Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].Cl.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([OH:35])=[O:34]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[C:33]([OH:35])=[O:34])=[C:4]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: O=C(O)C1COCCN1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Agent: Cl
Product: COC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 44.9 %

Procedure:
Methyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (3.02 g, 6.54 mmol) (The compound was synthesized according to the procedure as described in WO2010069147A) was reacted with morpholine-3-carboxylic acid hydrochloride (1.1 g, 6.54 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (1.5 g, 45%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C([O:3][P:4]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][C:16]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][CH:20]=3)=[CH:17][C:11]=2[CH:10]=1)(=[O:8])[O:5]CC)C.Br[Si](C)(C)C.CO>ClCCl>[CH2:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:16]2[CH:15]=[CH:14][C:12]3[S:13][C:9]([P:4]([OH:5])(=[O:3])[OH:8])=[CH:10][C:11]=3[CH:17]=2)=[CH:20][CH:21]=1)[CH3:26]
Reactant: CCOP(=O)(OCC)c1cc2cc(Cc3ccc(CC)cc3)ccc2s1
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: ClCCl
Product: CCc1ccc(Cc2ccc3sc(P(=O)(O)O)cc3c2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 84.2 %

Procedure:
To a solution of [5-(4-ethylbenzyl)benzo[b]thiophen-2-phosphonic acid diethylester (1.00 g) in dichloromethane (17.0 mL) was added bromotrimethylsilane (1.7 mL) at 0° C., and the reaction mixture was stirred for 19 hr at room temperature. Methanol (4.5 mL) was added to the reaction mixture, and the mixture was stirred for 10 min at room temperature. After evaporation, the residue was crystallized from ethyl acetate-n-hexane to give the title compound (0.72 g) as a colorless crystal.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][CH:5]([CH:7]2[O:9][CH2:8]2)[CH2:4][O:3]1.[NH3:11]>>[NH2:11][CH2:8][CH:7]([CH:5]1[CH2:4][O:3][C:2]([CH3:10])([CH3:1])[O:6]1)[OH:9]
Reactant: CC1(C)OCC(C2CO2)O1
Reactant: N
Product: CC1(C)OCC(C(O)CN)O1

Procedure:
A solution of 73.4 g of 2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethylene oxide in 400 ml of 25% strength ammonia is heated in an autoclave for 4 hours to 130° C. The slightly yellowish solution is concentrated to dryness under vacuum; during this step, the residue crystallizes. 2-Amino-1-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol is re-crystallized from ethanol/ether, mp 94°-96° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1.CCOC(C)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: Nc1cccc(Br)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Fc1ccc(CNc2cccc(Br)n2)cc1
Temperature: 100 °C
Yield: 62.3 %

Procedure:
To a suspension of 6-bromopyridin-2-amine (500 mg, 2.89 mmol), sodium tert-butoxide (695 mg, 7.24 mmol) in anhydrous toluene (20 ml) was added 4-fluorobenzylchloride (415 mg, 2.90 mmol) at room temperature. The reaction mixture was heated at 100° C. overnight. EtOAc was added and the mixture was washed with brine and was concentrated. Flash chromatography (10-14% EtOAc in hexanes) gave the title compound (506 mg, 63%). 1H NMR (CDCl3) δ 4.40 (m, 2H), 4.95 (br s, 1H), 6.20 (m, 1H), 6.73 (m, 1H), 7.00 (m, 2H), 7.25 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=O)=[O:9])=[CH:4][CH:3]=1.[C:19]([CH2:21][C:22]([NH2:24])=[S:23])#[N:20]>N1CCCCC1.C(Cl)(Cl)Cl>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([OH:9])[NH:24][C:22](=[S:23])[C:21]=2[C:19]#[N:20])=[CH:13][CH:14]=1
Reactant: N#CCC(N)=S
Reactant: O=C(C(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: N#CC1=C(c2ccc(Cl)cc2)C(O)(c2ccc(Cl)cc2)NC1=S

