Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]=NC2C=CC=CC=2)=[C:6]([CH3:16])[N:5]=[C:4]([NH2:17])[CH:3]=1.[H][H]>[Pd].CO>[CH3:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:16])[N:5]=[C:4]([NH2:17])[CH:3]=1
Reactant: [H][H]
Reactant: Cc1cc(N)nc(C)c1N=Nc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)nc(C)c1N
Yield: 72.8 %

Procedure:
A mixture of 7.5 parts of 4,6-dimethyl-5-(phenylazo)-2-pyridinamine and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 3.3 parts (72.8%) of 4,6-dimethyl-2,5-pyridinediamine as a residue (int. 96).
Reaction SMILES: C([O:6][CH2:7][C@H:8]1[CH2:10][C@@H:9]1[C:11]1[CH:12]=[N:13][CH:14]=[C:15]([O:17][CH2:18][C@@H:19]2[CH2:22][CH2:21][N:20]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:16]=1)(=O)C(C)C.C[O-].[Na+]>CO>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][C@H:19]1[CH2:18][O:17][C:15]1[CH:16]=[C:11]([C@H:9]2[CH2:10][C@@H:8]2[CH2:7][OH:6])[CH:12]=[N:13][CH:14]=1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)C(=O)OC[C@H]1C[C@@H]1c1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@H]2C[C@@H]2CO)c1
Reaction time: 6 h

