Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(S(N[C@H](C(OC(C)(C)C)=O)CC(O)=O)(=O)=O)CCCCC[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[CH:15]([C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:8]=[CH2:7])=[CH2:16].[CH2:16]=[CH:15][C:14]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)N[C@@H](CC(=O)O)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C=Cc1ccccc1
Product: C=Cc1ccccc1C=C
Temperature: 25 °C
Reaction time: 1 h
Yield: 10803.5 %

Procedure:
N-Hexadecylsulfonyl-(O-t-butyl)-L-aspartic acid (189 mg, 0.395 mmole), 1-hydroxybenzotriazole (55.1 mg, 0.395 mmole) and dicyclohexylcarbodiimide (82.5 mg, 0.395 mmole) in 0.50 mL DMF was stirred at room temperature for 45 minutes. A 0.050 mL aliquot of this solution was added to the tetrabutylammonium salt of 6 (25 mg) in 0.20 mL of DMF and stirred at room temperature for 60 minutes. The reaction mixture was quenched by dilution with 8 mL of 25% acetonitrile (AcN) 0.12 M in ammonium phosphate (pH 7.2), aged at room temperature, then filtered through a membrane (Whatman GD/X). The product was isolated from the filtrate by low resolution reverse phase chromatography on a 5 g styrene-divinylbenzene resin cartridge (25×45 mm, Supelco EnviChrom-P). The sample-loaded cartridge was eluted with stepwise increasing concentrations of AcN in sodium phosphate (aqueous pH 6.9); product was eluted with 57% AcN 0.010 M in pH 6.9 buffer. Product-containing fractions were pooled, diluted with an equal volume of distilled water and then desalted on the same 5g resin cartridge which had been rinsed with 75% and 25% AcN. The diluted fraction pool was applied to the cartridge, which was rinsed with 16 mL 25% AcN 0.125 M in ammonium phosphate (pH 7.2), then 24 mL salt-free 25% AcN. The product was stripped from the cartridge with 48 mL 67% AcN. AcN was removed under vacuum from the strip fraction and the aqueous solution was freeze dried to give the desired product. Yield: 4.7 mg of a white solid, 69% by HPLC (215 nm area %); C62H104N12O20S; FABMS m/z 1392 (M+Na)+. (calc. for C62H104N12O20S+Na, 1391.7).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:18][CH3:19])[CH:12]=3)=[CH:9][N:8]([CH:20]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:27](Cl)(=[O:36])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1.ClCCl>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:27](=[O:36])[CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:13]([O:18][CH3:19])[CH:12]=3)=[CH:9][N:8]([CH:20]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COc1cc(-c2cn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2cn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1NC(=O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a solution of 4-[4-amino-5-(4-amino-3-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-cyclohexanone (0.8 g, 2.3 mmol) in pyridine (13 mL) and dichloromethane (32 mL) at 0° C. was added hydrocinnamoylchloride (0.57 g, 3.4 mmol) in dichloromethane (5 mL) under nitrogen. The solution was stirred at 0° C. for 2 hr, warmed to room temperature and quenched by addition of saturated aqueous citric acid solution (50 mL). The organic layer was washed with saturated aqueous citric acid solution (2×50 mL), dried (sodium sulphate), filtered and evaporated to leave N1-{4-[4-amino-7-(4-oxocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-3-phenylpropanamide (1.0 g, 92% crude) as a brown foam. 1H NMR (d6 DMSO, 400 MHz):9.17(1H, s), 8.18(1H, s), 8.06(1H, d), 7.51(1H, s), 7.18-7.29(6H, m), 7.09(1H, m), 6.99(1H, d), 6.21(2H, bs), 5.18 (1H, m), 3.88(3H, s), 1.99-2.93(12H, m). HPLC: (5 to 95% CH3CN in 0.1 N aqueous ammonium acetate over 20 min.) tr=14.48 min, 92.2%.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[NH:16]C2C=CC=CC=2)[N:3]=1.NCCCN1CC[O:30]CC1>CC(O)C.CO>[NH2:16][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2](=[O:30])[NH:3]2
