Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)=[N+:2]=[N-:3].C([O-])([O-])=[O:15].[K+].[K+].OO>CO.O>[N:1]([CH2:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([NH2:11])=[O:15])=[CH:8][CH:7]=1)=[N+:2]=[N-:3]
Reactant: N#Cc1ccc(CCN=[N+]=[N-])cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=NCCc1ccc(C(N)=O)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To a solution of 4-(2-azidoethyl)benzonitrile (1.0 g, 5.81 mmol) in a 5:1 mixture of MeOH/H2O (100 mL), K2CO3 (4.41 g. 31.94 mmol) was added and the resulting solution cooled to 0° C. Then 15.4 mL of a 30% H2O2 solution was added and the reaction was allowed to warm to room temperature. After stirring at room temperature for approximately three hours, the crude reaction mixture was concentrated under reduced pressure to remove MeOH and then extracted with EtOAc (3×100 mL). Combined organics were dried over sodium sulfate, filtered, and concentrated in vacua. Crude product was subjected to silica gel purification eluting with 1% MeOH in CH2Cl2 to give 1.06 g (96%) of 4-(2-azidoethyl)benzamide.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][CH:9]=[N:8][CH:7]=1.C(B(CC)CC)C.C([Li])CCC.[C:23]([O:27][C:28](=[O:35])[NH:29][CH:30]([CH:33]=[O:34])[CH2:31][CH3:32])([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[C:23]([O:27][C:28](=[O:35])[NH:29][C@H:30]([CH:33]([OH:34])[C:9]1[O:10][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][N:8]=1)[CH2:31][CH3:32])([CH3:24])([CH3:25])[CH3:26]
Reactant: c1csc(-c2cnco2)c1
Reactant: CCC(C=O)NC(=O)OC(C)(C)C
Agent: CCB(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1ncc(-c2cccs2)o1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 38.2 %

Procedure:
To a solution of 5-thiophen-2-yl-oxazole (0.85 g, 5.62 mmol) in dry THF (4 mL) is added triethylborane (1.0 M in THF, 5.62 mmol, 5.62 mL). The mixture is stirred at room temperature for 45 min, then cooled to −78° C. and n-butyl lithium (1.6 M in hexane, 5.62 mmol, 3.51 mL) is added drop wise. The mixture is stirred at −78° C. for 45 min then a solution of (1-Formyl-propyl)-carbamic acid tert-butyl ester (2.81 mmol, 0.526 g) in dry THF (3 mL) is added slowly. The mixture is stirred at −78° C. for 4 h, then warmed to 0° C. and quenched by adding 30 mL of 10% (vol) HOAc in ethanol. The mixture is stirred at room temperature for 18 hr and then concentrated in vacuum. The residue is purified over 90 g of silica gel, eluted with ethyl acetate: heptane (1:2 then 1:1) to afford {(S)-1-[hydroxy-(5-thiophen-2-yl-oxazol-2-yl)-methyl]-propyl}-carbamic acid tert-butyl ester (363 mg, 38%) as an oil.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17].O>C(#N)C>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: CC(C)C(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Solvent: O
Product: CC(C)C(=O)Nc1ccc(I)cc1
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a dispersion of p-iodoaniline (219.0 g, 1 mol) in acetonitrile(1000 ml) was added pyridine (81.0 ml, 1 mol). Isobutyryl chloride (100.5 ml, 1 mol) was added dropwise to the mixture over 1 hour in an ice bath. The mixture was further stirred for one hour following the addition of isobutyryl chloride and to the mixture was added water (3000 ml). Precipitated crystalline solids were collected by filtration to give N-(4-iodophenyl)isobutyramide (281.7 g, Yield: 97%).
Reaction SMILES: C(OCC(C[O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)CCOC(=O)C)(=O)C.O>C(O)(=O)C>[C:15]([OH:14])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)OCCC(COC(C)=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.7 %

Procedure:
2-Trityloxymethyl-1,4-butanediol diacetate (60.90 g, 0.136 mol) was dissolved in acetic acid (320 ml) at 100° C. and water, (80 ml) was added. The solution was kept at 100° C. for 15 min, evaporated in vacuum to small volume and cooled to 0° C. The precipitate was filtered off and washed with cold ethyl acetate to give 26.44 g (theory 35.51 g) of tritylalcohol. The combined filtrate was evaporated to small volume. The compound was purified on a silica gel column (500 g SiO2); eluent 0-2700 ml ethyl acetate+n-hexane (1+1), 2700-3740 ml ethyl acetate+n-hexane (2+1), then neat ethyl acetate. The fractions 2540-4800 ml were evaporated to give 14.20 g (51%) of pure 4-acetoxy-2-hydroxy-methylbutyl acetate. TLC on silica (ethyl acetate+n-hexane 1+1): Rf 0.30.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][CH:6]=[C:7]=[CH:8][CH2:9][S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O.[OH-].[Li+].Cl>C(O)C>[C:3]([OH:22])(=[O:2])[CH2:4][CH2:5][CH:6]=[C:7]=[CH:8][CH2:9][S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCSCC=C=CCCC(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCSCC=C=CCCC(=O)O
Yield: 59.7 %