Procedure:
To a solution of (1S,2S)-2-[5-[[1-(tert-butoxycarbonyl)-(2S)-azetidinyl]methoxy]-3-pyridyl]cyclopropylmethyl isobutyrate (2.82 g, 6.97 mmol) in anhydrous methanol (35 mL) in a 250 mL round-bottom flask with magnetic stirrer was added a 25-30 wt % solution of sodium methoxide in methanol (0.4 mL; d 0.97 kg/L according to supplier, which makes approx. 2 mmol). The flask was fitted with an Ar balloon, the atmosphere was exchanged, and the reaction mixture was kept at 40° C. for 6 h. The reaction mixture was evaporated and the residue directly filtered over silica gel (24×3.8 cm, CH2Cl2/MeOH 93:7, then 9:1). Evaporation and drying (50° C./oil pump) gave 2.29 g (98%) of a slightly yellowish glass. 1H NMR (CDCl3, TMS, 400 MHz) δ 8.13 (d, 1H, J=2.8 Hz), 8.04 (narrow m, 1H), 6.89 (m, 1H), 4.50 (m, 1H), 4.29 (m, 1H), 4.12 (m, 1H; the main structure of this signal is a dd with J=2.8 and 10.1 Hz, accompanied by minor peaks that may result from the presence of a second rotamer), 3.93-3.85 (m, 2H), 3.68, 3.62 (ABq, 2H, J=11.4 Hz, low-field part d with J=6.4 Hz, high-field part d with J=6.9 Hz), 2.40-2.22 (m, 2H), 1.83 (m, 1H), 1.70 (very br, 1H, OH), 1.48 (m, 1H), 1.42 (s, 9H), 1.03-0.97 (m, 2H). MS (EI) m/z 334 (M+, 1.0%), 278 (M+-C4H8, 2.4%), 237 (10%), 178 (19%), 100 (21%), 57 (100%), 56 (76%), 41 (44%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:28]=[C:29](F)[CH:30]=1)[CH2:5][C@@H:6]([C@@H:10]([C@H:12]1[CH2:16][C@@H:15](OCC=C)[CH2:14]N1C(OC(C)(C)C)=O)O)C(O)=O.[F:32][C:33]1[CH:34]=[C:35]([CH:49]=[C:50]([F:52])[CH:51]=1)[CH2:36][C@H:37]1[C@@H:41]([C@H:42]2[CH2:47][CH2:46][CH2:45][CH2:44][NH:43]2)[O:40]C(=O)[NH:38]1.FC1C=C(C=C(F)C=1)C[C@H](C(N1[C@@H](CC2C=CC=CC=2)COC1=O)=O)[C@@H]([C@H]1C[C@@H](OCC=C)CN1C(OC(C)(C)C)=O)O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:38][C@@H:37]([CH2:36][C:35]1[CH:34]=[C:33]([F:32])[CH:51]=[C:50]([F:52])[CH:49]=1)[C@@H:41]([C@H:42]1[CH2:47][CH2:46][CH2:45][CH2:44][N:43]1[CH:5]([C:4]1[CH:3]=[CH:2][CH:30]=[CH:29][CH:28]=1)[C:6]1[CH:10]=[CH:12][CH:16]=[CH:15][CH:14]=1)[OH:40]
Reactant: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2CCCCN2)O1
Reactant: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)N(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CCCCN1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Step I (6): Preparation of (4S,5R)-4-(3,5-difluorobenzyl)-5-((R)-piperidin-2-yl)oxazolidin-2-one. A solution of (R)-tert-butyl 2-((4S,5S)-4-(3,5-difluorobenzyl)-2-oxooxazolidin-5-yl)piperidine-1-carboxylate (Step I (5), 200 mg) in CH2Cl2 (4 mL) was treated with TFA (2 mL). This reaction mixture was stirred at rt for 1 h. The mixture was then concentrated in vacuo with addition of toluene. 1N HCl solution (50 mL) was added and the mixture was extracted with diethyl ether, neutralized with 50% aqueous NaOH to pH=12. The mixture was extracted with ethyl acetate (50 mL) twice. The combined organic layers were dried (Na2SO4), and concentrated in vacuo to give 132 mg of the title compound:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][CH:8]([CH2:13][CH:14]=[CH:15][CH2:16][CH:17]([CH3:22])[C:18](OC)=[O:19])[C:9](OC)=[O:10]>C1COCC1>[CH3:22][CH:17]([CH2:16][CH:15]=[CH:14][CH2:13][CH:8]([CH3:7])[CH2:9][OH:10])[CH2:18][OH:19]
Reactant: COC(=O)C(C)CC=CCC(C)C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CO)CC=CCC(C)CO
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred suspension of LiAlH4 (1.64 g, 41.0 mmol) in THF (65 mL) was added a solution of the dimethyl ester (C) (4.67 g, 20.5 mmol) in THF (15 mL) at 0° C. The mixture was stirred at that temperature for 30 min, and warmed up and stirred at room temperature for 1 h. The reaction mixture was quenched with 5% NaOH solution, extracted with Et2O thoroughly, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by SiO2 flash column chromatography (hexanes:EtOAc=2:1) to give the diol (D) (3.53 g, 20.5 mmol) in 100% yield.
Reaction SMILES: C(OC1C(=O)N=C(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)N2CCNC(=O)C=12)C1C=CC=CC=1.[CH2:37]([O:44][C:45]1[C:46]([C:65]([NH:67][CH2:68][CH2:69]O)=[O:66])=[N:47][C:48]([CH2:52][C:53]2([C:58]3[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=3)[CH2:57][CH2:56][CH2:55][CH2:54]2)=[N:49][C:50]=1[OH:51])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([O:44][C:45]1[C:50](=[O:51])[N:49]=[C:48]([CH2:52][C:53]2([C:58]3[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=3)[CH2:57][CH2:56][CH2:55][CH2:54]2)[N:47]2[CH2:69][CH2:68][NH:67][C:65](=[O:66])[C:46]=12)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(NCCO)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: O=C1NCCn2c(CC3(c4cccc5ccccc45)CCCC3)nc(=O)c(OCc3ccccc3)c21
Product: O=C1NCCn2c(CC3(c4ccc(Cl)cc4)CCCC3)nc(=O)c(OCc3ccccc3)c21

Procedure:
This compound was prepared following the same method as described for pure 9-benzyloxy-6-(1-naphthalen-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (348) from 5-(benzyloxy)-2-((1-(4-chlorophenyl)cyclopentyl)methyl)-6-hydroxy-N-(2-hydroxyethyl)pyrimidine-4-carboxamide (515).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1O.[C:11](=[O:14])([O-])[O-].[K+].[K+]>CN(C)C=O>[I:8][CH:6]1[CH2:5][CH:4]([I:9])[CH2:3][CH:7]1[CH2:2][O:14][C:11]1[C:6]([I:8])=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1c(I)cc(I)cc1I
Agent: [K+]
Solvent: CN(C)C=O
Product: Ic1ccccc1OCC1CC(I)CC1I
Temperature: 100 °C
Yield: 108.3 %

