Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:3]([C:11]2([CH2:27][OH:28])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:12]2=[O:26])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[O:26]=[C:12]1[C:11]2([C:3]3=[CH:4][C:5]4[O:9][CH2:8][O:7][C:6]=4[CH:10]=[C:2]3[O:28][CH2:27]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Yield: 90 %

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using ethyl [3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained as a white powder in 90% yield: 1H NMR (300 MHz, DMSO-d6) δ 7.31-7.26 (m, 1H), 7.17-7.00 (m, 3H), 6.67 (s, 1H), 6.18 (s, 1H), 5.90-5.89 (m, 2H), 4.76-4.66 (m, 2H), 4.59 (s, 2H), 4.13 (q, 2H), 1.17 (t, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.3, 168.3, 155.6, 148.8, 142.4, 142.1, 132.0, 129.3, 124.1, 123.7, 120.4, 109.6, 103.3, 101.9, 93.8, 79.8, 61.8, 57.8, 41.8, 14.5; MS (ES+) m/z 390.2 (M+23).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([C:8]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][C:12]=2[C:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH:21]=2)=[O:9])[NH:6][CH:7]=1)#[N:2].Cl.C([O:31][C:32](=[O:42])[C@H:33]([CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])[NH2:34])C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[OH-].[K+].C(O)(C(F)(F)F)=O>CCOC(C)=O.C(Cl)Cl>[C:1]([C:3]1[N:4]=[C:5]([C:8]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH:34][C@H:33]([C:32]([OH:31])=[O:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:16])=[CH:13][C:12]=2[C:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH:21]=2)=[O:9])[NH:6][CH:7]=1)#[N:2]
Reactant: CC1(C)CC=C(c2cc(C(=O)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
A flask was charged with 4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-(4,4-dimethyl-cyclohex-1-enyl)-benzoic acid (36 mg, 99 μmol)(prepared in Example 65), L-glutamic acid diethyl ester hydrochloride (26 mg, 120 μmol), N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide (23 mg, 120 μmol), 1-hydroxybenzotriazole (13 mg, 99 μmol), DIEA (38 mg, 300 μmol) and 0.3 mL of DCM and stirred for 8 h at RT. The mixture was diluted with 20 mL EtOAc, washed with NaHCO3 (2×20 mL) and brine (20 mL), and the organic layer was dried (Na2SO4) and concentrated. The residue was dissolved in 2 mL of EtOH and a 7 N aqueous KOH solution (43 μL, 300 μmol) was added and the reaction stirred for 8 h at RT. The pH was adjusted to 2 with a 2 N TFA solution and the title compound was purified by RP-HPLC eluting with a linear gradient of 30% to 50% acetonitrile in 0.1% TFA/H2O over 10 min on a C18 column giving 25 mg (52%) of a white solid. 1H-NMR (CD3OD, 400 MHz): δ 8.35 (d, J=8.6 Hz, 1H), 7.92 (s, 1H), 7.72 (dd, J=8.6, 2.1 Hz, 1H), 7.66 (d, J=2.1 Hz, 1H), 5.74 (m, 1H), 4.54 (m, 1H), 2.39 (t, J=7.4 Hz, 2H), 2.30-2.16 (m, 3H), 2.07-1.95 (m, 3H), 1.54 (t, J=6.3 Hz, 2H), 1.03 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C25H27N5O6, 494.2 (M+H), found 494.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[S:11][C:10]=1[C:17]([O:19]C)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCCC1.CO.O>[CH2:1]([O:8][C:9]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[S:11][C:10]=1[C:17]([OH:19])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(C(C)C)cc1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cc(OCc2ccccc2)c(C(=O)O)s1
Temperature: 22 °C
Reaction time: 72 h