Procedure:
A suspension of 22.3 g. 4,4'-dichlorobenzil, 6.5 g. 2-cyanothioacetamide, 20 drops of piperidine and 200 ml. chloroform is stirred for 20 hours at ambient temperature. The yellow precipitate obtained is filtered off with suction, well washed with chloroform and dried. There are obtained 22.0 g. of the desired compound in the form of yellow crystals; m.p. 213° C. (decomp.).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[C:14]([NH2:17])[NH:15][N:16]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[N:18]1([CH2:24][CH2:25][CH2:26][C:27](O)=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C([O-])=O>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH:13]=[C:14]([NH:17][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:15][N:16]=3)=[CH:10][CH:11]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)CCCN1CCCCC1
Reactant: Nc1cc(-c2ccc(OCC3CC3)cc2)n[nH]1
Agent: O=C[O-]
Product: O=C(CCCN1CCCCC1)Nc1cc(-c2ccc(OCC3CC3)cc2)n[nH]1
Yield: 26.9 %

Procedure:
The product was prepared according to the general synthetic method for the synthesis of ω-amino-alkanoic acid (1H-pyrazol-3-yl-5-aryl)-amides via the amino acid route, starting from 5-(4-cyclopropylmethoxy-phenyl)-2H-pyrazol-3-ylamine (152.9 mg, 0.7 mmol, 1.0 eq) and 4-piperidin-1-yl-butyric acid (168 mg, 1.0 mmol, 1.5 eq). The crude product was purified via preparative HPLC; 72.0 mg of the title product (28% yield) was obtained as a formate salt.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=3)[CH:17]=1)[CH2:12]2.[CH3:30][O:31][C:32]1[CH:40]=[C:39]2[C:35]([CH2:36][CH2:37][NH:38]2)=[CH:34][CH:33]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:30][O:31][C:32]1[CH:40]=[C:39]2[C:35]([CH2:36][CH2:37][N:38]2[C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:29])=[CH:34][CH:33]=1
Reactant: COc1ccc2c(c1)NCC2
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)N(C(=O)c1cc(Nc3ccc4c(c3)CC3(C4)C(=O)Nc4ncccc43)ncn1)CC2

Procedure:
83 mg (0.20 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 30 mg (0.20 mmol) 6-methoxy-2,3-dihydro-1-H-indole, 51 μL (0.36 mmol) TEA and 70 mg (0.22 mmol) TBTU in 1.5 mL DMF were stirred for 1 h at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[CH3:10][O:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14].[Cl-].[NH4+]>O1CCCC1>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[CH2:12][O:11][CH3:10])=[CH:4][CH:5]=1
Reactant: COCC(=O)c1ccccc1
Reactant: Fc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCC(O)(c1ccccc1)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
4.4 g of magnesium, 2 cm3 of 4-bromofluorobenzene and 10 cm3 of tetrahydrofuran are heated to a temperature in the region of 60° C. 18 cm3 of 4-bromofluorobenzene in solution in 50 cm3 of tetrahydrofuran are added and the mixture is heated at a temperature in the region of 60° C. for 2 hours. 8.4 cm3 of 2-methoxyacetophenone in solution in 60 cm3 of tetrahydrofuran are added to the solution prepared above, cooled to a temperature in the region of 5° C. After stirring for 24 hours at a temperature in the region of 20° C., the reaction mixture is poured into 200 cm3 of saturated aqueous ammonium chloride solution and extracted with twice 150 cm3 of ethyl ether, and the organic phases are washed with twice 150 cm3 of distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure. The residue obtained is purified by flash chromatography on silica gel (35–70 μm), eluting with a cyclohexane/ethyl acetate (95/05) mixture; 13.2 g of 1-(4-fluorophenyl)-2-methoxy-1-phenylethanol are thus obtained in the form of a white oil, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH3:8])=[CH:3][CH:4]=[O:5].[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[C:9]([O:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:6][CH2:7][CH3:8])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CCCC(C)=CC=O
Product: CCCC(C)=CCOC(C)=O
Temperature: 100 °C