Procedure:
A stirred mixture of 36.2 g (0.08 mol) of 2,4,6-triiodophenol, 12.5 g (0.08 mol) of bromomethyleyelopentane [Noller and Adams, J. Org. Chem., 48, 1080-9 (1926)] and 10.6 g (0.08 mol) of milled anhydrous potassium carbonate in 100 ml dry dimethylformamide was heated at 100° C. under argon for 3.5 hrs. The mixture was cooled and concentrated in vacuo. The resulting residue was combined with 100 ml of ice-cold water and the oily product was extracted with ethyl acetate (3×100 ml). The combined ethyl acetate extracts were dried (MgSO4) and concentrated in vacuo to a dark oil. The oil was purified by chromatography (neutral alumina eluted by hexanes) to yield 24.0 g (57%) of the desired product as an oil. Bp: 220°-5° C./1 atm.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[C:15]([O:22][CH3:23])=[C:14]2[C:10]=1[CH2:11][CH:12]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:38]=[CH:37][C:32]([C:33](OC)=[O:34])=[CH:31][CH:30]=1)[CH2:13]2.Cl>C(OCC)C>[CH3:23][O:22][C:15]1[C:16]([O:20][CH3:21])=[C:17]([O:18][CH3:19])[C:9]([O:8][CH3:7])=[C:10]2[C:14]=1[CH2:13][CH:12]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:33][OH:34])=[CH:37][CH:38]=1)[CH2:11]2
Reactant: COC(=O)c1ccc(OCCCCC2Cc3c(c(OC)c(OC)c(OC)c3OC)C2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCOc1ccc(CO)cc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
Lithium aluminium hydride (68.3 mg, 1.80 mmols) was added to a diethyl ether (10 ml) solution of methyl 4-[4-(4,5,6,7-tetramethoxyindan-2-yl)butoxy]benzoate (400 mg, 0.900 mmols), with cooling with ice, then the mixture was warmed to room temperature, and stirred for 1 hour. 1N hydrochloric acid was added to the reaction mixture with cooling with ice, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo to obtain the entitled compound (370 mg) as an oil.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[C:27](O)(=O)[CH2:28][CH3:29]>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:27]([CH2:28][CH3:29])[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CCC(=O)O
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CCc1nc([C@@H]2CC(=NOC)CN2C(=O)c2ccc(-c3ccccc3)cc2)no1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and propionic acid, the title compound was obtained in 47% purity by HPLC. MS(ESI+): m/z=391.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10].[H-].[Na+].CCCCCC.[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10]
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(c1ccc(-n2ccnc2)cc1Cl)N1Cc2cccn2Cc2ccccc21
Yield: 25 %

Procedure:
In the manner of Example 9's Method 1, employing (2-chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (2.0 g), 60% sodium hydride in oil (0.50 g, degreased with hexane), imidazole (0.50 g) and dimethylformamide (25 ml), the title compound (0.57 g) was obtained as a tan amorphous solid, MS, m/z: 389 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:5]2[CH2:22][CH2:21][N:20]([CH3:23])[C:7]3([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)[C:6]=12.[C:28]([Zn]C#N)#[N:29]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:28]([C:2]1[CH:3]=[C:4]([C:24]([F:26])([F:25])[F:27])[N:5]2[CH2:22][CH2:21][N:20]([CH3:23])[C:7]3([CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]3)[C:6]=12)#[N:29]
Reactant: CN1CCn2c(C(F)(F)F)cc(Br)c2C12CCN(C(=O)OC(C)(C)C)CC2
Reactant: N#C[Zn]C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CN1CCn2c(C(F)(F)F)cc(C#N)c2C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 150 °C
Yield: 34.6 %