Procedure:
Methyl-8-thianonadeca-4,5-dienoate (210 mg) was treated in 10 ml of ethanol and 1 ml of water with 160 mg of lithium hydroxide at room temperature for 18 hours. The solution was acidified to pH 4 with dilute HCl and extracted with diethyl ether twice. The ethereal extracts were washed with brine and dried over potassium carbonate to give 120 mg of 8-thianonadeca-4,5-dienoic acid. This procedure can be used to convert the compounds of Example VI to their corresponding acid.
Reaction SMILES: [F:1][C:2]([F:55])([F:54])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4[C:32]4[CH:33]=[C:34]([C:40]5[CH:52]=[CH:51][C:43]([C:44]([O:46]C(C)(C)C)=[O:45])=[CH:42][C:41]=5[CH3:53])[CH:35]=[N:36][C:37]=4[O:38][CH3:39])[CH2:20][CH2:21][C@@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>ClCCl.C(O)(C(F)(F)F)=O>[F:55][C:2]([F:1])([F:54])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][C:23]=4[C:32]4[CH:33]=[C:34]([C:40]5[CH:52]=[CH:51][C:43]([C:44]([OH:46])=[O:45])=[CH:42][C:41]=5[CH3:53])[CH:35]=[N:36][C:37]=4[O:38][CH3:39])[CH2:20][CH2:21][C@@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1-c1ccc(C(F)(F)F)cc1[C@@H]1CC[C@H]2[C@@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)OC(=O)N12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ncc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(F)(F)F)cc1[C@@H]1CC[C@H]2[C@@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)OC(=O)N12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To tert-butyl 4-{5-[2-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-4-(trifluoromethyl)phenyl]-6-methoxypyridin-3-yl}-3-methylbenzoate (1 g, 1.28 mmol) was added dichloromethane:TFA (9:1, 10 mL). The reaction was stirred overnight at room temperature. Upon completion the solvent was removed under reduced pressure and the resultant residue was redissolved in acetonitrile for direct purification by reverse phase HPLC to yield 4-{5-[2-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-4-(trifluoromethyl)phenyl]-6-methoxypyridin-3-yl}-3-methylbenzoic acid (0.674 g, 0.931 mmol). 1H NMR indicated that this compound exists as a pair of rotamers at 1.2:1 ratio. 1H NMR (500 MHz, CDCl3) δ8.27 (s, 1H), 8.04 (m, 4H, peaks overlap for the two rotamers), 7.90 (s, 1H), 7.84 (s, 2H, minor rotamer), 7.83 (s, 2H, major rotamer), 7.75 (s, 1H, major rotamer), 7.67 (s, 1H, minor rotamer), 7.63 (d, J=8 Hz, 1H, major rotamer), 7.42 (m, 2H), 7.38 (d, J=7.9 Hz, 1H, major rotamer), 7.36 (d, J=7.9 Hz, 1H, minor rotamer), 6.11 (d, J=7.9 Hz, 1H, minor rotamer), 6.09 (d, J=7.9 Hz, 1H, major rotamer), 5.27 (t, J=7.9 Hz, 1H, major rotamer), 4.95 (t, J=7.9 Hz, 1H, minor rotamer), 4.62 (m, 1H, minor rotamer), 4.51 (m, 1H, major rotamer), 4.12 (s, 3H, minor rotamer), 3.94 (s, 3H, minor rotamer), 2.45 (s, 3H, minor rotamer), 2.45 (s, 3H, major rotamer), 2.37 (m, 1H), 2.2 (m, 1H), 2.05 (m, 1H), 1.85 (m, 1H), 1.55 (m, 1H), 1.4 (m, 1H), 1.1 (m, 2H). MS ESI calc'd. for C35H26F9N2O5 [M+H]+ 725.2, found 725.0. RTA (95% HS): 53.18 nM
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].[Br:11][C:12]1[CH:13]=[C:14]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=O)[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][Br:21]>>[Br:11][C:12]1[CH:13]=[C:14]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[C:1]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2][CH3:3])[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][Br:21]
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCBr)c(Br)c1
Reactant: CCC(=O)c1ccccc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCBr)c(Br)c1)c1ccccc1
Yield: 35.8 %

