Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:11])[C@@H:4]([CH2:9][OH:10])[NH:5][C:6](=[O:8])[CH3:7].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OC)(C)(C)C>[C:6]([NH:5][C@H:4]([CH2:9][OH:10])[C:3]([NH:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])(=[O:8])[CH3:7]
Reactant: COC(=O)[C@@H](CO)NC(C)=O
Reactant: NCc1ccccc1
Solvent: COC(C)(C)C
Product: CC(=O)N[C@H](CO)C(=O)NCc1ccccc1
Temperature: 65 °C
Reaction time: 12 h
Yield: 74.4 %

Procedure:
N-Acetyl-D-serine methyl ester (1.0 g, 0.0062 mole) was dissolved in benzylamine (6.64 g, 0.062 mole) at 0-5° C. The reaction mixture was heated and stirred at 65° C. for 12 hr. The excess benzylamine was removed by distillation under vacuum at 90° C. to get a thick white solid. To this was added 10 ml of methyl tert-butyl ether and stirred for 2 hr at room temperature. The product was filtered and dried under vacuum to obtain (R)-2-acetamido-N-benzyl-3-hydroxy-propionamide (1.09 g, Yield 75%, HPLC: 92%, Chiral HPLC: 78%).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[N:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)CCCOc1ccccc1C=O
Reactant: Nc1ccccc1
Solvent: CCO
Product: CN(C)CCCOc1ccccc1C=Nc1ccccc1
Yield: 83.2 %

Procedure:
A solution of 15 g of 2-(3-dimethylaminopropoxy)benzaldehyde and 8.0 g of aniline (distilled over zinc dust) in 300 ml of ethanol is kept at room temperature for 22 hours, refluxed for 2 hours, and the solvent removed on a rotary evaporator. The residue (21.3 g) is distilled to give 17 g of an oil; boiling point 171°-175° C./0.2 mm of Hg.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][C:4](=[O:7])[NH:3][C:2]1=[O:8].F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:1]2[CH:6]=[CH:5][C:4](=[O:7])[NH:3][C:2]2=[O:8])=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccn(-c2ccc([N+](=O)[O-])cc2)c(=O)[nH]1
Temperature: 80 °C

Procedure:
A mixture of 3.5 g 1H-Pyrimidine-2,4-dione and 3 g 1-Fluoro-4-nitro-benzene and 13.8 g Cs2CO3 in 60 mL DMF was heated to 80° C. for 12 h. This solution was poured on to 200 mL of water and the resulting precipitate was collected by filtration to yield a bright yellow crystalline product, which was dried under reduced pressure. Yield: 2.6 g.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][CH2:10][NH2:11].F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]>C1COCC1.C(OCC)(=O)C>[CH3:7][O:8][CH2:9][CH2:10][NH:11][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCNc1ccccc1[N+](=O)[O-]
Reaction time: 24 h

