]>[C].[Pd]>[C:1]1([C@@H:7]2[CH2:11][NH:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C(O)[C@@H]1C[C@H](C2=CCC=CC2)CN1
Reactant: [H][H]
Agent: [Pd]
Product: O=C(O)[C@@H]1C[C@H](C2=CCCCC2)CN1

Procedure:
cis-4-(1,4-Cyclohexadienyl)-L-proline is treated with a palladium-carbon catalyst and shaken on a Parr hydrogenator under 3 atmospheres of hydrogen to yield cis-4-(1-cyclohexenyl)-L-proline.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:3]=1[CH:4]=[C:5]1[S:9]C(=S)N[C:6]1=[O:11].[OH-:18].[Na+]>>[F:1][C:2]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:3]=1/[CH:4]=[C:5](\[SH:9])/[C:6]([OH:18])=[O:11]
Reactant: COc1ccc(F)c(C=C2SC(=S)NC2=O)c1
Reactant: [OH-]
Agent: [Na+]
Product: COc1ccc(F)c(/C=C(\S)C(=O)O)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
5-(2-Fluoro-5-methoxybenzylidene)-2-thioxo-1,3-thiazolidin4-one (8.00 g, 9.7 mmol) was added in one portion to 25% w/v sodium hydroxide solution (40 mL). This was allowed stir at reflux for 1 h. After this time the reaction was allowed to cool to room temperature and poured onto water (50 mL). This was washed with dichloromethane (50 mL), and the aqueous layer acidified to pH 2 with aqueous hydrochloric acid (2 N, 50 mL) to give a white suspension. Product was extracted with ether (2×60 mL), dried (MgSO4) and solvent removed in vacuo to give a white solid (6.71 g, 100%); δH (300 MHz, CD3OD) 7.85 (1H, s, Ar), 7.46-7.35 (1H, m, Ar), 7.11 (1H, t, Ar), 7.01-6.75 (2H, m, CH═, and SH), 3.80 (3H, s, OCH3).
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C@@H:17](O)[CH3:18])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:1]([N:8]([CH2:16][C@H:17]([N:24]1[C:20](=[O:30])[C:21]2[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:23]1=[O:25])[CH3:18])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](O)CN(Cc1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](CN(Cc1ccccc1)C(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 10 h
Yield: 89.5 %

Procedure:
209 mg of (S)-tert-butyl benzyl(2-hydroxypropyl)carbamate was dissolved in 10 mL of tetrahydrofuran in a nitrogen atmosphere and cooled to 0° C. 173 mg of phthalimide, 413 mg of triphenylphosphine, and 0.31 mL of diisopropyl azodicarboxylate were added thereto, and the mixture was stirred at room temperature for 10 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=6:1) to obtain 278 mg of the title compound as a pale yellow oil (89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:18])[C:12]=2[C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[CH:4][CH:3]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:18])[C:12]=2[C:13]2[N:14]=[CH:15][N:16]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=3)[CH:17]=2)=[CH:4][CH:3]=1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(F)(F)F)cn2)cn1
Temperature: 120 °C
Yield: 82.4 %

Procedure:
A mixture of 4-(4-fluoro-phenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-[1,2,3]triazole (36 mg, 0.15 mmol), 2-chloro-5(trifluoromethyl)pyridine (27 mg, 0.15 mmol) and potassium carbonate (41 mg, 0.3 mmol) in DMF (0.6 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 16 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (48 mg, 84%) as a white solid. MS: m/e=389.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:27][CH2:26][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][CH2:23]O)[C:12]2=[O:25])[CH2:10][CH2:9]1)=[O:7].[CH:37]([NH2:40])([CH3:39])[CH3:38]>>[F:32][C:31]([F:34])([F:33])[C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([C:2]([F:35])([F:1])[F:36])[CH:30]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][CH2:23][NH:40][CH:37]([CH3:39])[CH3:38])[C:12]2=[O:25])[CH2:26][CH2:27]1)=[O:7]
Reactant: CC(C)N
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCO)CN2c1ccccc1
Product: CC(C)NCCN1CN(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=557.2 (M+H+), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-hydroxy-ethyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and isopropylamine.
Reaction SMILES: [CH3:1][C:2]1[N:9]2[C:5]([S:6][CH:7]=[CH:8]2)=[CH:4][N:3]=1.[CH2:10]([O:13][C:14]([N:16]1[C@H:20]([CH:21]=[O:22])[CH2:19][C@@H:18]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:17]1)=[O:15])[CH:11]=[CH2:12]>>[CH2:10]([O:13][C:14]([N:16]1[C@H:20]([CH:21]([OH:22])[C:7]2[S:6][C:5]3=[CH:4][N:3]=[C:2]([CH3:1])[N:9]3[CH:8]=2)[CH2:19][C@@H:18]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[CH2:17]1)=[O:15])[CH:11]=[CH2:12]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Reactant: Cc1ncc2sccn12
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1cn2c(C)ncc2s1
Yield: 18.5 %