Procedure:
3-methylhex-2-enal (as a 40/60 Z/E isomers mixture) (112 g, 1 mol.), acetic anhydride (107 g, 1.05 mol) and (ethylenediamine)[1,2-bis(diphenylphosphino) ethane]ruthenium(bispivalate) (76 mg, 0.1 mmol, 0.01 mol.%) were loaded altogether in a 300 ml autoclave equipped with a mechanical stirring device. Sealed autoclave was then purged to under stirring with nitrogen (3 times 5 bars) and hydrogen (3 times 5 bars) before being pressurized to 50 bars hydrogen. It was then heated to 100° C. and hydrogen pressure was maintained to 50 bars during all the reaction to afford desired product with 96% selectivity as a 40/60 WE isomers mixture. Upon reaction completion (checked by both hydrogen consumption and GC), autoclave was then cooled down to 25° C. It was then depressurized and purged with nitrogen (3 times 5 bars) and reaction mixture was then transferred to a round-bottomed flask and concentrated under vacuum. After initial flash distillation followed by further fractional distillation, pure 3-methylhex-2-en-1-yl acetate was obtained in 90% yield.
Reaction SMILES: [CH3:1][NH2:2].C1COCC1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[O:17])=[CH:11][CH:10]=1>O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:2][CH3:1])=[O:17])=[CH:11][CH:10]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)Cc1ccc(F)cc1
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of methylamine in THF (2.0 M, 5 mL, 10 mmol) was added 4-fluorophenylacetyl chloride (518 mg, 3.0 mmol) at −78° C. The reaction mixture was stirred from −78° C. to room temperature for 1 h. The solution was diluted with H2O and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. Filtration, followed by concentration, provided the title compound (490 mg, 98%). MS(ESI+) m/z 168 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:16][C:17]1([F:21])[CH2:20][NH:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:19]2[CH2:20][C:17]([F:21])([F:16])[CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: FC1(F)CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CC(F)(F)C2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 959 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 4-oxopiperidine-1-carboxylic acid tert-butyl ester (0.4 g, 0.20 mmol), 3,3-difluoroazetidine hydrochloride (0.31 g, 0.24 mmol) and 4 Å molecular sieves (2.4 g) in DCE (10 mL). The reaction mixture was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.85 g, 4.01 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo to give 4-(3,3-Difluoroazetidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester as a colourless oil (0.53 g, 96%). 1H NMR (300 MHz, CDCl3): δ 3.94-3.90 (m, 2 H), 3.57 (t, J=11.9 Hz, 4 H), 2.96-2.81 (m, 2 H), 2.34-2.23 (m, 1 H), 1.71-1.58 (m, 2 H), 1.45 (s, 9 H), 1.35-1.21 (m, 2 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1.Cl.[C:29](=[NH:34])(OCC)[CH3:30].C(N(CC)CC)C>ClCCl>[C:29]([NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1)(=[NH:34])[CH3:30]
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(C)=N)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.01 %