Procedure:
A mixture of tert-butyl 8-bromo-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (1.67 g, 3.7 mmol) and dicyanozinc (234.9 μL, 3.7 mmol) in DMF (10 mL) was purged with N2 for 5 min. Pd(PPh3)4 (427.6 mg, 0.37 mmol) was added. The mixture was heated in a sealed microwave vial at 150° C. overnight. The mixture was partitioned between ethyl acetate and water. The layers were separated. The aqueous layer was extracted with ethyl acetate (3×). All organic layers were combined, washed with water (3×), brine, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by column chromatography (10-20% EtOAc/hexanes) to provide tert-butyl 8-cyano-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (510 mg, 35%) as a white solid. ESI-MS m/z calc. 398.2, found 399.3 (M+1)+; Retention time: 1.56 minutes (3 minute run).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[O:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:13]([CH3:16])([O-:15])=[O:14].C(N(CC)CC)C>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]([OH:12])([CH2:16][N+:13]([O-:15])=[O:14])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: C[N+](=O)[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(O)(C[N+](=O)[O-])C1
Yield: 97 %

Procedure:
3-Oxoazetidine-1-carboxylic acid tert-butyl ester (500 mg, 2.9 mmol) was dissolved in ethanol (1.5 mL) and to this was added nitromethane (0.6 mL) and triethylamine (cat.). The reaction was stirred for eighteen hours and the solvent was then removed under reduced pressure to yield the title compound as a white solid (650 mg, 97%). δH (d6-DMSO) 6.42 (1H, s), 4.86 (2H, s), 4.04 (2H, d, J 9.2 Hz), 3.75 (2H, d, J 9.2 Hz), 1.39 (9H, s). LCMS (ES+) RT (pH 10) 1.73 min (M−H)− 231.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:6])[CH3:2].[C:15]([OH:18])(=[S:17])[CH3:16]>>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][S:17][C:15](=[O:18])[CH3:16])[CH3:2]
Reactant: CC(O)=S
Reactant: C=C(Cc1ccccc1)C(=O)OCC
Product: CCOC(=O)C(CSC(C)=O)Cc1ccccc1
Reaction time: 20 h

Procedure:
A mixture of 576 mg of α-benzylacrylic acid ethyl ester and 0.259 ml of thioacetic acid is stirred for 20 hours at 70° and then concentrated by evaporation in vacuo. The residue is purified by flash chromatography with eluant F. Rf (C)=0.35.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[C:4]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:3]=1.[N-:26]=[N+:27]=[N-:28].[Na+]>CS(C)=O>[N:26]([C:2]1[N:7]=[C:6]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[C:4]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[CH:24][CH:25]=2)[N:3]=1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(Nc2nc(Cl)nc(Cc3c(Cl)cccc3Cl)n2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Nc2nc(Cc3c(Cl)cccc3Cl)nc(N=[N+]=[N-])n2)cc1
Temperature: 25 °C
Reaction time: 28 h

Procedure:
A solution of intermediate (27) in dimethylsulfoxide was treated with NaN3 in one portion and was stirred at RT for 28 hours. The reaction mixture was poured into ice and then filtered. The precipitate was washed with cold water and was recrystallized from ACN, yielding 0.46 g of 4-[[4-azido-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]amino]benzonitrile (compound 68).
Reaction SMILES: CC(C)([O-])C.[K+].C([Li])CCC.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20].[C:21](=[O:23])=[O:22]>O.O1CCCC1>[F:12][C:13]1[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[CH:17][C:18]=1[C:21]([OH:23])=[O:22]
Reactant: O=C=O
Reactant: COc1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(=O)O)c1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
A mixture of potassium tert-butoxide (30.80 g, 274 mmol) and anhydrous tetrahydrofuran (300 mL) was cooled to -78° C. and treated with a 1.6M solution of n-butyllithium (172 mL, 275 mmol) in hexanes. After stirring for 15 minutes, 2-fluoroanisole (31.35 g, 248 mmol) was added and the reaction was stirred an additional 1.8 hours. The reaction was poured into dry ice and warmed to room temperature. Water (250 mL) was added and after extracting with ether (160 mL), the aqueous layer was acidified with concentrated hydrochloric acid, and filtered to give 2-fluoro-3-methoxybenzoic acid (21.43 g, 51%) as a yellow solid: mp 155°-160° C.; 1H NMR (acetone-d6) 300 MHz 7.46 (ddd, J=6.0 Hz J=1.8 Hz J=1.4 Hz, 1H) 7.36 (dt, J=1.6 Hz J=8.1 Hz, 1H) 7.20 (dt, J=1.4 Hz J=8.1 Hz, 1H) 3.92 (s, 3H); 19F NMR (acetone-d6) 300 MHz -134.04 (m). Mass spectrum: M+H=171.
Reaction SMILES: C([O:3][C:4]([C:6]([CH3:37])([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([NH:20][N:21]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])=[O:19])=[CH:11][CH:10]=1)[CH3:7])=[O:5])C.[OH-].[Na+]>CO>[C:4]([C:6]([CH3:37])([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([NH:20][N:21]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])=[O:19])=[CH:11][CH:10]=1)[CH3:7])([OH:5])=[O:3]
Reactant: CCCNC(=O)N(Cc1ccc(Cl)c(Cl)c1)NC(=O)CCCc1ccc(OC(C)(C)C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCNC(=O)N(Cc1ccc(Cl)c(Cl)c1)NC(=O)CCCc1ccc(OC(C)(C)C(=O)O)cc1
Reaction time: 16 h
Yield: 96.4 %