Procedure:
Potassium carbonate (4.15 g) and 2-methoxyethylamine (1.3 ml) were added to a solution of 1-fluoro-2-nitrobenzene (1.56 ml) in dry THF (20 ml). The mixture was stirred at 23° for 24 h, then it was diluted with ethyl acetate, washed with a saturated ammonium chloride solution (100 ml), 10% sodium hydroxide solution (100 ml) and brine (100 ml), dried and concentrated in vacuo. The residue was purified by flash chromatography (eluting with CH-EA 3:1) to give the title compound as an orange oil (2.55 g). T.l.c. CH-EA (2:1), Rf 0.51.
Reaction SMILES: [O:1]1[C@@H:3]2[CH2:4][C:5]3[C:10]([C@H:2]12)=[CH:9][CH:8]=[CH:7][CH:6]=3.C(#[N:13])C.ClCCl.S(=O)(=O)(O)O>O>[NH2:13][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:1]
Reactant: c1ccc2c(c1)C[C@H]1O[C@@H]21
Reactant: CC#N
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: -30 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
Into a 300 ml four-neck flask, 10.0 g (75.8 mmol) of cis-(±)-1,2-epoxyindan (VI), 50 ml of acetonitrile, and 40 ml of dichloromethane were introduced. This mixture was cooled to -30° C. in a dry ice/acetone bath. To this mixture, 11.14 g (113.6 mmol) of 100% sulfuric acid (prepared from 97% sulfuric acid and fuming sulfuric acid) was dropwise added at -30° to -27° C. in a period of 1 hour. When left for 1 hour to return to room temperature, the mixture became white and turbid to form a slurry. An HPLC analysis of the contents revealed that 46.8% of cis-oxazoline derivative (IV: R=CH3) had been generated. No cis-amide derivative (III: R=CH3) was detected. As the mixture was heated while 72 ml of water being added thereto, 100 ml of an azeotrope of acetonitrile/dichloromethane/water was distilled off in a period of 1 hour. The remaining mixture was cooled to room temperature, washed twice with 100 ml of dichloromethane, and then subjected to liquid separation. The water phase was adjusted to a strongly alkali state by an addition of 25% sodium hydroxide. The crystal deposited thereby was filtered off under reduced pressure, washed with water, and then dried to yield 7.53 g (yield: 66.8%) of cis-(±)-1-aminoindan-2-ol (V) as a white crystal. Its purity determined by an HPLC was 95.5%.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.F[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19]>C1COCC1>[F:17][C:15]1[CH:14]=[CH:13][C:12]([N+:18]([O-:20])=[O:19])=[C:11]([NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:16]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Nc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
Prep 2: Sodium hydride (48.6 g, 60% by wt, 1.22 mol) was added piecewise to a solution of 2-aminopyridine (57.2 g, 0.61 mol) in THF (400 mL) at 0° C. at such a rate that T≦18° C. The reaction mixture was stirred at 0° C. for 10 min. then added via cannula to a solution of 2,4-difluoronitrobenzene in THF (350 mL) at −20° C. at such a rate that T≦10° C. The reaction was stirred at −40° C. for 1 h then allowed to warm to RT. As the reaction reached RT the temperature rose rapidly to 35° C. and effervescence was observed. The reaction mixture was poured onto ice (˜2 L) and the solid which formed collected by filtration. The solid was washed with pentane and dried in vacuo to give the (5-fluoro-2-nitrophenyl)pyridin-2-yl-amine as a bright orange solid (139.3 g, 94%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].C1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O>[CH3:23][S:24]([O:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:26])=[O:25]
Reactant: CCOC(=O)C(C#N)=NO
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C(C#N)=NOS(C)(=O)=O
Reaction time: 8 h
Yield: 86.3 %

Procedure:
Ethyl 2-hydroxyimino-2-cyanoacetate (28.4 g) and anhydrous potassium carbonate (13.8 g) are dissolved in water (100 ml) and thereto is added benzene (10 ml). To the mixture is added dropwise methanesulfonyl chloride (15.6 ml) with stirring under ice-cooling and the mixture is further stirred for 1 hour. After allowing to stand overnight, the reaction mixture is extracted with ethyl acetate (300 ml). The extract is washed with water and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off to give ethyl 2-methanesulfonyloxyimino-2-cyanoacetate (38.0 g; 86.3%), melting point: 79°-81° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.O.[NH2:10][NH2:11]>C1COCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:10][NH2:11])=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: NNc1ccc(Cl)nn1

Procedure:
A solution of 3,6-dichloropyridazine (3 g, 20.14 mmol) and hydrazine monohydrate (1 g, 20.14 mmol) in 20 mL THF in a sealed tube was heated at 80° C. for 5 h. Solvent was evaporated and the crude was used in the next step without purification (3.56 g, 100%). LCMS (method B): [MH]+=145.1, tR=0.574 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][OH:8].N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][O:8][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cc(Br)ccc1Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1Cl
Reaction time: 18 h
Yield: 95.3 %