Procedure:
1.16 g of methyl 3-benzyloxy-5-isopropyl-thiophene-2-carboxylate were dissolved in 10 ml of tetrahydrofuran (THF) and 10 ml of methanol, and a solution of 1.7 g of lithium hydroxide in 10 ml of water was added. The reaction mixture was stirred at 22° C. for 72 h. Methanol and THF were stripped off in the rotary evaporator. While cooling in ice, the reaction mixture was adjusted to pH=4 with 2 molar hydrochloric acid and extracted twice with 50 ml of ethyl acetate each time. The combined organic phases were dried over sodium sulfate and concentrated.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:11][N:12]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]#[C:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([O:40][CH3:41])[CH:36]=3)[CH:31]=2)CC2C=CC=CC=2)[OH:10])=[CH:4][C:3]=1[Cl:42].Cl>C(O)C.[Pd]>[NH2:1][C:2]1[C:3]([Cl:42])=[CH:4][C:5]([CH:9]([CH2:11][NH:12][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([O:40][CH3:41])[CH:36]=3)[CH:31]=2)[OH:10])=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc2cc(C#CCOCCCCCCN(Cc3ccccc3)CC(O)c3cc(Cl)c(N)c(Cl)c3)ccc2c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc2cc(CCCOCCCCCCNCC(O)c3cc(Cl)c(N)c(Cl)c3)ccc2c1
Yield: 53.9 %

Procedure:
A solution of 4-amino-3,5-dichloro-α-[[[6-[[3-[6-methoxy-2-naphthalenyl]-2-propynyl]oxy]hexyl](phenylmethyl)amino]methyl]benzenemethanol (1.11 g) in absolute ethanol (50 ml) was hydrogenated over pre-reduced 10% palladium on charcoal catalyst (0.4 g) in absolute ethanol (10 ml) containing hydrochloric acid (1:9 conc. hydrochloric acid/ethanol, 1.67 ml). The mixture was filtered through hyflo and evaporated in vacuo to give an oil. The oil was partitioned between dichloromethane (150 ml) and 8% sodium bicarbonate (100 ml). The aqueous phase was re-extracted with dichloromethane (100 ml) and the combined organic extracts dried and evaporated in vacuo to give an oil. Purification by FCC eluting with System C (95:5:1) gave the title compound as a white solid (513 mg), m.p. 102.5°-103.5°.
Reaction SMILES: C([NH:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][NH:17]C(=O)C)=[N:12][CH:13]=1)(=O)C.[OH-].[Na+]>Cl>[NH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][NH2:17])=[N:12][CH:13]=1
Reactant: CC(=O)NCCCc1ccc(CCCNC(C)=O)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NCCCc1ccc(CCCN)nc1
Yield: 191.3 %

Procedure:
A solution of N-(3-{5-[3-(acetylamino)propyl]pyridin-2-yl}propyl)acetamide (9-1) (1.5 g) in 3N HCl (15 mL) was heated under reflux for 3 hours. At room temperature, 5N NaOH (about 10 mL) was added to the solution until a pH of about 10 was achieved. The solution was extracted three times with sec-butyl alcohol (15 mL). The extracts were combined and concentrated under reduced pressure to give 12-1 (2 g). The melting point and NMR spectra were identical to those observed for 12-1 in Example 13.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:18][CH:19]([CH2:23][CH2:24][Br:25])[C:20](Cl)=[O:21]>C(OCC)C>[Br:18][CH:19]([CH2:23][CH2:24][Br:25])[C:20]([NH:10][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:9])=[O:21]
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: O=C(Cl)C(Br)CCBr
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[C@H](NC(=O)C(Br)CCBr)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of (S)-1-(4-fluorophenyl)ethanamine (3.2 g, 23 mmol) in diethyl ether (50 mL) and triethylamine (9.6 mL, 69 mmol) at 0° C. was added 2,4-dibromobutanoyl chloride (7.3 g, 27.6 mmole) and the mixture was allowed to warm to rt and stirred for 12 h. A solid formed which was removed by filtration, washed with ethyl acetate, and then discarded. The combined filtrates were evaporated under reduced pressure and the residue was subjected to silica gel chromatography eluting with 20-30% ethyl acetate/petroleum ether yielding 4.5 g of 2,4-dibromo-N—((S)-1-(4-fluorophenyl)ethyl)butanamide as a brown solid. LCMS (method O) RT=0.99 min, m/z 366, 368, 370 (M+H+, M+H++2, M+H++4); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25-1.44 (m, 3H) 2.27-2.46 (m, 2H) 3.46-3.58 (m, 2H) 4.55-4.66 (m, 1H) 4.81-5.00 (m, 1H) 7.03-7.24 (m, 2H) 7.30-7.45 (m, 2H) 8.89 (d, J=8.03 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[OH-:14].[Na+]>>[OH:14][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: [OH-]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Product: O=C(O)c1cc(O)ccc1[N+](=O)[O-]