Reactant: NCCCN1CCOCC1
Reactant: Clc1nc2nccc(Nc3ccccc3)c2c2ccccc12
Solvent: CC(C)O
Solvent: CO
Product: Nc1ccnc2[nH]c(=O)c3ccccc3c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
(6-Chloro-benzo[c][1,8]naphthyridin-1-yl)-phenyl-amine (25 mg, 0.08 mmol) and N-(3-aminopropyl)morpholine (18 mg, 0.12 mmol) were dissolved in iPrOH (2 mL), and stirred overnight at 100° C. The reaction mixture was diluted with MeOH, filtered through a membrane, and purified via prep-LC-MS. The purified product was converted to the HCl salt via dissolving in methanolic HCl, and concentration on the Genevac to provide 141 (5 mg, 12% yield) as a dark solid. LC-MS (M+H=414, obsd.=414). 1H NMR (400 MHz, d6-DMSO): δ 10.32 (s, 1H), 9.31 (t, 1H), 8.87 (d, 1H), 8.58 (d, 1H), 8.09 (t, 1H), 7.89 (t, 1H), 7.80 (t, 1H), 7.49 (m, 2H), 7.40 (d, 2H), 7.32 (t, 1H), 6.90 (d, 1H), 3.95 (d, 2H), 3.86 (d, 2H), 3.75 (m, 2H), 3.46 (m, 2H), 3.28 (m, 2H), 3.08 (m, 2H), 2.22 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](=[O:11])[CH:9]=[C:8]([CH3:12])O[C:6]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[O:4].C(O)(=O)C.[CH2:24]([NH2:27])[CH:25]=[CH2:26].Cl>O.CO>[CH2:24]([N:27]1[C:8]([CH3:12])=[CH:9][C:10](=[O:11])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:6]1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:25]=[CH2:26]
Reactant: COC(=O)c1c(-c2ccc(Cl)cc2)oc(C)cc1=O
Reactant: C=CCN
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: C=CCn1c(C)cc(=O)c(C(=O)OC)c1-c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 87.7 %

Procedure:
10 gms of 3-methoxycarbonyl-6-methyl-2-(4'-chlorophenyl)-4-pyrone, 1.65 gms glacial acetic acid and 100 mls of methanol are mixed in 500 ml flask fitted with a magnetic stirring bar and sidearm additionl funnel. 6.15 gms of allylamine are slowly added (one hour addition time). Three hours later 20 mls of water and 8 mls of concentrate HCl are added. This reaction mixture is allowed to stand at room temperature for one hour, then is poured into 400 mls of water and extracted with methylene chloride (2×100 mls). Removal of the solvent yields 10 gms of crude methyl 1-allyl-6-methyl-2-(4'-chlorophenyl)-4-oxonicotinate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:6]=[CH:7][C:8]1[C:14]2[CH:15]=[C:16]3[O:21][CH2:20][O:19][C:17]3=[CH:18][C:13]=2[CH2:12][C:11]([CH3:22])=[N:10][N:9]=1.ClCCl.[B-][N+](C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:6]=[CH:7][C:8]1[C:14]2[CH:15]=[C:16]3[O:21][CH2:20][O:19][C:17]3=[CH:18][C:13]=2[CH2:12][CH:11]([CH3:22])[NH:10][N:9]=1
Reactant: COc1ccc(C=CC2=NN=C(C)Cc3cc4c(cc32)OCO4)cc1OC
Agent: O=C([O-])[O-]
Agent: [B-][N+](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C=CC2=NNC(C)Cc3cc4c(cc32)OCO4)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To a solution of 2.04 g (5.6 mmoles) 1-(3,4-dimethoxystyryl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 40 ml of anhydrous dichloromethane 1.0 ml (8.4 mmoles) of borotrifluoride etherate is added under cooling with tap water, and 0.45 g (6.16 mmoles) of borane trimethylamine complex is added to it. The reaction mixture is stirred at 25° C. for 0.5 hour, and then 30 ml of 10% aqueous sodium carbonate solution are dropped to it under cooling with tap water, and the mixture is stirred further for 1 hour. The organic phase is separated, washed four times with 30 ml each of distilled water, dried and evaporated. The crystalline residue is suspended in 10 ml of ethanol, filtered, washed three times with 1 ml each of ethanol and dried at a temperature between 80° C. and 100° C. Thus 1.76 g of the desired product is obtained. M.p.: 166-168° C.