Procedure:
To a solution of 5-bromo-2-chlorobenzyl alcohol (3.00 g, 13.6 mmol) in DMF (10 ml) was added under a nitrogen atmosphere imidazole (2.89 g, 42.0 mmol). After cooling to 0° C. tert-butyldimethylchlorsilan (3.37 g, 22.3 mmol) was added and the reaction mixture was stirred for 18 h in a thawing ice bath. It was diluted with water (20 ml) and extracted with EtOAc (20 ml). The aqueous layer was extracted with ethyl acetate (20 ml) and the organic layers were washed with water (20 ml) and brine (20 ml) and were dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 80:20) afforded the title compound (4.35 g, 96%) as a colorless liquid. MS m/e: 279.0 [M−tBu]+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:10]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)[O:9][C:7](=[O:8])[C:5]=2[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].F[C:32]1[CH:46]=[CH:45][C:35]([C:36]([C:38]2[CH:43]=[CH:42][C:41](F)=[CH:40][CH:39]=2)=[O:37])=[CH:34][CH:33]=1.C1(C)C=CC=CC=1>CN(C)C(=O)C>[CH:1]1[CH:2]=[CH:3][C:4]2[C:10]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[O:9][C:7](=[O:8])[C:5]=2[CH:6]=1.[C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])[C:35]1[CH:45]=[CH:46][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
Polymerization was carried out similar to the P(BPZ-BNZPH) polymerization, except phenolphthalein (15.0000 g, 47.12 mmol), potassium carbonate (13.02 g, 94.28 mmol), 4,4′-difluorobenzophenone (10.2819 g, 47.12 mmol), toluene (117 g) and N,N-dimethylacetamide 100 g) were used. The yield was about 21.87 g. The number average molecular weight of the polymer was about 40.4 K.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:13]=1[C:14]#N.Cl.[O:22]1CCCC1>O>[Cl:11][C:12]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:13]=1[CH:14]=[O:22]
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Product: O=Cc1ccc(O)cc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Diisobutylaluminium hydride (1M in hexane, 240 mL, 240 mmol) was added to a solution of 2-chloro-4-hydroxybenzonitrile (15 g, 97.7 mmol) in tetrahydrofuran (200 mL), cooled to −78° C., and the mixture was stirred at this temperature for 1 hour then at room temperature for 18 hours. The mixture was then cooled to 0° C. and 1M hydrochloric acid (80 mL) was added dropwise. The reaction mixture was diluted with water (200 mL) and filtered, washing through with ethyl acetate (×2). The layers of the filtrate were separated and the organic solution was dried over magnesium sulfate and concentrated in vacuo. Trituration of the residue with dichloromethane afforded the title compound as a solid in 84% yield, 12.92 g.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[F:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[O:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)c(F)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1,2-Difluoro-4-nitrobenzene (21.6 g) and phenol (14.0 g) were dissolved in 100 mL of DMF and cooled to 0° C. NaH (6.5 g) was added portionwise and the reaction mixture was stirred at room temperature overnight. The reaction mixture was taken up in EtOAc and washed with water and brine, and dried over Na2SO4. The solution was concentrated to provide 2-fluoro-4-nitro-1-phenoxybenzene as an oil, which was used in Step B without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.[C:58]1(=[O:64])[O:63][C:61](=[O:62])[CH2:60][CH2:59]1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:35]([CH:30]1[CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3][CH:4]([O:56][CH3:57])[CH:5]2[O:10][C:9]([OH:52])([CH:8]([CH3:53])[CH2:7][CH:6]2[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]2[CH:20]([CH2:19][CH2:18][CH2:17][CH2:16]2)[C:21](=[O:22])[O:23][CH:24]([C:40]([CH3:51])=[CH:41][CH:42]2[CH2:43][CH2:44][CH:45]([O:50][C:58](=[O:64])[CH2:59][CH2:60][C:61]([OH:63])=[O:62])[CH:46]([O:48][CH3:49])[CH2:47]2)[CH:25]([CH3:39])[CH:26]([OH:38])[CH2:27][C:28]1=[O:29])[CH:36]=[CH2:37]
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Reactant: O=C1CCC(=O)O1
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC(=O)CCC(=O)O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of the FR-900506 substance (248 mg) in pyridine (7 ml) were added succinic anhydride (145 mg) and 4-(N,N-dimethylamino)pyridine (7 mg), and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue was subjected to chromatography on silica gel (20 g) with ethyl acetate to give 17-allyl-12-[2-[4-(3-carboxypropionyloxy)-3-methoxycyclohexyl]-1-methylvinyl]-1,14-dihydroxy-23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10, 16-tetraone (90 mg).
Reaction SMILES: Cl[C:2]1[C:3](=[O:25])[O:4][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][C:7]=1[OH:8].ClC1C(=O)OC(CCC2CCCCC=2)(C2CCCC2)CC=1O.[C:48]1([C:54]2[NH:58][N:57]=[C:56]([SH:59])[N:55]=2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.N1C=CC(C2NC(S)=NN=2)=CC=1.Cl>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[CH:2]([S:59][C:56]3[NH:55][C:54]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[N:58][N:57]=3)[C:7](=[O:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: Sc1n[nH]c(-c2ccccc2)n1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cl)C(=O)O2)cc1Cl
Agent: Cl
Agent: O=C1OC(CCC2=CCCCC2)(C2CCCC2)CC(O)=C1Cl
Agent: Sc1nnc(-c2ccncc2)[nH]1
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Sc3nnc(-c4ccccc4)[nH]3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example C(4), where 3-Chloro-6-[2-(3-chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one Step 1 of example C(40), was substituted in place of 3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one and 5-Phenyl-1H-1,2,4-triazole-3-thiol was substituted in place of 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol of that example. 1H NMR (DMSO-d6): δ 1.53-1.85 (m, 10H), 2.17-2.34 (m, 1H), 2.69-2.75 (m 2H), 2.95 (d, J=17.0, 1H), 3.08 (d, J=17.0 Hz, 1H), 3.90 (s, 3H), 7.08 (d, J=8.4 Hz, 1H) 7.22-7.26 (m, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.40-7.53 (m, 4H), 7.91-7.94 (m, 2H), 12.0 (brs, 1H); Anal. Calcd. For C27H28ClN3O4S.1.0 HCl.1.0H2O: C, 55.86; H, 5.38; N, 7.24; Found: C, 55.75; H, 5.17; N, 7.17. ESIMS (MH+): 527
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][CH2:11][NH2:12]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:8][CH2:9][CH2:10][CH2:11][NH2:12]
Reactant: Brc1ccccn1
Reactant: NCCCN
Product: NCCCNc1ccccn1
Yield: 44.9 %