Procedure:
124.6 g (0.618 mol) of 5-chloro-2-nitro-benzoic acid (Fluka Buchs, Switzerland) are heated under reflux in an aqueous sodium hydroxide solution [197.8 g (4.94 mol) of NaOH in 1.23 l water] for 18 h. The cold reaction mixture is extracted several times with ether-ethyl acetate, washed with brine and dried over sodium sulfate. The raw material is crystallized from isopropyl ether-hexane. The crystals are filtered off and dried at 50° C. (high-vacuum). mp: 167-171° C.; MS: 182 (M+−1); HPLC: W-=6.315 min (Grad 1).
Reaction SMILES: CC(C)([O-])C.[K+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[C:8]1([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1CCNCC1
Reactant: Brc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: c1ccc(N2CCCCC2)cc1
Temperature: 110 °C

Procedure:
224 mg (2 mmoles) of potassium tert.-butoxide, 70 mg (2.5 mole % calculated for the bromobenzene substrate) of the catalyst of formula (I), 105 μl (1 mmole) of bromobenzene, 198 μl (2 mmoles) of piperidine and 5 ml of solvent were charged into an oven-dried Schlenk tube. The reaction mixture was heated on an oil bath at 110° C. for 24 hours, allowed then to cool to room temperature, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (eluant: hexane/ethyl acetate) to give the desired product; 1H NMR (300 MHz, CDCl3) δ 7.31-7.26 (m, 2H), 7.00-6.97 (m, 2H), 6.89-6.84 (m, 1H), 3.19 (t, J=5.6 Hz, 4H), 1.79-1.72 (m, 4H), 1.64-1.59 (m, 2H).
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]CC.O>C1C=CC=CC=1>[CH2:2]([O:3][CH2:4][C@H:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: CCCCCCCCCCCCCCCCCCCCBr
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCOC[C@@H](O)CO
Temperature: 25 °C
Yield: 74.1 %

Procedure:
8.6 ml (76.08 mmol) of (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol, 15 grams of powdered potassium hydroxide and 27.5 grams (76.08 mmol) of 1-bromoeicosane were stirred in 150 ml benzene and refluxed for 6 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 70 ml. The reaction mixture was then cooled to room temperature and 150 ml of water was added. The reaction mixture was then extracted thrice with 150 ml diethyl ether, the combined organic phase was washed with 100 ml water, and the solvent was then removed under reduced pressure. The obtained residue was dissolved in 105 ml of a 90:10:5 (v/v) methanol:water:concentrated hydrochloric acid mixture, and the resulting solution was refluxed until the solution became clear. The solution was then cooled to room temperature and 100 ml water was added. The product was extracted with 150 ml chloroform, washed consecutively with 150 ml water, 150 ml saturated aqueous solution of sodium carbonate, and again with 150 ml water. The solvent was then removed under reduced pressure and the product was crystallized from 200 ml hexane, yielding 21.0 grams of pure 1-eicosanyl-sn-glycerol, which was dried in a desiccator under reduced pressure with phosphorus oxide. The yield was 81.5%.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:15]=[CH:14][C:7]([NH:8][C:9](=[O:13])[CH2:10][O:11][CH3:12])=[CH:6][C:5]=1[N+:16]([O-])=O)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:30]([N:37]1[C:41](=[O:42])[C:40](=[C:43]2[N:47]([CH3:48])[C:46]3[CH:49]=[C:50]([O:53][CH2:54][CH2:55][Cl:56])[CH:51]=[CH:52][C:45]=3[S:44]2)[S:39][CH2+:38]1SC)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([N:37]1[C:41](=[O:42])[C:40](=[C:43]2[N:47]([CH3:48])[C:46]3[CH:49]=[C:50]([O:53][CH2:54][CH2:55][Cl:56])[CH:51]=[CH:52][C:45]=3[S:44]2)[S:39][C:38]1=[N:16][C:5]1[CH:6]=[C:7]([NH:8][C:9](=[O:13])[CH2:10][O:11][CH3:12])[CH:14]=[CH:15][C:4]=1[NH:3][CH2:1][CH3:2])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CS[CH2+]1SC(=C2Sc3ccc(OCCCl)cc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNc1ccc(NC(=O)COC)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)COC)cc1N=C1SC(=C2Sc3ccc(OCCCl)cc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 4′-ethylamino-2-methoxy-3′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-[5-(2-chloroethoxy)-3-methyl benzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. MS(ESI): 638 (M H+).
Reaction SMILES: C([O:8][C:9](=[O:35])[CH2:10][CH:11]([S:19]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:23]1)(=[O:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[CH2:28]([CH:25]1[CH2:26][CH2:27][N:22]([S:19]([CH:11]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:10][C:9]([OH:35])=[O:8])(=[O:21])=[O:20])[CH2:23][CH2:24]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(CC(Cc1ccccc1)S(=O)(=O)N1CCC(Cc2ccccc2)CC1)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)CC(Cc1ccccc1)S(=O)(=O)N1CCC(Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 99.6 %

