Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])=[CH:14][CH:13]=2)=[N:4][N:5]([CH2:7][C:8]([F:11])([F:10])[F:9])[CH:6]=1.CC1(C)C(C)(C)OB([C:36]2[CH:41]=[CH:40][N:39]=[C:38]3[NH:42][CH:43]=[CH:44][C:37]=23)O1.C(=O)(O)[O-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[C:22]1([NH:21][C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([C:3]3[C:2]([C:36]4[CH:41]=[CH:40][N:39]=[C:38]5[NH:42][CH:43]=[CH:44][C:37]=45)=[CH:6][N:5]([CH2:7][C:8]([F:11])([F:10])[F:9])[N:4]=3)=[CH:13][CH:14]=2)=[O:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Nc1ccccc1)Nc1ccc(-c2nn(CC(F)(F)F)cc2Br)cc1
Reactant: CC1(C)OB(c2ccnc3[nH]ccc23)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)Nc1ccc(-c2nn(CC(F)(F)F)cc2-c2ccnc3[nH]ccc23)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 35 %

Procedure:
A mixture of N-{4-[4-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]phenyl}-N′-phenylurea (0.059 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.059 mmol), tetrakis(triphenylphosphine)palladium(0) (0.003 mmol), saturated sodium bicarbonate (0.177 mL) and anhydrous N,N-dimethylformamide (1 mL) was stirred at 100° C. in a sealed tube for 4 h and cooled to room temperature. Filtration through a pad of Celite, concentration in vacuo and Gilson reverse phase HPLC purification furnished the title compound as a white solid (35%). ESMS [M+H]+: 477.2
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([CH2:10][NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])([OH:9])=[O:8].[C:21](OC(=O)C)(=[O:23])[CH3:22].Cl>O>[C:21]([N:11]([CH2:10][C:7]([OH:9])=[O:8])[C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:23])[CH3:22]
Reactant: O=C(O)CNc1ccccc1C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)N(CC(=O)O)c1ccccc1C(=O)O

Procedure:
To a solution of sodium carbonate (89 g, 0.84 mol) in water (830 mL), 2-(carboxymethylamino)benzoic acid of Example 1a (100 g, 0.84 mol) was added in small portions at room temperature under stirring while a clear solution was formed. Acetic anhydride (85.68 g, 0.84 mol) was added dropwise at room temperature under stirring. The reaction mixture was stirred for 30 min, and 37% aqueous hydrochloric acid (140 mL) was added dropwise. The product precipitated slowly. The solid product was filtered off in 12 h, washed with water (3×150 mL) and air-dried to afford 110 g (91%), m.p. 206° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([F:12])([F:11])[F:10])[N+:5]([O-])=[C:4]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH:3]=1.P(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([F:18])([F:17])[F:16])[N:5]=[C:6]([CH2:8][C:9]([F:11])([F:10])[F:12])[CH:7]=1
Reactant: [O-][n+]1c(CC(F)(F)F)cc(Br)cc1CC(F)(F)F
Agent: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: FC(F)(F)Cc1cc(Br)cc(CC(F)(F)F)n1

Procedure:
A solution of 4-bromo-2,6-bis-(2,2,2-trifluoro-ethyl)-pyridine 1-oxide (2.1 g, 6.2 mmol) and PBr3 (1 mL) in CH2Cl2 (15 mL) was stirred at room temperature for 4 hours. The reaction mixture was poured into ice, made basic with 15% NaOH and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to a pale yellow solid (1.77 g, 89%). 1H NMR (400 MHz, CDCl3): δ 3.59 (t, J=10.4 Hz, 4 H), 7.51 (s, 2 H).
Reaction SMILES: O=[CH:2][CH2:3][C@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:5].[C:14]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:16][CH2:17][CH3:18])=[O:15]>C1COCC1>[C:9]([O:8][C:7]([NH:6][C@H:4]([CH3:5])[CH2:3]/[CH:2]=[CH:19]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: C[C@H](CC=O)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.4 %