Procedure:
To substrate 1-[4-[4-(1-Ethoxycarbonyl-1-methylethoxy)-phenyl]butyryl]-2-(3,4-dichlorophenylmethyl)-4-(propyl)semicarbazide (0.609 g, 1.10 mmol) in methanol (5 mL) at rt was added 1 N NaOH (2.0 mL, 2.0 mmol) and the resulting solution stirred for 16 h. The solution was then concentrated to an oil, and partitioned between ethyl acetate and 1 N HCl. The organic phase was then washed with sat'd aq. NaCl, dried (MgSO4), filtered and concentrated to afford the title compound as an amorphous solid (0.5563 g, 1.06 mmol, 96%): 1H NMR (DMSO-d6, 60° C.) δ 9.61 (s, 1 H), 7.50 (d, 1 H, J=8 Hz), 7.47 (d, 1 H, J=1.5 Hz), 7.23 (dd, 1 H, J=8, 1.5 Hz), 7.01 (d, 2 H, J=8.5 Hz), 6.75 d, 2 H, J=8.5 Hz), 6.40 (br m, 1 H), 4.53 (br s, 2 H), 2.99 (q, 2 H, J=6.5 Hz), 2.46 (t, 2 H, J=7.5 Hz), 2.09 (t, 2 H, J=7.5 Hz), 1.74 (m, 2 H), 1.47 (s, 6 H), 1.40 (q, 2 H, J=7.5 Hz), 0.81 (t, 3 H, J=7.5 Hz); 13C NMR (DMSO-d6) δ 175.8, 172.1, 158.1, 154.1, 140.4, 135.3, 131.5, 130.9, 130.6, 130.1, 129.6, 129.1, 119.1, 78.9, 50.9, 42.3, 40.7, 34.4, 33.5, 27.1, 25.7, 23.7, 11.9; IR (CHCl3) 3379, 3291, 2960, 2915, 1719, 1671, 1618, 1542, 1508 cm−1; Anal. Calcd. for C25H31Cl2N3O5: C, 57.26; H, 5.96; N, 8.01. Found: C, 57.15; H, 5.89; N, 7.94.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH:8][C:9]1[S:10][CH2:11][CH2:12][N:13]=1>[Ag]=O.C(OCC)(=O)C>[C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]=[N:8][C:9]1[S:10][CH2:11][CH2:12][N:13]=1
Reactant: Cc1ccccc1NNC1=NCCS1
Agent: O=[Ag]
Solvent: CCOC(C)=O
Product: Cc1ccccc1N=NC1=NCCS1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 8.0 g. 2-(o-tolylhydrazino)-2-thiazoline in 400 ml. of ethyl acetate is added 4.0 g. of silver oxide. The reaction mixture is stirred for 18 hours at room temperature and filtered. The filtrate is evaporated to dryness in vacuo and the residue recrystallized from aqueous ethanol affording 6.7 g. of 2-(o-tolylazo)-2-thiazoline, m.p. 79°-80° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Br:10])=[N:8][CH:9]=1)(=[O:3])[CH3:2].I[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[Li]CCCC.CCCCCC>C1COCC1>[Br:10][C:7]1[N:8]=[CH:9][C:4]([C:1]([C:17]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)([OH:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Br)nc1
Reactant: Ic1cccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)(c1ccncc1)c1ccc(Br)nc1
Temperature: 25 °C

