Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.[Br:44][C:45]1[CH:46]=[N:47][C:48](I)=[N:49][CH:50]=1>>[Br:44][C:45]1[CH:46]=[N:47][C:48]([C:11]2[CH:10]=[CH:9][C:8]([C:7]3[N:6]=[C:5]4[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:43])[CH3:42])[C:24]([O:26][C@H:27]5[C@H:31]6[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]6[O:29][CH2:28]5)=[N:25][C:4]4=[CH:3][C:2]=3[Cl:1])=[CH:13][CH:12]=2)=[N:49][CH:50]=1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Reactant: Brc1cnc(I)nc1
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(-c4ncc(Br)cn4)cc3)nc21

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and 5-bromo-2-iodopyrimidine following a procedure analogous to that described for Intermediate 3 (Step 3). LC (method 1): tR=1.28 min; Mass spectrum (ESI+): m/z=660, 662 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([O:14][P:15]([CH2:20][NH2:21])(=[O:19])[O:16][CH2:17][CH3:18])[CH3:13]>>[CH2:12]([O:14][P:15]([CH2:20][NH:21][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])(=[O:19])[O:16][CH2:17][CH3:18])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCOP(=O)(CN)OCC
Product: CCOP(=O)(CNc1cc(F)ccc1[N+](=O)[O-])OCC
Yield: 75.6 %

Procedure:
1.1 g of 2,4-difluoronitrobenzene is heated with 2.8 g of aminomethanephosphonic acid diethyl ester for 2 hours to 40° C. Then, it is chromatographed on silica gel with methylene chloride:ethanol=10:1. 1.6 g of N-(2-nitro-5-fluorophenyl)aminomethanephosphonic acid diethyl ester is obtained.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:21])[C:4]([C:18]([OH:20])=O)=[CH:5][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[C:7]=1[CH3:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH3:54][S:55]([C:58]1[CH:65]=[CH:64][C:61]([CH2:62][NH2:63])=[CH:60][CH:59]=1)(=[O:57])=[O:56].[NH4+].[OH-]>CN(C=O)C.CO>[CH3:54][S:55]([C:58]1[CH:65]=[CH:64][C:61]([CH2:62][NH:63][C:18]([C:4]2[C:3](=[O:21])[C:2]([Br:1])=[C:7]([CH3:8])[N:6]([CH2:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=3)[CH:5]=2)=[O:20])=[CH:60][CH:59]=1)(=[O:56])=[O:57]
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Reactant: Cc1c(Br)c(=O)c(C(=O)O)cn1Cc1ccc(C#N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(Br)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cn1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-bromo-1-(4-cyano-benzyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 1c, 1.00 g, 2.88 mmol), TBTU (0.925 g, 2.88 mmol), DIPEA (1.50 mL, 8.67 mmol) in DMF (7 mL) is stirred for 30 min. Then, 4-(methylsulfonyl)benzylamine hydrochloride (0.766 g, 3.46 mmol) is added and the reaction mixture is stirred for 18 h at room temperature. The reaction mixture is diluted with MeOH, basified with NH4OH, filtered and purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.3% NH4OH, 60° C.). Yield: 0.66 g (29% of theory); ESI mass spectrum: [M+H]+=514 (bromine isotope pattern); Retention time HPLC: 0.88 min (Z003—001).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=O)[CH2:3]1.[Br:12][C:13]1[CH:26]=[CH:25][C:16]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)=[CH:15][CH:14]=1.C1COCC1.Cl>C1(C)C=CC=CC=1.[Zn].Cl[Ti](Cl)(Cl)Cl.CCOC(C)=O.O>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:4]2[CH2:3][C:2]([CH3:11])([CH3:1])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5]2)=[CH:25][CH:26]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)CC(=C(c2ccccc2)c2ccc(Br)cc2)CC(C)(C)C1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 56.8 %