Procedure:
A mixture of N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide (30 mg, 81.9 μmol), ethyl acetimidate hydrochloride (12.1 mg, 98.2 μmol) and triethylamine (22.8 μL, 164 μmol) in dichloromethane was stirred at room temperature overnight. The mixture was concentrated and the crude product was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 7.01% yield. LCMS m/z (%)=408 (M+H, 100). 1H NMR (400 MHz, MeOH-d4) δ 2.2 (s, 2H) 2.7 (s, 3H) 3.0 (s, 1H) 3.6 (t, J=5.1 Hz, 2H) 3.7 (s, 3H) 3.9 (s, 3H) 4.2 (t, J=5.1 Hz, 2H) 6.3 (d, J=2.0 Hz, 1H) 7.2 (dd, J=7.3, 2.8 Hz, 1H) 7.2 (d, J=8.6 Hz, 1H) 7.4 (t, J=7.8 Hz, 1H) 7.5 (m, 2H) 7.6 (d, J=2.0 Hz, 1H) 7.7 (d, J=3.0 Hz, 1H) 7.8 (dd, J=9.1, 2.5 Hz, 1H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]([Si](C)(C)C)([F:22])[F:21].[CH:27]([C:29]1[O:30][C:31]2[C:38]([Br:39])=[CH:37][CH:36]=[CH:35][C:32]=2[C:33]=1[CH3:34])=[O:28].Cl>C1COCC1.O>[F:19][C:20]([F:22])([F:21])[CH:27]([C:29]1[O:30][C:31]2[C:38]([Br:39])=[CH:37][CH:36]=[CH:35][C:32]=2[C:33]=1[CH3:34])[OH:28]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1c(C=O)oc2c(Br)cccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(O)C(F)(F)F)oc2c(Br)cccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
14 mg of tetrabutylammonium fluoride and 1.22 ml of trifluoromethyltrimethylsilane, dropwise, are added to a solution, cooled to 0° C. with an ice bath, of 1.58 g (6.6 mmol) of 2-formyl-3-methyl-7-bromobenzofuran in 60 ml of THF. The solution is left stirring for 30 min at 0° C. and then for 1 h at room temperature and a solution of 6 ml of THF and of 3 ml of hydrochloric acid (3M) is added. Stirring is continued for 2 h at room temperature, 100 ml of water are added and extraction is carried out with ethyl acetate (3×60 ml). The organic phases are combined, dried over magnesium sulphate and concentrated. 198 g (Yield: 97%) of 2-(2,2,2-trifluoro-1-hydroxyethyl)-3-methyl-7-bromobenzofuran are obtained--M.p.: 93° C.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH2:27]1[O:38][C:37]2[CH:36]=[CH:35][C:31]([CH2:32][CH2:33][NH2:34])=[CH:30][C:29]=2[O:28]1>ClCCCl>[C:10]([O:9][C:7](=[O:8])[NH:1][C@H:2]([C:4](=[O:6])[NH:34][CH2:33][CH2:32][C:31]1[CH:35]=[CH:36][C:37]2[O:38][CH2:27][O:28][C:29]=2[CH:30]=1)[CH3:3])([CH3:13])([CH3:12])[CH3:11]
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
Boc-Ala-OH (222 mg, 1.20 mmol) was dissolved in DCE (4 mL), followed by addition of CDI (209 mg, 1.20 mmol). The mixture was stirred at room temperature for 30 min. 3,4-Methylenedioxyphenethylamine hydrochloride (240 mg, 1.20 mmol) and TEA (2.4 mmol) were added and the reaction was stirred at room temperature under Nitrogen for 16 hours. Next, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in DCM and transferred to a separatory funnel and washed with saturated NaHCO3 (aq). The organic layer was dried with Na2SO4 and concentrated down. The crude material was purified by flash chromatography (DCM to 9:1 DCM/MeOH) to yield 350 mg (88%) of (S)—[1-(2-benzo[1,3]dioxol-5-yl-ethylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester. [M+H]+ 337.05.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+]([O-])=O)[CH:6]=1.[PH2:25]([O-:27])=[O:26].[Na+]>O>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=2[Cl:1])=[CH:6][C:7]=1[PH:25](=[O:26])[OH:27])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Reactant: O=[PH2][O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[PH](=O)O

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene (1.8 g, 4.97 mmol), sodium hypophosphite (0.88 g, 9.94 mmol) and cupric sulfate (180 mg) in 20 ml of methyl nitrile/water (4:1) is heated under reflux for 24 hours. The reaction is poured into water, extracted with methylene chloride, dried and chromatographed (silica gel, eluting with 10% methanol/chloroform) to yield 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][CH2:27][CH2:28][OH:29])=[N:24][CH:25]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C=O)C>[OH:29][CH2:28][CH2:27][NH:26][C:23]1[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][CH:22]=1
Reactant: Nc1ccc(NCCO)nc1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(NCCO)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (311 mg, 1.21 mmol), 2-(5-amino-pyridin-2-ylamino)-ethanol (84 mg, 0.55 mmol), N-hydroxybenzotriazole (185 mg, 1.38 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (264 mg, 1.38 mmol) in a mixture of methylene chloride (5 mL) and DMF (1 mL) was stirred at room temperature for 5 hr. The solvents were removed, and lithium hydroxide hydrate (excess) in a mixed solvent of methanol, tetrahydrofuran, and water (3:1:1, 5 mL) was added. The reaction mixture was stirred at room temperature for overnight. Solvents were removed, and water was added. The resulted mixture was extracted twice with ethyl acetate. The organic layers were collected, and washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck silica gel 60, 230-400 mesh, 0-15% methanol in methylene chloride for 30 min), and then preparative HPLC (0-90% acetonitrile in water for 20 min), followed by lyophilization gave 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-hydroxy-ethylamino)-pyridin-3-yl]-amide as a light yellow solid. LCMS calcd for C18H15F3N4O3 (m/e) 392, obsd 393 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.O.[N:10]([C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15])=[N+:11]=[N-:12].[OH-].[Na+]>O1CCOCC1>[OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:14](=[O:15])[C:13]([N:10]=[N+:11]=[N-:12])([CH3:18])[CH3:17])[CH2:5][CH2:4]1
Reactant: OCC1CCNCC1
Reactant: CC(C)(N=[N+]=[N-])C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(N=[N+]=[N-])C(=O)N1CCC(CO)CC1