Procedure:
A solution of 5-acetyl-2-bromopyridine (Aldrich) (1.2 g, 5.82 mmol) and 3-iodopyridine (EGA-Chemie) (1.193 g, 5.82 mmol) in THF (10 ml) was immersed in a dry ice-acetone bath. n-BuLi (1.6M) in hexane (4.00 ml, 6.40 mmol) was added slowly by a syringe at −70° C. (exothermic reaction!). The reaction was allowed to warm up slowly to room temperature and was stirred over night. The reaction mixture was cooled to −20° C. and quenched with H2O before dilution with ethyl acetate. The organic phase was separated and washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo and dried to obtain title compound as off-white solid.
Reaction SMILES: [C:1]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20](O)[CH3:21])=[CH:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)([Cl:25])=O>C(Cl)Cl>[C:1]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]([Cl:25])[CH3:21])=[CH:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(O)c1cn(C(=O)OCc2ccccc2)c2ccccc12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(Cl)c1cn(C(=O)OCc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-(N-carbobenzoxy indol-3-yl)ethanol (1.02 g, 3.45 mmol) in CH2Cl2 (20 ml) at -78° C. under nitrogen was added thionyl chloride (0.63 ml, 8.62 mmol). After warming to room temperature and stirring for 2 hrs, the mixture was evaporated to a brown oil. This was dissolved in CHCl3, treated with activated carbon and filtered through a pad of Super Cel; the filtrate was evaporated to give 1.03 g (95%) of light brown oil: NMR (CDCl3) δ 1.90 (3, d, CH3), 5.26 (1, q, CHCl), 5.33 (2, s, PhCH2), 7.20-7.85 (9, m, aromatic H's) 8.04 ppm (1, m, H-7). This material was relatively unstable, and therefore was used immediately without further purification (e.g., as in Example 13).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].O=[C:13]([CH3:20])[CH2:14][C:15](OCC)=[O:16]>CC(O)=O>[OH:16][C:15]1[N:1]([C:3]2[CH:8]=[C:7]([CH:6]=[CH:5][N:4]=2)[C:9]([OH:11])=[O:10])[N:2]=[C:13]([CH3:20])[CH:14]=1
Reactant: NNc1cc(C(=O)O)ccn1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(O)n(-c2cc(C(=O)O)ccn2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
A mixture of 2-hydrazinylpyridine-4-carboxylic acid (306 mg, 2 mmol, PREPARATION 1) and ethyl 3-oxobutanoate (390 mg, 3 mmol) in AcOH (5 mL) was stirred at 100° C. overnight. The reaction mixture was cooled, concentrated, and purified by prep-HPLC to afford the title compound (72 mg, 16%) as yellow solid. 1H NMR (400 MHz, CD3OD): δ 2.72 (3H, s), 4.86 (1H, s), 7.71 (1H, d, J=4.8 Hz), 8.55 (1H, d J=4.8 Hz), 8.81 (1H, s). [M+H] Calc'd for C10H9N3O3, 220; Found, 220.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]([OH:14])[C:12]3([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]>[O-2].[O-2].[O-2].[Cr+6]>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13](=[O:14])[C:12]3([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C2=NOC3(CCCCC3)C2O)cc1Br
Agent: [Cr+6]
Agent: [O-2]
Product: Cc1ccc(C2=NOC3(CCCCC3)C2=O)cc1Br

Procedure:
The crude product was purified with column chromatography (silica gel, ethyl acetate and hexane) to afford the desired product 170 mg of the title product along with 100 mg of the 3-(3-bromo-4-methylphenyl)-1-oxa-2-azaspiro[4.5]dec-2-en-4-ol. The 3-(3-bromo-4-methylphenyl)-1-oxa-2-azaspiro[4.5]dec-2-en-4-ol was again converted to the title product by the oxidation with chromium trioxide by following the procedure described for step-5 of the intermediate 1.