Procedure:
The product from Step E (360 mg, 0.73 mmol) was taken up in EtOAc (10 mL) with stirring under a blanket of argon. 10% palladium on charcoal (130 mg) was added. The resulting suspension was hydrogenated in a PARR apparatus at room temperature overnight. The system was purged with argon and the catalyst removed by filtration. The filtrate was evaporated under reduced pressure to give the desired product as a gum (292mg, Quant). 1H-NMR δ(MeOD) 7.24-7.10 (10H, m), 3.89 (1H, m), 3.69 (2H, m), 3.25 (1H, dd, J=4.8, 17.1 Hz), 2.81-2.64 (4H, m), 2.53 (2H, d, J=6.7 Hz), 2.45 (1H, dd, J=4.8, 17.1 Hz), 1.61 (3H, m) and 1.28 (2H, m). 13C-NMR δ(MeOD) 174.3, 141.7, 138.8, 130.8, 130.6, 130.2, 129.7, 128.4, 127.4, 61.0, 47.6, 44.2, 39.2, 36.6, 34.8, 33.7. ESMS=(M+1) 402.2, (M−1) 400.0.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:10][CH2:11][CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[CH3:13])=[N:4][CH:5]=[N:6][C:7]=1[CH2:8][CH3:9].[C:23]([O:31][CH2:32]Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[I-:34].[Na+]>CC(C)=O>[I-:34].[C:23]([O:31][CH2:32][N+:6]1[C:7]([CH2:8][CH3:9])=[C:2]([Br:1])[C:3]([NH:10][CH2:11][CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[CH3:13])=[N:4][CH:5]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCc1ncnc(NCC(C)Oc2ccc(C)cc2C)c1Br
Reactant: O=C(OCCl)c1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCc1c(Br)c(NCC(C)Oc2ccc(C)cc2C)nc[n+]1COC(=O)c1ccccc1

Procedure:
0.3 g (8.2 mmol) of 5-bromo-6-ethyl-4-[2-(2,4-dimethylphenoxy)-propylamino]pyrimidine (according to EP-A-57 440), 0.17 g (9.8 mmol) of chloromethyl benzoate and 0.12 g (8.2 mmol) of sodium iodide in 25 ml of acetone were heated under reflux for 8 hours. After cooling, the precipitated sodium chloride was filtered off and the filtrate was concentrated. The residue was taken up in dichloromethane and washed by stirring with water. The organic phase was dried and concentrated. The residue was digested with ethyl acetate. Filtration with suction gave 0.97 g (53.3% of theory) of light-yellow crystals. mp.: 159-161° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]([F:22])([F:21])[C:14]1[N:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>>[CH:10]([C:7]1[CH:8]=[CH:9][C:2]([O:20][C:17]2[CH:18]=[N:19][C:14]([C:13]([F:22])([F:12])[F:21])=[CH:15][CH:16]=2)=[C:3]([CH:6]=1)[C:4]#[N:5])=[O:11]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1ccc(C(F)(F)F)nc1
Product: N#Cc1cc(C=O)ccc1Oc1ccc(C(F)(F)F)nc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 6-(trifluoromethyl)pyridin-3-ol
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[F:20][C:21]1[C:26](B(O)O)=[CH:25][CH:24]=[CH:23][N:22]=1>>[F:20][C:21]1[C:26]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: OB(O)c1cccnc1F
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Product: O=C(O)c1cccc(COc2ccc(-c3cccnc3F)cc2)c1