Procedure:
The procedure of Synthesis Example 10-a) is repeated, except that 1.53 g of 5-methylimidazo[5,1-b]thiazole and 3.46 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-formylpyrrolidine is used and the purification is successively performed by column chromatography on silica gel (ethyl acetate:methanol=9:1) and on Sephadex LH-20 (dichloromethane:methanol=1:1) to give 0.92 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-[1-hydroxy-1-(5-methylimidazo[5,1-b]thiazol-2-yl)methyl]pyrrolidine (a diastereomer mixture) as a slightly yellow amorphous material.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][N:12]=2)[C:5]=1[OH:19].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:25][C@@H:26]1[O:28][CH2:27]1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][N:12]=2)[C:5]=1[O:19][CH2:25][C@H:26]1[CH2:27][O:28]1
Reactant: COC(=O)c1cccc(Nc2ccc(OC)cn2)c1O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Nc2ccc(OC)cn2)c1OC[C@H]1CO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.1 %

Procedure:
To a solution of methyl-2-hydroxy-3-(5-methoxypyridin-2-ylamino)benzoate 0.91 g (3.3 mmol) of step 4 in dimethylformamide 10 mL were (R)-glycidyl nosylate 1.0 g (4 mmol) and K2CO3 0.5 g (3.6 mmol), followed by stirring at room temperature for 12 hrs. The reaction mixture was concentrated in a vacuum, diluted with ethylacetate, and washed with distilled water and a saturated NaCl solution. After drying over magnesium sulfate and vacuum concentration, purification by column chromatography (developing solvent: ethylacetate/hexane=1/2) afforded 0.95 g of the title compound (yield 87%).
Reaction SMILES: CC(N(C)C)=O.Cl[C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[H-].[Na+].[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([F:24])[CH:18]=1>O>[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:19]([F:24])[CH:18]=1
Reactant: Clc1ncccn1
Reactant: Nc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Fc1cc(Br)ccc1Nc1ncccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
Dimethylacetamide (10 ml) was added slowly to a mixture of 2-chloropyrimidine (1 g, 8.7 mmol), sodium hydride (0.8 g, 34.9 mmol), and 4-bromo-2-fluoro-aniline (1.6 g, 8.7 mmol) and the resulting mixture was stirred overnight at room temperature. Water was added slowly and the resulting mixture extracted three times with ethyl acetate. The organic phase bas washed with brine, dried over sodium sulfate and concentrated to dryness. Flash chromatography on silica gel chromatography using a gradient of ethyl acetate and hexane afforded (4-bromo-2-fluoro-phenyl)-pyrimidin-2-yl-amine (1.3 g, 56% yield). 1H NMR (500 MHz, DMSO-d6) δ 6.85 (m, 1H), 7.37 (d, 1H), 7.55 (d, 1H), 7.74 (m, 1H), 8.44 (s, 2H), 9.21 (s, 1H). MS: m/z 269.0 (M+H+).
Reaction SMILES: [C:1]([C@:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1>>[CH3:17][C@@:3]1([C:1]#[C:2][C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: Ic1cccs1
Reactant: C#C[C@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(C#Cc1cccs1)O2

Procedure:
This enantiomer was obtained as described in Example 4 by reacting the (S)-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol from Example 11 with 2-iodothiophene. It was isolated by chromatography as above and was crystallized from ether/hexane to yield colorless crystals with m.p. 131°-134° C. [α]D25 =+34.9° (c=1.145 in MeOH).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[CH2:19]([O:26][C:27]([NH:29][C@H:30]([C:34](O)=[O:35])[CH:31]([CH3:33])[CH3:32])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.CN(C=O)C>[CH2:19]([O:26][C:27]([NH:29][C@H:30]([C:34]([O:14][CH2:13][C@H:12]1[O:15][C@@H:7]([N:6]2[CH:16]=[C:2]([F:1])[C:3](=[O:18])[NH:4][C:5]2=[O:17])[C@H:8]([OH:9])[C@@H:10]1[OH:11])=[O:35])[CH:31]([CH3:33])[CH3:32])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1F
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To a solution of 5-fluorouridine (5-FU, 521 mg, 1.98 mmol) in 6 mL of anhydrous THF-DMF (1:1 under nitrogen was added N-(benzyioxycarbonyl)-L-valine (500 mg, 1.99 mmol), triphenylphosphine (521 mg, 1.98 mmol), and diisopropyl azodicarboxylate (402 mg, 1.98 mmol). The mixture was stirred overnight at 25 °C. The volatile components were removed under reduced pressure and the residue chromatographed over silica gel eluting with methyl alcohol:chloroform (1:5 ) to provide 5'-O-[N-(benzyloxycarbonyl)-L-valinyl]-5-fluorouridine (413 mg., 40% yield) as a white solid melting at about 64° C.-67° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[CH:22][N:21]=[C:20](S(C)(=O)=O)[N:19]=3)=[CH:13][C:12]=2[F:39])[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2].[C-:40]#[N:41].[K+]>CN(C=O)C>[C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[CH:22][N:21]=[C:20]([C:40]#[N:41])[N:19]=3)=[CH:13][C:12]=2[F:39])[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2]
Reactant: [C-]#N
Reactant: CS(=O)(=O)c1ncc(C(=O)Nc2ccc(F)cc2F)c(Nc2ccc(Oc3ccnc(C(N)=O)c3)c(F)c2)n1
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ncc(C(=O)Nc2ccc(F)cc2F)c(Nc2ccc(Oc3ccnc(C(N)=O)c3)c(F)c2)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
To a solution of 4-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)-2-(methylsulfonyl)pyrimidine-5-carboxamide (200 mg, 0.36 mmol) in DMF (4 mL) was added potassium cyanide (94 mg, 1.44 mmol) and the mixture was heated to 80° C. After 5 h. The mixture was cooled to rt and the solvent was removed in vacuo. The residue was diluted with brine and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo to give the nitrile (171 mg, 94%) as a solid. MS(ESI+) m/z 506 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:21]([N:28]1[CH2:32][C@@H:31]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])[C@H:30]([NH:41][CH3:42])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:21]([N:28]1[CH2:32][C@@H:31]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])[C@H:30]([N:41]([CH3:42])[C:14](=[O:15])[C:13]([C:5]2[CH:4]=[C:3]([C:2]([F:20])([F:19])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)([CH3:18])[CH3:17])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1C
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)ccc1[C@@H]1CN(Cc2ccccc2)C[C@H]1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 54 %