Procedure:
2-Bromopyridine (100 g; 0.633 mol) and 1,3-diaminopropane (234.5 g; 3.16 mol) was refluxed for 7 h. After the reaction was complete, the mixture was evaporated. Distillation of the remaining residue under oil pump vacuum afforded 43 g of the required product.
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[C:4]([F:22])[C:5]2[C:15](=[O:16])[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][N:7]3[C@@H:8]([CH3:12])[CH2:9][O:10][C:11]=1[C:6]=23.[CH3:24][C:25]1[CH:30]=[C:29]([Sn](C)(C)C)[CH:28]=[C:27]([CH3:35])[N:26]=1>C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][C:25]1[CH:30]=[C:29]([C:2]2[C:3]([F:23])=[C:4]([F:22])[C:5]3[C:15](=[O:16])[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][N:7]4[C@@H:8]([CH3:12])[CH2:9][O:10][C:11]=2[C:6]=34)[CH:28]=[C:27]([CH3:35])[N:26]=1
Reactant: CCOC(=O)c1cn2c3c(c(Br)c(F)c(F)c3c1=O)OC[C@@H]2C
Reactant: Cc1cc([Sn](C)(C)C)cc(C)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cn2c3c(c(-c4cc(C)nc(C)c4)c(F)c(F)c3c1=O)OC[C@@H]2C
Temperature: 150 °C
Yield: 72.1 %

Procedure:
A mixture of 19.35 g ethyl (S)-10-bromo-8,9-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate, 16.20 g 2,6-dimethyl-4-(trimethylstannyl)pyridine, 0.88 g dichlorobis(triphenylphosphine)palladium in 200 ml ethanol was placed in a stainless steel Parr apparatus and the system flushed with nitrogen and pressurized to about 80 psi with nitrogen. The system was heated at 150° C. for 4 hours. The reaction mixture was cooled and concentrated in vacuo, and the residue was taken up in chloroform, filtered and chromatographed on silica gel using 5% methanol in chloroform to give 14.90 g ethyl (S)-10-(2,6-dimethyl-4-pyridinyl)-8,9-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16]>CC(C)=O.CCOC(C)=O>[CH3:14][Si:15]([CH3:17])([CH3:16])[CH2:18][CH2:19][O:20][CH2:21][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7]
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ccnc1C=O
Temperature: 60 °C
Yield: 60.2 %