Procedure:
3-[4-(2-Fluoro-pyridin-3-yl)-phenoxymethyl]-benzoic acid was prepared using the procedure described above for the synthesis of Example 4 from 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and 2-fluoropyridine-3-boronic acid (ASDI Incorporated, Newark, Del.). Mass spectrum MH+=324.
Reaction SMILES: C(N1CCOCC1)C.C1CCC(N=C=NC2CCCCC2)CC1.[NH:24]([C:36]([O:38][CH2:39][CH:40]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[C@@H:25]([C:33]([OH:35])=O)[CH2:26][C:27]1[CH:32]=[N:31][CH:30]=[CH:29][CH:28]=1.Cl.[NH2:54][C@H:55]([C:62]([NH:64][C@H:65]([C:78]([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])=[O:79])[CH2:66][C:67]1[CH:72]=[CH:71][C:70]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[CH:69][CH:68]=1)=[O:63])[CH2:56][O:57][C:58]([CH3:61])([CH3:60])[CH3:59].C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[NH:24]([C:36]([O:38][CH2:39][CH:40]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[C@@H:25]([C:33]([NH:54][C@H:55]([C:62]([NH:64][C@H:65]([C:78]([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])=[O:79])[CH2:66][C:67]1[CH:72]=[CH:71][C:70]([O:73][C:74]([CH3:76])([CH3:75])[CH3:77])=[CH:69][CH:68]=1)=[O:63])[CH2:56][O:57][C:58]([CH3:60])([CH3:61])[CH3:59])=[O:35])[CH2:26][C:27]1[CH:32]=[N:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(N[C@H](Cc1cccnc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC[C@H](N)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC[C@H](NC(=O)[C@@H](Cc1cccnc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.3 ml of ethylmorpholine and 2.2 g of DCC are added to a stirred solution of 3.88 g of Fmoc-D-Pal-OH (10 mmol), 4.73 g of HCl.H-Ser(tBu)-Tyr(tBu)-OtBu and 1.35 g of HOBt in 40 ml of dimethylformamide at 0° C. The mixture is stirred at 0° C. for 1 hour and left to stand at room temperature overnight. The precipitate is filtered off with suction and the residue is dissolved in ethyl acetate. The solution is extracted successively with water, saturated NaHCO3 solution, KHSO4 buffer and water, dried over sodium sulfate and concentrated.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([C:6](O)=[O:7])[CH2:5][CH2:4]1>C1COCC1>[F:1][C:2]([F:10])([F:9])[C:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Solvent: C1CCOC1
Product: OCC1(C(F)(F)F)CC1
Temperature: 40 °C
Yield: 90.2 %