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, propiophenone (0.2 g, 3.0 eq) was reacted with (3-bromo-4-(2-bromoethoxy) phenyl)(4-hydroxyphenyl)methanone (0.2 g, 1.0 eq) to give 0.09 g desired product (36% yield, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 7.01-7.0 (m, 7H), 6.87 (d, J=8.4 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 6.48 (d, J=8.4 Hz, 1H), 4.36 (t, J=6.8 Hz, 1H), 4.19 (t, J=6.4 Hz, 1H), 3.70 (t, J=6.4 Hz, 1H), 3.59 (t, J=6.8 Hz, 1H), 2.46 (q, J=6.4 Hz, 2H), 0.92 (t, J=6.0 Hz, 3H)
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[NH:20][C:19]3=[O:29])=[CH:35][CH:34]=1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc3nc(-n4cc(C(=O)O)cn4)[nH]c(=O)c3c2)cc1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 4-methoxyphenylboronic acid in step C. MS (ESI): mass calcd. for C19H14N4O4, 362.1; m/z found, 363.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 12.99 (br s, 1H), 12.88 (br s, 1H), 8.97 (s, 1H), 8.28 (d, J=13.9 Hz, 2H), 8.13 (d, J=8.4 Hz, 1H), 7.78-7.72 (m, 3H), 7.09-7.06 (m, 2H), 3.82 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][N:3]=1.[Br:10]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][Br:10])[CH:5]=[CH:4][N:3]=1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1ccnc(Cl)c1
Solvent: ClCCl
Product: Clc1cc(CBr)ccn1
Reaction time: 1 h
Yield: 34.8 %

Procedure:
A solution of 0.2 g of 2-chloro-4-(hydroxymethyl)pyridine in 2.5 ml of dichloromethane is added dropwise to a solution of 0.706 g of dibromotriphenylphosphorane in 9.5 ml of dichloromethane, under an inert atmosphere of argon at a temperature in the region of 20° C. Stirring is continued at this temperature for about 1 hour. The reaction medium is taken up in 50 ml of dichloromethane and then washed with 3×50 ml of water. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The residue thus obtained is purified by flash chromatography using a cartridge 20 mm in diameter packed with 10 g of 20-40 μm conditioned silica, and then eluted with a mixture (cyclohexane/ethyl acetate) (8/2) (v/v) at a flow rate of 8 ml/minute. The fractions between 8 and 24 ml are concentrated under reduced pressure. 0.1 g of 2-chloro-4-(bromomethyl)-pyridine is thus obtained.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C:2]1[NH:9][C:7](=[O:8])[NH:6][C:4](=[O:5])[CH:3]=1.II.[I:15](O)(=O)(=O)=O>CO>[CH3:12][O:11][C:1]([C:2]1[NH:9][C:7](=[O:8])[NH:6][C:4](=[O:5])[C:3]=1[I:15])=[O:10]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: COC(=O)c1cc(=O)[nH]c(=O)[nH]1
Agent: II
Solvent: CO
Product: COC(=O)c1[nH]c(=O)[nH]c(=O)c1I
Temperature: 25 °C
Yield: 546.9 %

Procedure:
Methyl orotate (20.0 g, 118 mmol) was combined with iodine (12.8 g, 50 mmol) and periodic acid (4.8 g, 21 mmol) in methanol (250 mL) and heated at reflux for 20 h. After cooling to ambient temperature, the volatiles were removed by rotary evaporation. The solid residue was slurried in water, collected by filtration, washed well with water and dried under vacuum at 70° C. to provide the title compound (34 g, 97% yield) as a solid. It was used without further purification. MS: m/z=296.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH2:11]([C:13]([CH2:18][OH:19])([CH2:16][OH:17])[CH2:14][CH3:15])[OH:12]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[C:2]([C:15]([C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[O:4])([C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[O:4])[CH2:14][C:13]([CH2:18][OH:19])([CH2:16][OH:17])[CH2:11][OH:12])([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[O:4]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC(CO)(CO)CO
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Product: CCOC(=O)C(=O)C(CC(CO)(CO)CO)(C(=O)C(=O)OCC)C(=O)C(=O)OCC
Yield: 87 %