Reaction SMILES: [C:1](O)(=O)[CH3:2].[CH:5](=O)[CH3:6].Cl.[CH2:9]([O:11][C:12](=[O:23])[CH:13]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[NH2:14])[CH3:10].C([BH3-])#N.[Na+]>CO>[CH2:5]([N:14]([CH:13]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)[C:12]([O:11][CH2:9][CH3:10])=[O:23])[CH2:1][CH3:2])[CH3:6]
Reactant: CCOC(=O)C(N)Cc1ccc(O)cc1
Reactant: CC(=O)O
Reactant: CC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C(Cc1ccc(O)cc1)N(CC)CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.3 ml of acetic acid and 0.5 ml of acetaldehyde were added to a solution of 491 mg of DL-tyrosine ethyl ester hydrochloride in 5 ml of methanol. Sodium cyanoborohydride (126 mg) was added thereto under ice-cooling, followed by stirring of the mixture at room temperature for 2 hours. After the reaction, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate and water, and then the ethyl acetate layer was separated. The extract was washed with an aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane=1:20) to obtain 420 mg of the desired compound as a syrup.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C(OC(=O)C1C=C[C:19]([F:22])=[CH:18][CH:17]=1)C.Cl.[CH2:25]1[CH2:29][O:28][CH2:27][CH2:26]1>C(OCC)(=O)C.O>[F:22][C:19]1[CH:18]=[CH:17][CH:29]=[CH:25][C:26]=1[C:27]([CH:7]1[CH2:8][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]1=[O:9])=[O:28]
Reactant: O=C1CCc2sccc21
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1F)C1Cc2sccc2C1=O
Temperature: 100 °C
Yield: 15 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one (2.1 g, 15.0 mmol) in 15 mL of THF was treated with NaH (60 percent, 1.5 g, 36 mmol). After the addition of 4-Fluoro-benzoic acid ethyl ester, the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (80 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(2-Fluoro-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (0.56 g, 2.15 mmol) as brown solid in 15% yield.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:32][C:33]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([C:45]([OH:47])=O)[CH2:41][CH2:40]1)=[O:38])([CH3:35])[CH3:34].[Br:48][C:49]1[N:54]=[CH:53][C:52]([NH2:55])=[CH:51][CH:50]=1>CN(C=O)C.O>[Br:48][C:49]1[N:54]=[CH:53][C:52]([NH:55][C:45]([CH:42]2[CH2:41][CH2:40][N:39]([C:37]([O:36][C:33]([CH3:32])([CH3:34])[CH3:35])=[O:38])[CH2:44][CH2:43]2)=[O:47])=[CH:51][CH:50]=1
Reactant: Nc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(Br)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
TBTU (2.86 g, 8.9 mmol) and diisopropylethylamine (1.55 mL, 8.9 mmol) were added to a mixture of 1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinecarboxylic acid (1.35 g, 5.9 mmol) in DMF (20 mL) at ambient temperature. The mixture was stirred at ambient temperature for 1 h, charged with 6-bromo-3-pyridinamine (1.13 g, 6.5 mmol), then stirred at 50° C. overnight. The mixture was cooled to ambient temperature, charged with water (200 mL), and extracted with EtOAc. The organics were dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 50% EtOAc/hexanes to give 1.75 g (77%) of 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)amino]carbonyl}-1-piperidinecarboxylate as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.32 (d, 1H, J=2.7 Hz), 8.07 (dd, 1H, Ja=8.6 Hz, Jb=2.8 Hz), 7.44-7.39 (m, 2H), 4.16 (bs, 2H), 2.90-2.65 (m, 2H), 2.45-2.35 (m, 1H), 1.95-1.80 (m, 2H), 1.79-1.65 (m, 2H), 1.44 (s, 9H); LRMS (ESI), m/z 384 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[O:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:18](=[O:19])[N:17]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[O:14][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCl
Reactant: O=C(N[C@H]1COc2ccccc2NC1=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)OCc2ccccc2)COc2ccccc21
Yield: 96.4 %

Procedure:
3(S)-Benzyloxycarbonylamino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one (1.9 g) obtained in Example 14 is reacted with 1.1 g of tert-butyl chloroacetate in a manner similar to that of Example 4 to give 2.5 g of tert-butyl 3(S)-benzyloxycarbonylamino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate as a pale yellow oil.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][NH:5][CH2:6][C:7]1[N:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[S:10][CH:11]=1.[O:15]([C:22]([NH:24][C@H:25]([C:29]([OH:31])=[O:30])[CH:26]([CH3:28])[CH3:27])=O)C1C=CC=CC=1>C1COCC1.C1(C)C=CC=CC=1>[CH3:4][N:5]([C:22]([NH:24][C@H:25]([C:29]([OH:31])=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:15])[CH2:6][C:7]1[N:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[S:10][CH:11]=1