Procedure:
To a solution of (R)-tert-butyl 4-oxobutan-2-ylcarbamate (1.54 g, 8.22 mmol) in THF (25 mL) at rt was added (carbethoxymethylene)triphenylphosphorane (6.30 g, 18.1 mmol) in portions. The resulting clear solution was stirred at rt under argon for 3 days. The reaction mixture was concentrated and the oily residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-60% EtOAc/Hex to give (R,E)-ethyl 5-(tert-butoxycarbonylamino)hex-2-enoate (1.70 g, 6.61 mmol, 80% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 6.91 (dt, J=15.3, 7.5 Hz, 1H), 5.92-5.82 (m, 1H), 4.37 (s, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.83 (s, 1H), 2.37 (t, J=6.6 Hz, 2H), 1.44 (s, 9H), 1.29 (t, J=7.1 Hz, 3H), 1.15 (d, J=6.7 Hz, 3H).
Reaction SMILES: [CH2:1]([C@H:8]([NH:26]C(=O)OC(C)(C)C)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([C@H:8]([NH2:26])[C:9]([N:11]1[CH2:12][CH2:13][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC(Oc2ccc(F)c(F)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)C(=O)N1CCC(Oc2ccc(F)c(F)c2)CC1
Yield: 106.5 %

Procedure:
The product from Example 5, Step (a) (1.2 g) was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (5 ml) was added. After 1 hr at room temperature the solution was evaporated and aqueous NaOH (2M) added. The product was extracted with ethyl acetate, the combined organic extracts dried, filtered and concentrated to give the sub-title product as an oil (1 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:13])[CH2:11]Br.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:13])[CH2:11][N:31]1[CH2:30][CH2:29][N:28]([C:25]2[CH:24]=[CH:23][C:22]([CH2:21][C:18]3[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=3)=[CH:27][CH:26]=2)[CH2:33][CH2:32]1
Reactant: Cc1cccc(C)c1NC(=O)CBr
Reactant: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Product: Cc1cccc(C)c1NC(=O)CN1CCN(c2ccc(Cc3ccc(F)cc3)cc2)CC1

Procedure:
The compound (18) synthesized in Reference Example 18 and the compound (5) synthesized in Reference Example 5 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [C:1]([O:6][CH:7]([O:11][C:12]([CH3:14])=[S:13])[CH:8]([CH3:10])[CH3:9])(=[O:5])[CH2:2][CH2:3][CH3:4].P([O-])([O-])([O-])=O>C(OC(C)C)(C)C.CCOCC>[C:1]([O:6][C@H:7]([O:11][C:12]([CH3:14])=[S:13])[CH:8]([CH3:10])[CH3:9])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OC(OC(C)=S)C(C)C
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)OC(C)C
Solvent: CCOCC
Product: CCCC(=O)O[C@H](OC(C)=S)C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 32 %

Procedure:
To a solution of 2-methyl-1-methylthiocarbonyloxypropyl butanoate (2d) (0.5 g) in 2 mL of diisopropyl ether, 0.025 g of lipase from Candida rugosa was added, followed by 10 mL of phosphate buffer. The mixture was stirred at room temperature for ca. 24 hrs. The reaction mixture was diluted with ether and the organic solution filtered through a pad of CELITE® 545. The ether solution was washed with water (2 times) and brine, and dried over anhydrous sodium sulfate (Na2SO4). The solvent was evaporated under reduced pressure to provide 0.16 g (64% yield) of the title compound (7). 1H-NMR using a chiral solvating agent showed a single isomer and the absolute configuration was confirmed by derivatization to a compound having a known stereochemistry.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=3)[CH2:10][C:9]2([CH3:25])[CH3:24])=[CH:5][CH:4]=1>[Ni].CO.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[N:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=3)[CH2:10][C:9]2([CH3:25])[CH3:24])=[CH:26][CH:27]=1
Reactant: COc1ccc(CN2CCN(Cc3ccc([N+](=O)[O-])cn3)CC2(C)C)cc1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CN2CCN(Cc3ccc(N)cn3)CC2(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.7 %