Procedure:
A stirred suspension of Zn dust (3.76 g, 57.5 mmol), 3,3,5,5-tetramethyl cyclohexanone (2.95 g, 19.2 mmol), 4-bromobenzophenone (5.00 g, 19.15 mmol) and anhydrous THF (100 mL) under N2 was cooled to −10° C. and a 1 M solution of TiCl4 in toluene (30 mL) added, dropwise, over 10 min. The temperature was maintained below 0° C. during the addition. After addition was complete the reaction was allowed to warm to RT and then heated at 90° C. for 2 h. The reaction was cooled to −10° C. and concentrated HCl (15 mL) added dropwise followed by water (15 mL). After stirring 30 min, EtOAc (100 mL) was added and the pale yellow 2-phase mixture washed with water (2×75 mL) and brine (1×75 mL) then dried (MgSO4) and concentrated to 8.26 g of a pale yellow oil. The crude oil is purified by column chromatography on 250 g silica gel with 2% EtOAc/hexanes to afford 4.17 g (58%) of the title compound (16) as a white solid. 1H-NMR indicated that the product (16) was contaminated with ˜8% of an impurity consistent with the pinacol intermediate formed during the McMurry reaction. 1H NMR (400 MHz, DMSO-d6): δ7.46 (d, J=8.3 Hz, 2H), 7.28 (t, J=7.5 Hz, 2H), 7.04-7.19 (m, 5H), 1.87 (s, 4H), 1.24 (s, 2H), 0.87 (s, 6H), 0.86 (s, 6H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[C:10]([OH:17])[C:9]=1[CH2:18][CH2:19][CH3:20].[C-:21]#[N:22].[Na+].[I-].[Na+]>CN(C)C=O>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][C:21]#[N:22])=[C:9]([CH2:18][CH2:19][CH3:20])[C:10]=1[OH:17])(=[O:16])[CH3:15]
Reactant: [C-]#N
Reactant: CCCc1c(OCCOCCBr)ccc(C(C)=O)c1O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCOCCC#N)ccc(C(C)=O)c1O
Yield: 97.1 %

Procedure:
A solution of 2.60 g of 1-[4-[2-(2-bromoethoxy)ethoxy]-2-hydroxy-3-propylphenyl]ethanone, 0.50 g of sodium cyanide and 1.13 g of sodium iodide in 50 ml of dimethyl formamide was stirred and heated at 80° for 6 hours. The solvent was removed in vacuo, water was added to the residue and the product was extracted with ether. The dried (over magnesium sulfate) extract was concentrated in vacuo to give 2.13 g of impure 3-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]propanenitrile.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[NH:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].O.[OH-].[Li+]>O1CCCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[NH:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: COC(=O)c1ccc(Br)c(NCC(C)(C)C)c1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)CNc1c(Br)ccc(C(=O)O)c1[N+](=O)[O-]
Reaction time: 15 h

Procedure:
0.88 g (2.55 mmol) of methyl 4-bromo-3-[(2,2-dimethylpropyl)amino]-2-nitrobenzoate was dissolved in 10 ml of tetrahydrofuran and 10 ml of water and admixed with 0.064 g (2.67 mmol) of lithium hydroxide. The mixture was left with stirring for 15 h and then concentrated. The residue was taken up in water and washed with methylene chloride and the aqueous phase was adjusted to a pH of 1 using a KHSO4 solution. The precipitate was isolated by filtration with suction, washed with water and dried under reduced pressure at 70° C.
Reaction SMILES: COC([N:5]([C:13]1[CH:59]=[CH:58][C:16]([C:17]([NH:19][CH2:20][C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]([OH:32])=[O:31])[C:25](=[O:33])[C@@H:24]2[CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:57])[C:39]2[CH:44]=[CH:43][C:42]([N:45](C(OC)=O)[C:46]([NH:48][C:49]([O:51][CH3:52])=[O:50])=[NH:47])=[CH:41][CH:40]=2)=[O:22])=[O:18])=[CH:15][CH:14]=1)[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])=[NH:7])=O.[OH-].[Li+].[ClH:62]>CO.O>[ClH:62].[CH3:12][O:11][C:9]([NH:8][C:6](=[NH:7])[NH:5][C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH2:20][C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]([OH:32])=[O:31])[C:25](=[O:33])[C@@H:24]2[CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:57])[C:39]2[CH:40]=[CH:41][C:42]([NH:45][C:46]([NH:48][C:49]([O:51][CH3:52])=[O:50])=[NH:47])=[CH:43][CH:44]=2)=[O:22])=[O:18])=[CH:58][CH:59]=1)=[O:10]
Reactant: COC(=O)NC(=N)N(C(=O)OC)c1ccc(C(=O)NCCC[C@H]2C(=O)N(CC(=O)O)CCN2C(=O)CNC(=O)c2ccc(N(C(=N)NC(=O)OC)C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)NC(=N)Nc1ccc(C(=O)NCCC[C@H]2C(=O)N(CC(=O)O)CCN2C(=O)CNC(=O)c2ccc(NC(=N)NC(=O)OC)cc2)cc1
Yield: 58 %