Reactant: CNCc1csc(C(C)C)n1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To lithium hydroxide monohydrate (1.06 g, 25.2 mmol) slurried in 20 mL of THF and cooled to less than 5° C. in an ice bath was added N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amine (3.78 g, 22.2 mmol) followed by a 5 mL THF rinse. A solution of N-phenoxycarbonyl-L-Valine (5.0 g, 21.1 mmol) in 20 mL of THF was added followed by a 5 mL THF rinse. Water (1.04 mL) was added, the cooling bath was removed, and the reaction was stirred at ambient temperature for 4.5 hours. Water (55 mL) was added, and the THF was removed under reduced pressure. Methyl tert-butyl ether (50 mL) was added, and as the solution stirred, the pH was adjusted to 9 with 4 N HCl. The aqueous phase was separated and washed with another 50 mL portion of MTBE. The aqueous product layer was stirred with 50 mL of toluene and adjusted to pH 3 with 4 N HCl. The aqueous layer was separated and extracted once more with toluene (50 mL). The combined toluene extracts were concentrated under reduced pressure. The residue obtained was redissolved in toluene, filtered, and rinsed with toluene. The combined filtrates were concentrated under reduced pressure. The product was crystallized from toluene-heptane (50 mLs of a 1:1 v/v solution), washed with heptane, and dried under vacuum to afford the title compound as a white powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[C:15]1([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+].O>C(O)C>[C:15]1([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][NH:14][CH2:13][CH2:12][CH2:11][N:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:25][C:24]4[CH:27]=[CH:28][C:21]([C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:22][CH:23]=4)[CH2:10][CH2:9]3)=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: NCCCN1CCN(CCCN)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc(-c2ccc(CNCCCN3CCN(CCCNCc4ccc(-c5ccccc5)cc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.513 mL, 2.49 mmol) and 4-phenylbenzaldehyde (955 mg, 5.24 mmol) in absolute ethanol (20 mL) was added 3 Å molecular sieves (5 g). After stirring the mixture for 12 h at room temperature, sodium borohydride (1.9 g, 49.9 mmol) was added and the mixture was stirred for 12 h at room temperature. Then the reaction mixture was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were extracted with HCl 1N (2×50 mL). The combined aqueous layers were neutralized with NaOH 1N (50 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over MgSO4, evaporated to dryness and the oily residue purified by flash chromatography (neutral aluminium oxide, CH2Cl2/MeOH: 90/10).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([OH:7])=O.[O:12]([CH2:19][C:20]1[O:21][C:22]2[CH2:23][NH:24][CH2:25][CH2:26][C:27]=2[N:28]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[F:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([F:1])[CH:10]=1)[C:5]([N:24]1[CH2:25][CH2:26][C:27]2[N:28]=[C:20]([CH2:19][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:21][C:22]=2[CH2:23]1)=[O:7]
Reactant: O=C(O)c1cc(F)cc(F)c1
Reactant: c1ccc(OCc2nc3c(o2)CNCC3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cc(F)cc(F)c1)N1CCc2nc(COc3ccccc3)oc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
3,5-Difluorobenzoic acid (0.082 g, 0.52 mmol) was added to a stirred solution of 4,5,6,7-tetrahydro-2-(phenoxymethyl)-oxazolo[5,4-c]pyridine (0.10 g, 0.43 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.10 g, 0.52 mmol), 1-hydroxybenzotriazole (0.070 g, 0.52 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.87 mmol) in anhydrous DMF (2.2 mL) under N2. The reaction mixture was stirred at room temperature for 16 hours, diluted with H2O and extracted with AcOEt. The organic layer was separated, extracted with brine, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7 N solution of ammonia in MeOH in DCM 0/100 to 5/95). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-(3,5-difluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-oxazolo[5,4-c]pyridine (0.086 g, 53% yield) as a colorless oil. C20H16F2N2O3. (mixture of rotamers 65:35) 1H NMR (500 MHz, CDCl3) δ ppm 2.71 (br. s., 1.3 H), 2.79 (br. s., 0.7 H), 3.66 (br. s., 1.3 H), 4.02 (br. s., 0.7 H), 4.50 (br. s., 0.7 H), 4.80 (br. s., 1.3 H), 5.13 (br. s., 2 H), 6.82-6.95 (m, 1 H), 6.95-7.09 (m, 5 H), 7.31 (t, J=7.8 Hz, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[F:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C=O.CN1CCCC1=O>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([F:46])=[C:24]([NH:23][C:8]([C:6]5[N:5]([CH3:11])[N:4]=[C:3]([O:2][CH3:1])[CH:7]=5)=[O:10])[CH:25]=4)=[N:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: COc1cc(C(=O)O)n(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)n(C)n1
Yield: 36.5 %

Procedure:
Using 3-methoxy-1-methyl-1H-pyrazole-5-carboxylic acid (156 mg, 1.0 mmol), N,N-dimethylformamide (2 drops), tetrahydrofuran (15 mL), oxalyl chloride (0.172 mL, 2.0 mmol), N-methylpyrrolidone (5 mL) and N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (164 mg, 0.50 mmol), and in the same manner as in Example 173, the title compound (85 mg, yield 36%) was obtained.