Procedure:
A solution of 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (3 g, 19.47 mmol) in THF (32.4 mL) was treated with borane-THF complex (1.0 M, 31.2 mL, 31.2 mmol) and heated at 40° C. overnight. The mixture was cooled in an ice bath, carefully quenched with satd. NH4Cl, filtered through diatomaceous earth and rinsed well with EtOAc. The filtrate was extracted with EtOAc (2×) and the combined organics were washed with satd. NaHCO3, then brine, dried over Na2SO4 and concentrated to afford (1-(trifluoromethyl)cyclopropyl)methanol (2.46 g, 90%). 1H NMR (400 MHz, DMSO-d6): δ 4.93 (t, J=6.0 Hz, 1H), 3.52 (d, J=6.0 Hz, 2H), 0.86-0.75 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].[OH:8][NH:9][CH2:10][CH2:11][CH2:12][P:13](=[O:16])([OH:15])[OH:14].FC(F)(F)C(OC(=O)C(F)(F)F)=O.N>C(O)C.O>[OH:8][N:9]([CH2:10][CH2:11][CH2:12][P:13](=[O:14])([OH:16])[OH:15])[C:3](=[O:4])[C:2]([F:7])([F:6])[F:1]
Reactant: O=C(O)C(F)(F)F
Reactant: O=P(O)(O)CCCNO
Agent: N
Solvent: O
Solvent: CCO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(N(O)CCCP(=O)(O)O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Trifluoroacetic acid (4 ml) was added to 3-(N-hydroxyamino)propylphosphonic acid (1.55 g). After the mixture was stirred at ambient temperature for 15 minutes, to the mixture was added trifluoroacetic anhydride (2.52 g) with stirring under ice-cooling. After the stirring was continued at the same temperature for 1.5 hours, to the mixture was further added trifluoroacetic anhydride (2.73 g). The mixture was further stirred for an hour. Then, the resultant mixture was concentrated under reduced pressure to give a residue, which was dissolved in ethanol (10 ml). The solution was adjusted to pH 6-7 with aqueous ammonia, stirred for an hour under ice-cooling and concentrated under reduced pressure to give a residue, which was subjected to a column chromatography on cellulose (100 ml). This column was washed with isopropylalcohol (200 ml) and then the object compound was eluted with a mixture of isopropyl alcohol and water (9:1 ) (200 ml). The eluate was concentrated under reduced pressure to give a residue, which was pulverized with a mixture of ethanol and water to give powdery monoammonium salt of 3-(N-hydroxy-N-trifluoroacetylamino)propylphosphonic acid (0.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:24]([C:26]2[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=2)[C:29]([O:31]C)=O)[CH3:25])[C:16]=1[CH3:36])=[O:14].OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O.C(O)C.[CH3:52][NH2:53]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:24]([C:26]2[CH:35]=[CH:34][CH:33]=[C:28]([C:29](=[O:31])[NH:53][CH3:52])[CH:27]=2)[CH3:25])[C:16]=1[CH3:36])=[O:14]
Reactant: COC(=O)c1cccc(C(C)n2c(C)c(C(=O)NCc3c(OC)cc(C)[nH]c3=O)c3cccnc32)c1
Reactant: CN
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCO
Product: CNC(=O)c1cccc(C(C)n2c(C)c(C(=O)NCc3c(OC)cc(C)[nH]c3=O)c3cccnc32)c1
Yield: 30 %

Procedure:
Methyl 3-(1-(3-(((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)ethyl)benzoate (20 mg, 0.041 mmol) was added to 30% methylamine ethanol solution (10 mL). The mixture was stirred under 50 Psi at 100° C. for 12 hours in a 100 mL of sealed tube. The solvent was evaporated and the residue was purified by preparative-HPLC (Instrument: Gilson GX281 Column: ASB C18 150*25 mm*5 um Mobile phase A: water with 0.05% ammonia solution Mobile phase B: MeCN Column temperature: 30° C. Gradient: 17-47% B 15 min) to afford the title compound (17.4 mg, yield: 30%). LRMS (M+H+) m/z: calcd 488.22. found 488.0. 1H NMR (400 MHz, chloroform-d) δ ppm 2.01 (d, J=7.28 Hz, 3 H) 2.26 (s, 3 H) 2.50 (s, 3 H) 2.96 (d, J=4.63 Hz, 3 H) 3.91 (s, 3 H) 4.64 (d, J=5.51 Hz, 2 H) 5.95 (s, 1 H) 6.14 (br. S., 1 H) 6.55 (d, J=8.16 Hz, 1 H) 7.05-7.13 (m, 1 H) 7.33 (t, J=8.05 Hz, 1 H) 7.51-7.59 (m, 1 H) 7.60-7.64 (m, 1 H) 8.24 (d, J=5.51 Hz, 2 H).