Procedure:
In a mixture of 1,4-dioxane (3.0 ml) and H2O (3.0 ml) was dissolved (S)-[4-[(4-guanidinobenzoylamino)acetyl]-3-[3-(4-guanidinobenzoylamino)propyl]-2-oxopiperazin-1-yl]acetic acid hydrochloride (another name: (S)-4-[(4-guanidinobenzoylamino)acetyl]-3-[3-(4-guanidinobenzoylamino)propyl]-2-oxopiperazine-1-acetic acid hydrochloride) (0.3 g, 0.51 mmol) produced in Working Example 15. To the solution were added gradually, under stirring at 0° C. while keeping the pH at 10 or below, a 2N aqueous solution of sodium hydroxide (2.60 ml, 5.10 mmol) and chlorocarbonic acid methyl ester (0.31 ml, 4.00 mmol). The reaction mixture was stirred for 10 minutes at 0° C., whose pH was adjusted to 4 with a 1N aqueous solution of hydrochloric acid, followed by shaking together with ethyl acetate for extraction. The organic layer was dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The concentrate was purified by means of a column chromatography (CHP-20, 10% CH3CNaq-15% CH3CNaq-20% CH3CNaq-25% CH3CNaq-35% CH3CNaq) to give (S)-[4-[[4-(1,3-dimethoxycarbonylguanidino)benzoylamino]acetyl]-3-[3-(4-(1,3-dimethoxycarbonylguanidino)benzoylamino]-propyl]-2-oxopiperazin-1-yl]acetic acid (another name: (S)-4-[(4-(1,3-dimethoxycarbonylguanidino)benzoylamino]acetyl]-3-[3-[4-(1,3-dimethoxycarbonylguanidino)benzoylamino]-propyl]-2-oxopiperazine-1-acetic acid) (0.26 g, 62%) as a colorless amorphous powdery product. This product (0.26 g, 0.31 mmol) was dissolved in a mixture of methanol (2.6 ml) and H2O (0.26 ml). To the solution was added, under ice-cooling, lithium hydroxide.1.0hydrate (42 mg, 1.00 mmol). One hour later, the reaction system was adjusted to pH 4 with a 1N aqueous solution of hydrochloric acid, followed by concentration under reduced pressure. The concentrate was purified by means of a column chromatography [(CHP-20, 5% CH3CNaq-10% CH3CNaq-15% CH3CNaq-20% CH3CNaq) and (LH-20, H2O)] to afford the title compound (0.13 g, 58%) as a colorless amorphous powdery product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]3[C:16](=[O:17])[C:15]([C:18]([O:20]CC)=[O:19])=[CH:14][N:13]=[C:10]32)=[CH:5][CH:4]=1>C(O)(=O)C.Cl.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]3[C:16](=[O:17])[C:15]([C:18]([OH:20])=[O:19])=[CH:14][N:13]=[C:10]32)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cnc2c3cc(OC)ccc3ccn2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2ccn3c(=O)c(C(=O)O)cnc3c2c1
Yield: 96 %

Procedure:
A solution of ethyl 10-methoxy-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (3.0 g., 0.010 mole) in a mixture of acetic acid (45 ml.) and 37% hydrochloric acid (23 ml.) was refluxed for 45 minutes. The mixture was cooled, diluted with water, and the yellow solid collected and dried to give the title acid: 2.6 g.(96% yield) m.p. 261°-263°. Recrystallization from acetic acid followed by n-butyl acetate gave the analytical sample, m.p. 262°-264°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.[CH2:32]([NH2:35])[CH2:33][NH2:34].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:34][CH2:33][CH2:32][NH:35][C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: NCCN
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(NCCN)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of example 6, [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with ethane-1,2-diamine, [rac]-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, palladium(II) acetate and cesium carbonate in toluene at reflux to give the title compound as light yellow solid. MS: 476.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)[CH:7]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:33])=[O:32])[CH2:14][C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc3c(c2)OCO3)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc3c(c2)OCO3)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared following the method described in Step A of Example 1 from 3-(3-{[(benzo[1,3]dioxol-5-ylmethyl)-amino]-methyl}-phenyl)-propionic acid methyl ester of Step A and benzenesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.85 (d, 2H), 7.62-7.50 (m, 3H), 7.13 (m, 1H), 7.03 (m, 1H), 6.88 (m, 1H), 6.78 (s, 1H), 6.62 (d, 1H), 6.54 (s, 1H), 6.46 (d, 1H), 5.90 (s, 2H), 4.28 (s, 2H), 4.21 (s, 2H), 3.67 (s, 3H), 2.81 (t, 2H), 2.50 (t, 2H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Br[CH:20]([CH:27](Br)[CH3:28])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH:27]([CH3:28])[CH:20]=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CCOC(=O)CC(Br)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C=CC(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Yield: 82 %