Reaction SMILES: C(O)=O.CCN(CC)CC.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([C:25](=[O:29])[CH2:26][C:27]#[N:28])[CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([C@H:25]([OH:29])[CH2:26][C:27]#[N:28])[CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CCC(=O)c1cccc(OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: CCOC(C)=O
Product: N#CC[C@@H](O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
HCOOH (30.75 mL, 795 mmol) was added dropwise to a cooled (0° C.) solution of Et3N (41.0 mL, 318 mmol) in EtOAc (400 mL) while maintaining the temperature at 0° C. (R,R)—RuCl-TsDPEN (p-cymene) (100 mg, 0.2 mol %) was added to the reaction mixture followed by the addition of oxonitrile (3) (40.0 g, 159 mmol) and the reaction mixture was stirred at room temperature for 24 h. NaHCO3 (10%, 500 mL) was added and the mixture was extracted with EtOAc (500 mL). Organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give (R)-3-(3-(benzyloxy)phenyl)-3-hydroxypropanenitrile (4) as a pale yellow solid. Yield (38.0 g, 95%); 1H NMR (400 MHz, DMSO-d6) δ 7.46-7.44 (m, 2H), 7.41-7.37 (m, 2H), 7.33 (t, J=7.2 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.07 (s, 1H), 6.99 (d, J=7.6 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 5.95 (d, J=4.4 Hz, 1H), 5.09 (s, 2H), 4.86 (d, J=5.2 Hz, 1H), 2.90 (dd, J=16.8, 4.8 Hz, 1H), 2.80 (dd, J=16.8, 6.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH:12][C:13]([C:15]2[CH:16]=[C:17]([C:24](O)=[O:25])[N:18]3[CH2:23][CH2:22][O:21][CH2:20][C:19]=23)=[O:14])[CH2:10][CH3:11])=[CH:5][CH:4]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[F:51][C:52]([F:59])([F:58])[C@H:53]1[CH2:57][CH2:56][CH2:55][NH:54]1.C(N(CC)CC)C>CN(C)C=O.O>[F:28][C:2]([F:27])([F:1])[C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH:12][C:13]([C:15]2[CH:16]=[C:17]([C:24]([N:54]3[CH2:55][CH2:56][CH2:57][C@@H:53]3[C:52]([F:59])([F:58])[F:51])=[O:25])[N:18]3[CH2:23][CH2:22][O:21][CH2:20][C:19]=23)=[O:14])[CH2:10][CH3:11])=[CH:5][CH:4]=1
Reactant: CC[C@@H](NC(=O)c1cc(C(=O)O)n2c1COCC2)c1ccc(C(F)(F)F)nc1
Reactant: FC(F)(F)[C@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C(F)(F)F)n2c1COCC2)c1ccc(C(F)(F)F)nc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To a solution of 8-[(R)-1-(6-trifluoromethyl-pyridin-3-yl)-propylcarbamoyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylic acid (Comp. No. 11h) (62 mg, 0.187 mmol) in dimethylformamide (0.6 ml) was added 1-hydroxybenzotriazole (28 mg, 0.206 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (40 mg, 0.206 mmol). The mixture was stirred for 3 h at 50° C., then (R)-2-trifluoromethyl-pyrrolidine (42 mg, 0.206 mmol) and triethylamine (38 mg, 0.37 mmol) were added and the mixture was stirred at 25° C. for 24 h. An excess of water was added, the solid which precipitated was filtered off, washed with a small amount of water and dried in vacuo to give 66 mg (68%) of 6-((R)-2-trifluoromethyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(6-trifluoromethyl-pyridin-3-yl)-propyl]-amide. LC/MS (method 5): Rt=4.55 min; m/z=519.13 (M+H+).