Procedure:
A suspension of 1-(4-methoxy-benzyl)-2,2-dimethyl-4-(5-nitro-pyridin-2-ylmethyl)-piperazine (Step 112.2) (0.640 g, 1.72 mmol) and Raney Nickel (0.150 g) in MeOH/THF (1:1, v/v; 50 mL) was stirred for 20 h at rt, under a hydrogen atmosphere. The mixture was filtered through a pad of celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (DCM/NH3aq, 99:1→DCM/MeOH/NH3aq, 97:2:1) to afford 455 mg of the title compound as a yellow foam. Title compound: ESI-MS: 341.3 [M+H]+; tR=1.71 min (System 1); TLC: Rf=0.30 (DCM/MeOH, 9:1).
Reaction SMILES: [C:1]([CH2:5][NH:6][NH2:7])([F:4])([F:3])[F:2].C([O:10][C:11]([C:13]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:18](=O)[CH2:17][CH2:16][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14]1)=O)C.C(O)(=O)C>C1(C)C=CC=CC=1>[C:23]([O:22][C:20]([N:15]1[CH2:16][CH2:17][C:18]2=[N:7][N:6]([CH2:5][C:1]([F:4])([F:3])[F:2])[C:11](=[O:10])[C:13]2([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:14]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)C1(Cc2ccccn2)CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: NNCC(F)(F)F
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2=NN(CC(F)(F)F)C(=O)C2(Cc2ccccn2)C1
Temperature: 70 °C
Yield: 110.6 %

Procedure:
A 70% aqueous solution of CF3CH2NHNH2 (325 mL, 1.986 mol) (obtained from Aldrich) was extracted with toluene (3×1200 mL). To a solution of the product from step A (600 g, 1.655 mol) in toluene (900 mL) was first added the combined toluene extracts containing the anhydrous 2,2,2-trifluoroethyl hydrazine, followed by acetic acid (121.4 g, 1.986 mol). The reaction mixture was heated at about 70° C. for about 2 hours, then another toluene extraction of 70% aqueous 2,2,2-trifluoroethyl hydrazine (50 g) was added. The reaction mixture was heated at about 80° C. for about 3.5 hours, cooled to room temperature and diluted with saturated aqueous NaHCO3 (2 L). The toluene layer was separated and washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated in vacuo to give an oil (754.8 g). Crystallization from methanol/water afforded the desired product as a white solid (609.5 g). 1H-NMR (CDCl3) δ 1.50 (s, 9H), 2.53 (d, 1H), 2.70 (br s, 2H), 2.88 (br s, 1H), 3.31 (m, 2H), 3.97 (m, 1H), 4.19 (m, 1H), 4.46 (br s, 1H), 4.63 (br s, 1H), 7.06 (m, 2H), 7.51 (m, 1H), 8.34 (m, 1H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[C:9]([C:11](OCC)=[O:12])[CH:8]=[CH:7][C:6]=1[C:16]([F:19])([F:18])[F:17].O>CO>[CH3:3][O:4][C:5]1[N:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][C:6]=1[C:16]([F:19])([F:17])[F:18]
Reactant: CCOC(=O)c1ccc(C(F)(F)F)c(OC)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(CO)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Sodium borohydride (405 mg) was added to a solution of ethyl 6-methoxy-5-(trifluoromethyl)pyridine-2-carboxylate (670 mg, described in WO 2005058830) in methanol (20 mL) under ice-cooling, and the mixture was stirred at room temperature for two hours. The reaction solution was poured into water, followed by extraction with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the filtrate was concentrated under reduced pressure to give [6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanol (540 mg).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:14][S:15](Cl)(=[O:17])=[O:16])[CH2:9]1)=O)(C)(C)C.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[CH2:30]([NH:37][S:15]([CH2:14][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)(=[O:16])=[O:17])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@@H](CS(=O)(=O)Cl)Oc2ccc(C(F)(F)F)cc2)C1
Reactant: NCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(C[C@@H](Oc1ccc(C(F)(F)F)cc1)[C@H]1CCNC1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-3-[(S)-2-Chlorosulfonyl-1-(4-trifluoromethylphenoxy)ethyl]pyrrolidine-1-carboxylic acid t-butyl ester (50 mg, 109 μmol, 1.0 eq.) in DCM (1.0 mL) was combined with benzylamine (47.7 μL, 4.0 eq.) and the resulting mixture was stirred at room temperature for 2 hours. TFA (1.0 mL) was added and stirred for 1 minute. The mixture was then concentrated and purified by preparative HPLC to yield the title compound as a TFA salt (7.3 mg). MS m/z: [M+H]+ calcd for C20H23F3N2O3S, 429.14. found 429.0.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=2[F:24])[NH2:20])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=1[S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([NH:20][S:39]([C:33]3[C:34]([F:38])=[CH:35][CH:36]=[CH:37][C:32]=3[F:31])(=[O:41])=[O:40])[CH:21]=[CH:22][C:23]=2[F:24])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)c1nc(-c2cc(N)ccc2F)c(-c2ccnc(Cl)n2)s1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1nc(-c2cc(NS(=O)(=O)c3c(F)cccc3F)ccc2F)c(-c2ccnc(Cl)n2)s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 20.9 %