Procedure:
A reaction vessel equipped with a stirrer, a condenser and a decanter was charged with 743.1 g (5 mol) of diethyl oxalate, 56.9 g (0.42 mol) of trimethylolpropane and 0.55 g (0.8 mmol) of dibutyltin dilaurate, and mixed at 130° C. for 5 hours. After removing 58.6 g of ethanol, it was then cooled and excess amount of diethyl oxalate was evaporated to obtain 158.7 g of crude triethoxalyltrimethylolpropane (yield 87%). 1
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]4[CH2:20][CH2:19]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:21]=1.[CH3:23][C:24]([OH:29])([C:27]#[CH:28])[CH2:25][OH:26]>>[CH:18]1([C:12]2[N:8]3[CH2:9][CH2:10][O:11][C:5]4[CH:4]=[C:3]([F:22])[C:2]([C:28]#[C:27][C:24]([OH:29])([CH3:23])[CH2:25][OH:26])=[CH:21][C:6]=4[C:7]3=[N:14][C:13]=2[C:15]([NH2:17])=[O:16])[CH2:20][CH2:19]1
Reactant: C#CC(C)(O)CO
Reactant: NC(=O)c1nc2n(c1C1CC1)CCOc1cc(F)c(Br)cc1-2
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C1CC1)CO
Yield: 50 %

Procedure:
10-bromo-3-cyclopropyl-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-methylbut-3-yne-1,2-diol via General Procedure E to yield 21 mg (50%) of (±)-3-cyclopropyl-10-(3,4-dihydroxy-3-methyl-but-1-ynyl)-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:14][C:15]=1[CH2:16][CH2:17][CH3:18])C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[C:19]1([C:13]2[O:14][C:15]([CH2:16][CH2:17][CH3:18])=[C:11]([CH2:10][CH2:9][OH:8])[N:12]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCCc1oc(-c2ccccc2)nc1CCOCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1oc(-c2ccccc2)nc1CCO
Reaction time: 1.5 h

Procedure:
4-(2-Benzyloxyethyl)-2-phenyl-5-propyloxazole (340 mg, 1.05 mmol) was dissolved in THF (5 mL) and treated with Pearlman's catalyst (170 mg). The solution was stirred vigorously under a hydrogen atmosphere (1 atm) for 90 min, and then the mixture was filtered through celite. The celite was rinsed with CH2Cl2 and the solution dried (MgSO4), filtered and concentrated to a clear, colorless oil: Rf=0.25 in 60% EtOAc/hexanes; 1H NMR (300 MHz, CDCl3) δ 8.00-7.96 (m, 2H), 7.44-7.22 (m, 2H), 3.92 (br s, 2H), 2.73 (t, J=5.5 Hz, 2H), 2.65 (t, J=7.0 Hz, 2H) 1.70 (sextet, J=7.0 Hz, 2H), 0.98 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1)=C.I([O-])(=O)(=O)=[O:15].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[O:13]=[C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([CH:1]=[O:15])[CH:12]=2)[CH2:7][CH2:8][NH:9]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc2c(c1)C(=O)NCC2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccc2c(c1)C(=O)NCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of 7-ethenyl-3,4-dihydro-1(2H)-isoquinolinone (232 mg, 1.341 mmol) in 1,4-dioxane (15 ml) and water (3 ml) at 0° C. was added sodium periodate (660 mg, 3.08 mmol) and osmium tetroxide (1.5 ml of a 4% aqueous solution). The reaction mixture was warmed to room temperature and stirred for 0.5 h before evaporation of the reaction mixture. The residue was dissolved in 1,4-dioxane (50 ml) and evaporated again. The mixture was then dissolved in dichloromethane (100 ml), dried with magnesium sulphate and evaporated. Chromatography on silica, eluting with 0-100% ethyl acetate/hexane, gave the product (133 mg, 57%).
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]2[C:20]([N:23]3[CH2:27]CC[CH2:24]3)=[N:21][N:22]=[C:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][N:29]1CCCC1=O>>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:28]#[N:29])[CH:15]=2)[N:10]2[C:20]([N:23]([CH3:27])[CH3:24])=[N:21][N:22]=[C:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCCC1=O
Reactant: O=c1c2cc(Br)ccc2n2c(N3CCCC3)nnc2n1Cc1ccccc1
Product: CN(C)c1nnc2n(Cc3ccccc3)c(=O)c3cc(C#N)ccc3n12
Reaction time: 12 h
Yield: 90 %