Procedure:
A solution of 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride (the preparation of which is described in WO2002079134) (90 mg, 0.28 mmol) in CH2Cl2 (5 ml) was added drop wise to a stirred solution of rac-[(3S,4R)-1-benzyl-4-(4-fluoro-2-methyl-phenyl)-pyrrolidin-3-yl]-methyl-amine (77 mg, 0.26 mmol) and ethyl-diisopropyl-amine (0.07 ml, 0.38 mmol) in CH2Cl2 (5 ml). The reaction mixture was stirred 1 h, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/H, 1:4) yielded 80 mg (54%) of the title product as colorless oil. ES-MS m/e: 581.2 (M+H+).
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[S:14][C:15]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:19]=[C:18]([O:28][CH3:29])[C:16]=2[N:17]=1)=[S:11])(=O)C1C=CC=CC=1.C1COCC1.C[O-].[Na+]>CO>[CH3:29][O:28][C:18]1[C:16]2[N:17]=[C:13]([NH:12][C:10]([NH2:9])=[S:11])[S:14][C:15]=2[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=S)NC(=O)c3ccccc3)nc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccc2)c2sc(NC(N)=S)nc12
Reaction time: 72 h
Yield: 86.9 %

Procedure:
To a solution of 1-benzoyl-3-(4-methoxy-7-phenyl-benzothiazol-2-yl)-thiourea (1.3 g, 3.1 mmol) in methanol (20 ml)/THF (40 ml) was added NaOMe (250 mg, 4.6 mmol) and the mixture stirrd for 72 h at r.t. After evaporation of the solvents water (100 ml) was added with stirring followed by aceticacid (1 ml) which caused a solid to precipitate. This solid was collected and on a glass sinter, washed with water (100 ml), followed by EtOAc (30 ml) then finally cyclohexane (30 ml). After drying the title compound was obtained as a white solid (850 mg, 87% yield), MS: m/e=316.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([NH2:9])=[C:6]([NH2:8])[CH:7]=1.[OH-].[NH4+].[CH:13](O)=O>Cl>[Cl:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]2[N:9]=[CH:13][NH:8][C:6]=2[CH:7]=1
Reactant: O=CO
Reactant: Cc1cc(N)c(N)cc1Cl
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc2nc[nH]c2cc1Cl
Temperature: 50 °C

Procedure:
A solution of 5-chloro-4-methyl-1,2-phenylenediamine (7.8 g) in a mixture of formic acid (35 mL) and hydrochloric acid (300 mL) was heated at 50° C. for 3 hours then treated with ammonium hydroxide solution until the solution was basic. The reaction mixture was then extracted with dichloromethane. The extracts were evaporated to give 6-chloro-5-methyl-1H-benzoimidazole (7 g).
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].Cl([O-])(=O)(=O)=O.[Li+].[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[NH2:15]>C(#N)C>[Br:11][C:12]1[CH:13]=[C:14]([NH:15][CH2:1][CH:2]([OH:4])[CH3:3])[CH:16]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:18]=1
Reactant: CC1CO1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: CC(O)CNc1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.7 %

Procedure:
Add propylene oxide (36 mg, 0.624 mmol) and lithium perchlorate (56 mg, 0.458 mmol) to the solution of 3-bromo-5-(trifluoromethyl)aniline (100 mg, 0.416 mmol) in acetonitrile (5 mL), stir the resulting mixture overnight at ambient temperature. Upon completion of the reaction, concentrate the mixture under reduced pressure. Purify the residue by flash chromatography (silica gel, PE:EtOAc=5:1) to afford the product (136 mg, 100%).