Procedure:
To a solution of 3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-4-fluoroaniline (7.4 g, 20.4 mmol) in DCM (200 mL) was added pyridine (4.85 g, 61.3 mmol) and cooled to 0° C. 2,6-Difluorobenzene-1-sulfonyl chloride (4.76 g, 22.5 mmol) in DCM (10 mL) was added dropwise to the mixture. The reaction was stirred at rt overnight. Then the reaction was washed with water (200 mL), and extracted with DCM (2×100 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether:EtOAc 5:1) to afford the title compound of Step E (2.3 g, 7.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.56 (d, J=5.3 Hz, 1H), 7.62-7.75 (m, 1H), 7.20-7.32 (m, 5H), 6.92 (d, J=5.3 Hz, 1H), 1.40 (s, 9H). m/z (ES+): 539 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:3][CH:2]=1.N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C=O)C.O>[Si:26]([O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][NH:11][C:4]2[C:5]3[C:10](=[N:9][CH:8]=[CH:7][N:6]=3)[N:1]=[CH:2][N:3]=2)=[CH:15][CH:16]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(CCNc2ncnc3nccnc23)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCNc2ncnc3nccnc23)cc1
Temperature: 2.5 °C
Reaction time: 20 h
Yield: 92.1 %

Procedure:
4-[2-(Pteridin-4-ylamino)-ethyl]-phenol (1.0 g, 3.7 mmol) was partially dissolved in dry DMF (75 mL), treated with imidazole (630 mg, 9.3 mmol), cooled to 0-5° C. and treated dropwise with a solution of t-butyldimethylsilyl chloride (680 mg, 4.5 mmol) in DMF (15 mL). After warming to 25° C. the mixture was stirred for 20 h, diluted with H2O (75 mL) and extracted with EtOAc. The extracts were washed with H2O, brine, dried (Na2SO4), filtered and concentrated in vacuo to give {2-[4-(tert-butyldimethylsilanyloxy)-phenyl]-ethyl}-pteridin-4-yl-amine (1.3 g) as a white solid: mp 164-165° C.; 1H NMR (300 MHz, CDCl3) δ 8.99 (s, 1H), 8.61 (s, 1H), 8.59 (s, 1H), 8.26 (d, J=5.9 Hz, 1H), 6.8-7.2 (m, 5H), 3.98 (t, J=6.2 Hz, 2H), 2.99 (t, 6.3 Hz, 2H), 1.02 (s, 6H), 0.18 (s, 9H).
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH:33]([OH:41])[CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH:33]([OH:41])[CH2:34][CH2:35][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Reactant: NCCC(O)CCN1CCCC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCC(O)CCN3CCCC3)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 1-amino-5-pyrrolidin-1-yl-pentan-3-ol by the procedure analogous to Example 1. MS (APCI, m/z): 498 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[C:13]1(=[O:18])[O:17][CH:15]([CH3:16])[CH2:14]1>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:15]([CH3:16])[CH2:14][C:13]([OH:18])=[O:17])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC1CC(=O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 23 °C

Procedure:
4-Nitrophenol (34.78 g, 0.25 mol) was added to a solution of 10 g (0.25 mol) sodium hydroxide in 100 ml water and the solution heated at reflux for 15 minutes. To the solution at reflux, 20.4 ml (0.25 mol) betabutyrolactone was added dropwise over a 1.5 hour period. The reaction was cooled to 23° C. and extracted with 2×150 ml diethyl ether. The combined ether layers were extracted with 4×140 ml saturated sodium bicarbonate solution and the bicarbonate then acidified with 60 ml concentrated hydrochloric acid and back-extracted with 200 ml diethyl ether. The ether back extract was washed with 50 ml water and 50 ml brine, and dried over magnesium sulfate. Concentration in vacuo gave the product as a yellow oil, 31.2 g (55%).
Reaction SMILES: [C:1](OC(C)(C)C)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)[NH2:17].CS(O)(=O)=O.O>C1(C)C(C)=CC=CC=1>[CH3:22][O:21][C:19]1[CH:20]=[C:14]([O:13][CH3:12])[CH:15]=[C:16]2[C:18]=1[C:3]([CH3:5])=[CH:2][C:1](=[O:6])[NH:17]2
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: COc1cc(N)cc(OC)c1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1cc(OC)c2c(C)cc(=O)[nH]c2c1
Temperature: 125 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl acetoacetate (1.58 g) was heated to 120° C. and 3,5-dimethoxyaniline (1.53 g) dissolved in xylene (4 ml) was added. The mixture was heated at 120-130° C. for 20 minutes and then cooled to room temperature. Methanesulfonic acid (2 ml) was added and the mixture was stirred at ambient temperature for 10 minutes. Water (40 ml) was added and the precipitate filtered and dried. Yield 1.31 g (60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17](=[O:18])[CH:16]=[C:15]([NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:14]1.[CH2:28](O)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]C>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4]>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH3:28])=[O:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17](=[O:18])[CH:16]=[C:15]([NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:14]1
Reactant: CCCCCCCCCCCCCCO
Reactant: COC(=O)c1cc(Cl)c(-n2[nH]c(NC(=O)c3ccccc3)cc2=O)c(Cl)c1
Agent: [Ti+4]
Agent: CCCC[O-]
Product: CCCCCCCCCCCCCCOC(=O)c1cc(Cl)c(-n2[nH]c(NC(=O)c3ccccc3)cc2=O)c(Cl)c1