Procedure:
In a reactor, 30 g of ethanol was charged and 12.7 g (0.05 mole) of 4-(4-trifluoromethylphenoxy)phenol, 15.8 g (0.055 mole) of ethyl 3,4-dibromopentanoate, 8.7 g (0.063 mole) of potassium carbonate were charged. They were refluxed for 6 hours to react them. After the reaction, ethanol was distilled off from the reaction mixture and then 50 ml of toluene was added to the resulting mixture, and resulting solution was washed with water and then, the organic phase was washed with 5% hydrochloric acid and with water and then ethyl 3,4-dibromopentanoate and a lower boiling by-products were distilled off at 100° C. under a reduced pressure of 0.02-0.05 mmHg to obtain 15.6 g of ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-2-pentenoate (nD20 1.5175). The yield was 82.0%. The same process was repeated to obtain same compound except using ethyl 3,4-dichloropentanoate 10.9 g (0.055 mole) instead of ethyl 3,4-dibromopentanoate 15.8 g (0.055 mole). The yield was 73.6%.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].[CH3:28][O:29][C:30]1[C:31]([NH2:36])=[CH:32][CH:33]=[CH:34][CH:35]=1.Cl.CN(C)CCCN=C=NCC.CN(C1C=CC=CN=1)C>C(Cl)Cl.C(N(CC)CC)C>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)=[O:2]
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Reactant: COc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)c1cccc([C@H](C)Nc2nccc(-n3cnc4ccccc43)n2)c1
Temperature: 25 °C
Yield: 30.6 %

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 58, 23.0 mg) and o-anisidine (22 μL, 0.20 mmol) were mixed in CH2Cl2 (2 mL) under nitrogen. Triethylamine (45 μL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (38.5 mg) and dimethylaminopyridine (approx. 1 mg) were added and the mixture stirred at room temperature. After 19 h the mixture was concentrated in vacuo then eluted directly on silica gel (2:1 hexanes:acetone to 1:1 hexanes:acetone) to yield 9.1 mg of the title compound. Mass spectrum (ESI) 465.2 (M+1).
Reaction SMILES: C(=O)(O[CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)OC.C1([C@@H]([N:23]([C@H:47]([C:49]2[CH:54]=[CH:53][CH:52]=CC=2)C)P2OC3C=CC4C=CC=CC=4C=3C3C4C(C=CC=3O2)=CC=CC=4)C)C=CC=CC=1.CCO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Ir].[Ir]>[C:8]1([C@@H:7]([NH:23][CH:47]2[CH2:49][CH2:54][CH2:53][CH2:52]2)[CH:6]=[CH2:5])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H](c1ccccc1)N([C@@H](C)c1ccccc1)p1oc2ccc3ccccc3c2c2c(ccc3ccccc32)o1
Reactant: COC(=O)OC/C=C/c1ccccc1
Agent: [Ir]
Agent: C1=C\CC/C=C\CC/1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1=CCCC=CCC1
Solvent: CCO
Solvent: C1CCOC1
Product: C=C[C@H](NC1CCCC1)c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of Methyl (2E)-3-phenylprop-2-en-1-yl carbonate (384 mg) in THF (5 ml), was added N,N-bis[(1S)-1-phenylethyl]dinaphtho[1,2-f:2′,1′-d][1,3,2]dioxaphosphepin-4-amine (108 mg), and chloro(1,5-cyclooctadiene)iridium(I) dimer (27 mg) at RT under N2. The mixture was heated at reflux overnight. Evaporated material then redissoled in a 50:50 mixture of EtOH:THF. To this solution was added macro porous p-toluenesulfonic acid resin (6 g) and the mixture was gently agitated for 3 h. At this time the resin was washed completely with THF, THF:EtOH and EtOH. To a suspension of the resin in MeOH (75 ml) was added 7 N NH3.MeOH (75 ml). This mixture was gently agitated for 2 hours and filered, washing with MeOH, THF, THF:MeOH, and DCM. Evaporating this filtrate left the title compound as a yellow oil (360 mg, 89%). 1H NMR (300 MHz, CDCl3) δ 1.25-1.87 (m, 9H), 2.98-3.07 (m, 1H), 4.24 (d, 1H, J=7 Hz), 5.06-5.21 (m, 2H), 5.87-5.99 (m, 1H), 7.20-7.34 (m, 5H). MS APCI, m/z=202 (M+1), LC/MS, 1.35 min.
Reaction SMILES: Cl.C([O:5][C:6]1[C:7]([CH3:14])=[N:8][CH:9]=[C:10]([CH2:12][OH:13])[CH:11]=1)(=O)C.Cl.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O.N1C=CC=CC=1>[OH:5][C:6]1[C:7]([CH3:14])=[N:8][CH:9]=[C:10]([CH2:12][O:13][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH:11]=1
Reactant: CC(=O)Oc1cc(CO)cnc1C
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1ncc(COC(=O)c2ccncc2)cc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2.4 g. of 3-acetoxy-5-hydroxymethyl-2-methylpyridine hydrochloride in 20 ml. of pyridine was added a solution of 2.0 g. of isonicotinoyl chloride hydrochloride in 15 ml. of dimethylformamide under cooling and the resulting mixture was stirred at room temperature for 16 hours. Then, the reaction mixture was poured into ice-water and the mixture was extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off to give an oily substance. The substance was taken into 25 ml. of 2N HCl and the resulting mixture was stirred at 80°C. for 30 minutes. The mixture was neutralized with sodium bicarbonate, filtered and recrystallized from methanol to give 0.9 g. of the desired product. m. p. 180° - 180.5°C.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][CH2:16][C:17]([OH:21])([CH:19]=[CH2:20])[CH3:18])[CH3:13])[CH3:8])[CH3:3].[NH3:22]>>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][CH2:16][C:17]([OH:21])([C:19]#[CH:20])[CH3:18])[CH3:13])[CH3:8])[CH3:1].[NH3:22]
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Agent: N
Product: C#CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C