Procedure:
15 g. (0.13 mole) 4-Hydroxymethylpiperidine are dissolved in 130 ml. water and 30 ml. dioxan and 19.4 g. (0.13 mole) 2-azido-2-methylpropionic acid chloride (according to analogous literature: J.A.C.S., 77, 112/1955) added dropwise thereto. The pH of the solution is kept at 12 to 12.5 by the simultaneous dropwise addition of 2N aqueous sodium hydroxide solution. After ending of the reaction, the reaction mixture is extracted with diethyl ether. After drying with anhydrous sodium sulphate and evaporating, there are obtained 17.8 g. of crude oil, i.e. 60% of theory, which can be used in the next step without further purification.
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][C@@H:23]1[CH:24]=O)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.C([O-])(O)=O.[Na+]>[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][C@@H:23]1[CH2:24][NH:12][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CNc1ccc(Oc2ccccc2)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
To a solution of 4-phenoxy aniline (100 mg, 0.54 mmol) in dichloroethane (1.5 mL) was added a solution of N-(t-butoxycarbonyl)-D-prolinal (118 mg, 0.594 mmol) in dichloroethane (1.5 mL) at 0-5° C. Sodium triacetoxyborohydride (194 mg, 0.92 mmol) was added to the above solution. Acetic acid (32 mg, 0.54 mmol) in dichloroethane (1 mL) was added dropwise, over a period of 5 min at 0-5° C. The reaction mixture was stirred at 0-10° C. for 3 h. The mixture was diluted with saturated aq NaHCO3 and extracted with dichoromethane. Organic layer was dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (155 mg, 78%); MS; m/z 369 (M+H).
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][CH2:9][CH2:10]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][NH:19][CH:20]([NH:23][CH3:24])[CH2:21][CH3:22]>C1(C)C=CC=CC=1>[C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][CH2:9][CH2:10][C:20]([NH:23][CH3:24])([NH:19][CH3:18])[CH2:21][CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCOC(c1ccccc1)c1ccccc1
Reactant: CCC(NC)NC
Solvent: Cc1ccccc1
Product: CCC(CCOC(c1ccccc1)c1ccccc1)(NC)NC
Yield: 63 %

Procedure:
A mixture of 3 g (12.2 mmole) of 2- (diphenyl-methoxy)ethyl chloride, 5 g (49 mmole) of N,N' -dimethyl-propanediamine and 40 ml of toluene was heated under reflux overnight. At the end of this time, the toluene layer was separated and washed with water; 25 ml of a 10% w/v aqueous solution of acetic acid was then added thereto. The aqueous layer was separated, and a 10% w/v aqueous solution of sodium hydroxide was added to make it alkaline. The mixture was then extracted with diethyl ether, and the solvent was removed by distillation under reuced pressure, to obtain 2.4 g (yield 63%) of the title compound as an oil.
Reaction SMILES: S(O[CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[C:9]1[CH2:17][C:18]([O:20][CH3:21])=[O:19])(C)(=O)=O.[I-:22].[Na+]>C(#N)C>[I:22][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[C:9]1[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: [I-]
Reactant: COC(=O)Cc1c(C(=O)OC)ccn1CCOS(C)(=O)=O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)Cc1c(C(=O)OC)ccn1CCI
Yield: 97.3 %

Procedure:
A solution of 785 mg of methyl N-(2-mesyloxyethyl)-3-carbomethoxypyrrole-2-acetate and 1.83 g of sodium iodide in 10 ml of acetonitrile is refluxed for 1 hour. The cooled reaction mixture is evaporated to dryness under reduced pressure and the residue is triturated with water. The insoluble material is separated by filtration and is air dried, thus obtaining 840 mg (97%) of methyl N-(2-iodoethyl)-3-carbomethoxypyrrole-2-acetate (VI, R=H), m.p. 137°-138° C.