Procedure:
In a 500 ml balloon flask, equipped with a shaker, refrigeration and nitrogen feeding, we add 10.8 g (27.1 mmol) of 4-benzyl-7-bromo-1-(pyrrolidin-1-yl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (example 164) in 100ml of N-methylpyrrolidinone (NMP). We add 4.4 g (49 mmol) of cuprous cyanide then heat the mixture, under shaking and under nitrogen for 12 hours. The solvent is eliminated by evaporation under vacuum; the residue is stirred in mixture of methylene chloride and 2N ammonia solution, the insoluble residue is eliminated by filtration, then the phases are separated by decantation. The organic phase is washed in a NaCl-saturated solution, dried on Na2SO4 and evaporated to give 24.0 g of crude product. This is purified by chromatography on silica column by elution using mixture of ethyl acetate 65/cyclohexane 35. The fractions pure in CCM are joined and evaporated under vacuum: we obtain 8.4 g of compound from example 237.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]1[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([O:26][C:27]([NH:29][CH2:30][C:31]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:32]=1[CH2:33][NH:34][C:35](=[O:41])[C@@H:36]1[CH2:40][CH2:39][CH2:38][NH:37]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(Cl)CCl>[O:5]([C:6]([N:8]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@H:9]1[C:10]([N:37]1[CH2:38][CH2:39][CH2:40][C@H:36]1[C:35]([NH:34][CH2:33][C:32]1[CH:42]=[C:43]([Cl:46])[CH:44]=[CH:45][C:31]=1[CH2:30][NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:28])=[O:41])=[O:11])=[O:7])[C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2)C1C(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@@H]1C(c2ccccc2)CCN1C(=O)OC(C)(C)C
Reaction time: 0.08 h

Procedure:
1-(tert-Butoxylcarbonyl)-3-phenylprolyl-N-(2-{[(tert-butoxycarbonyl)amino]methyl}-5-chlorobenzyl)-L-prolinamide was prepared as a mixture of diastereomers from 1-(tert-Butoxycarbonyl)-3-phenyl-D,L-proline (88 mg, 0.30 mmol) from the previous step and L-prolin-N-(2-{[(tert-butoxycarbonyl)amino]methyl}-5-chlorobenzyl)amide (111 mg, 0.30 mmol) essentially according to the EDC coupling procedure described in Step 3 of Example 46. The diastereomeric products separated under the following analytical conditions: Chiralcel OD (250×4.6 m) column eluting with A/B 85/15 where A=hexane/0. 1% diethylamine and B=ethanol, with detection at 220 nm and flow rate of 1.0 mL/min. Under these conditions, the early peak elutes at 4.87 min. and later peak at 8.51 min. The products were separated on preparative scale using these conditions. Diastereomer A: LCMS RT=2.72 min. LCMS (M+H)=641.2. Diastereomer B: LCMS RT=2.75 min. LCMS (M+H)=641.0
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=O)[CH2:12][NH:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:14]([NH:13][CH2:12][CH2:11][NH:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[CH:3]2)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(CNCc1ccccc1)Nc1ccc2[nH]ncc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(CNCCNc2ccc3[nH]ncc3c2)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 43.2 %

Procedure:
N1-(1H-5-Indazolyl)-2-(benzylamino)acetamide (Example 173) (56 mg) was dissolved in tetrahydrofuran (1 ml), and a borane-tetrahydrofuran complex (1.0 ml) was added to the solution at room temperature. The reaction mixture was stirred at 50° C. for 6 hr, and 1 N hydrochloric acid (0.5 ml) was then added, followed by stirring at the same temperature for one hr. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by preparative TLC [chloroform/methanol] to give the title compound (23 mg, yield 43%)
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[C:29]([NH2:34])([CH2:32][CH3:33])([CH3:31])[CH3:30]>C(Cl)(Cl)Cl>[C:29]([NH:34][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])([CH2:32][CH3:33])([CH3:31])[CH3:30]
Reactant: CCC(C)(C)N
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(C)(C)NC(=O)c1cnc2cccc(C)n2c1=O
Reaction time: 0.08 h
Yield: 54 %

Procedure:
A mixture containing 8.16 g (0.04 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 6.2 ml (0.044 mol) of triethylamine in 240 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 4 ml (0.042 mol) of ethyl chloroformate in 20 ml of chloroform is dropped to the above mixture at a temperature between -12° C. and -17° C. during 15 minutes. After stirring for 5 minutes, 3.84 g (0.044 mol) of tert.-pentylamine dissolved in 40 ml of chloroform are dropped to the above solution at the same temperature during 15 minutes. The reaction mixture is stirred for 1 hour at about -10° C. and then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 50 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 50 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated. The residue slowly becomes crystalline to give 5.9 g (54%) of the named compound, m.p.: 87°-89° C. after recrystallization from ethanol.