Procedure:
The isophytol, pretreated according to the invention with ammonia or an amine, which is employed as the starting material may also be a product obtained by catalytic hydrogenation of dehydroisophytol in the presence of an amine or ammonia.
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11]2)(=[O:7])=[O:6])([CH3:3])[CH3:2].[O:18]=[C:19]1[C:24]2=[CH:25][NH:26][C:27]([CH:28]=O)=[C:23]2[CH2:22][CH2:21][O:20]1>>[CH:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[C:11]2=[CH:28][C:27]1[NH:26][CH:25]=[C:24]2[C:19](=[O:18])[O:20][CH2:21][CH2:22][C:23]=12)(=[O:7])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: CC(C)NS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCOC3=O)C(=O)N2

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid isopropylamide was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([O:18][CH3:19])[CH:12]=1)C)(C)(C)C.[ClH:21].C(OCC)(=O)C>C(OCC)(=O)C.C(OCC)C>[ClH:21].[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][NH:7][CH3:6])=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: COc1cc(CCN(C)C(=O)OC(C)(C)C)ccc1F
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CNCCc1ccc(F)c(OC)c1
Reaction time: 2.5 h

Procedure:
To a solution of [2-(4-fluoro-3-methoxyphenyl)ethyl]methylcarbamic acid t-butyl ester (506 mg) in ethyl acetate (2 mL) was added a solution of 4N hydrochloric acid-ethyl acetate (2 mL) at room temperature and allowed to stand for 2.5 hours. The resulting solid was diluted with diethyl ether, then filtered, and washed with diethyl ether. After drying by aeration, the title compound (338 mg) was obtained as a colorless solid.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]([NH:10][CH2:11][CH3:12])=[N:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][N:14]=[C:15]=[O:16]>O>[CH2:11]([N:10]([C:7]1[S:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:9][N:8]=1)[C:15]([NH:14][CH3:13])=[O:16])[CH3:12]
Reactant: CN=C=O
Reactant: CCNc1nnc(C(C)(C)C)s1
Solvent: O
Product: CCN(C(=O)NC)c1nnc(C(C)(C)C)s1

Procedure:
A solution of 9.25 g of 2-tert.butyl-5-ethylamino-1,3,4-thiadiazole and 3.5 g of methyl isocyanate is heated several hours on the steam bath and poured into water to give 1-ethyl-1-(5-tert.butyl-1,3,4-thiadiazol-2-yl)-3-methylurea, m.p. 112°.