Procedure:
1-(2,6 -Dichloro-4-methoxycarbonylphenyl)-3-benzamido-5-pyrazolone prepared by the method as described in step (1) was reacted with 1-tetradecanol in the presence of butyl titanate as catalyst in a manner similar to Synthesis Example 1 to obtain the desired coupler, 1-(2,6 -dichloro-4-n-tetradecyloxycarbonylphenyl)-3-benzamido-5-pyrazolone as colorless crystals. The melting point of the product as 146°-147°C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[OH:34][C@H:35]1[CH2:39][NH:38][C@H:37]([C:40]([OH:42])=[O:41])[CH2:36]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:38]5[CH2:39][CH:35]([OH:34])[CH2:36][CH:37]5[C:40]([OH:42])=[O:41])[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Agent: OC1CCNC1
Product: O=C(O)C1CC(O)CN1c1cc(-c2ccc(Sc3ccc4c(c3)OCCO4)c(C(F)(F)F)c2)ccn1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with trans-4-hydroxy-L-proline. A yellow solid 131 was obtained (0.017 g, 33%). 1H-NMR(CDCl3,400 MHz)62.42–2.51 (m, 1H),3.66–3.72(m, 1H), 3.85–3.91 (m, 1H), 4.00–4.06 (m, 1H), 4.28–4.34 (m, 4H), 4.64–4.69 (m, 1H), 4.89–4.95 (m, 1H), 6.81 (s, 1H), 6.92–6.96 (m, 2H), 7.03 (dd, J=1.8 Hz, 8.4 Hz, 1H), 7.06–7.10 (m, 2H), 7.50 (d, J=8.4 Hz, 1H), 7.79 (s, 1H), 7.92–7.96 (m, 1H); MS (APCI) m/z 519 (M+H)+.
Reaction SMILES: [Mg].II.[CH2:4](Cl)[CH:5]=[CH2:6].[CH2:8](Cl)/[CH:9]=[C:10](/[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])\[CH3:11]>C(O)(=O)C.CCOCC>[CH3:11][C:10]([CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:9][CH2:8][CH2:6][CH:5]=[CH2:4]
Reactant: CC(C)=CCC/C(C)=C/CCl
Reactant: C=CCCl
Agent: II
Agent: [Mg]
Solvent: CC(=O)O
Solvent: CCOCC
Product: C=CCCC=C(C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Magnesium turnings (51 g., 2.1 mole) were suspended in 1700 ml. of ether and activated with a crystal of iodine. Allyl chloride (153 g., 2.0 mole) in 200 ml. of ether was added dropwise so as to maintain the mixture at reflux temperature throughout the addition. The mixture was refluxed for an additional 2 hours, then a solution of technical 82% pure geranyl chloride (210 g., 1.05 mole) in 200 ml. of ether was added dropwise at reflux temperature. The mixture was stirred for 2 hours at room temperature, then it was cooled down to 10° and slightly acidified with 20% aqueous acetic acid. The mixture was extracted with ether. The extracts were neutralised with 10% NaOH, washed with water, dried as usual and concentrated. The residue gave 217 g. of crude triene as a light yellow liquid the purity of which was 80% according to vapour phase chromatography; it was used without further purification.