Procedure:
A mixture of 1H-imidazole-2-carbaldehyde (1.1 g, 11 mmol), potassium carbonate (3.0 g, 23 mmol), and SEM-Cl (2.4 mL, 14 mmol) in 10 mL of acetone was heated to 60° C. for 8 h. The mixture was diluted with EtOAc (100 mL) and washed with NaHCO3 (2×100 mL) and brine (100 mL) and the organic layer dried (Na2SO4) and concentrated. The title compound was purified by elution from a 20-g SPE column with 50% EtOAc to give 1.5 g (58%) of a colorless oil. 1H-NMR (CDCl3, 400 MHz): δ 9.82 (s, 1H), 7.38 (d, J=1.0 Hz, 1H), 7.34 (d, J=1.0 Hz, 1H), 5.78 (s, 2H), 3.55 (m, 2H), 0.94 (m, 2H), −0.02 (s, 9H).
Reaction SMILES: N(CCC[C@@]1(C2C=CC=CC=2)N(C(=O)[C@@H](O[Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)C)N=C(C2C=C(F)C=CC=2F)S1)=[N+]=[N-].[NH2:48][CH2:49][CH2:50][CH2:51][C@:52]1([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[N:56]([C:57](=[O:62])[C@@H:58]([O:60][CH3:61])[CH3:59])[N:55]=[C:54]([C:63]2[CH:68]=[C:67]([F:69])[CH:66]=[CH:65][C:64]=2[F:70])[S:53]1>>[NH2:48][CH2:49][CH2:50][CH2:51][C@@:52]1([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[N:56]([C:57](=[O:62])[C@@H:58]([O:60][CH3:61])[CH3:59])[N:55]=[C:54]([C:63]2[CH:68]=[C:67]([F:69])[CH:66]=[CH:65][C:64]=2[F:70])[S:53]1
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN)c1ccccc1
Agent: C[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@]1(CCCN=[N+]=[N-])c1ccccc1
Product: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@]1(CCCN)c1ccccc1

Procedure:
Prepared as previously described in Example 71 using (S)-1-((R)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(tert-butyldiphenylsilyloxy)propan-1-one from Step C. MS ESI (+) m/z 420 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.51 (m, 1H), 7.44 (m, 2H), 7.36 (m, 2H), 7.29 (m, 1H), 7.12 (m, 2H), 4.71 (q, 1H, J=6 Hz), 3.32 (s, 3H), 3.23 (m, 1H), 2.84 (m, 2H), 2.43 (m, 1H), 1.93 (m, 1H), 1.50 (d, 3H, J=6 Hz), 1.44 (m, 2H), 1.34 (m, 1H). Stereochemistry was assigned by inference from (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3 (2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[C:5]([C:9]([O:11]CC)=[O:10])[S:6][C:7]=1[I:8])#[N:2].[OH-].[Na+]>O1CCCC1.O>[C:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[C:5]([C:9]([OH:11])=[O:10])[S:6][C:7]=1[I:8])#[N:2]
Reactant: CCOC(=O)c1sc(I)c(C#N)c1-c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(I)sc(C(=O)O)c1-c1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 111.2 %

Procedure:
To a solution of ethyl 4-cyano-3-(2,4-dichlorophenyl)-5-iodothiophene-2-carboxylate (1.44 g, 0.00318 mol) in tetrahydrofuran (20 mL) and water (10 mL) was added a solution of 1.00M sodium hydroxide in water (16 mL). The solution was allowed to stir overnight. The reaction was quenched with a solution of 1N hydrogen chloride in water (18 mL) and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the crude title compound (1.50 g, 100%) used directly in the next reaction. LCMS: (FA) ES+, 378. 1H NMR (400 MHz, d6-DMSO) δ: 7.68 (d, 1H, J=2.0 Hz), 7.46-7.34 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[CH:4][CH:3]=1.C[Si]([C:13]#[N:14])(C)C.CN(C)C(Cl)=O.C([O-])([O-])=O.[K+].[K+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:13]#[N:14])[CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1ccc(Cl)cc1
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#Cc1cc(Cl)ccn1
Temperature: 0 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a mixture of 4-chloropiridine-N-oxide (5.00 g, 38.6 mmol) and trimethylsilyl cyanide (4.84 g, 46.3 mmol) in dichloromethane (60 ml) cooled to 0° C. was added dropwise N,N-dimethylcarbamoyl chloride (3.8 ml, 40.5 mmol). The mixture was allowed to warm to ambient temperature and stirred for 16 h. The mixture was cooled to 0° C. and a 30% aqueous solution of K2CO3 (100 ml) was added. The crude product was extracted with dichloromethane (100 ml×2), the organic extracts dried (MgSO4) and evaporated to give 4-chloro-2-pyridinecarbonitrile (5.35 g, 100%). 1H-NMR (CDCl3) δ: 8.63 (1 H, d, J=4.8 Hz), 7.72 (1 H, d, J=2.6 Hz), 7.55 (1 H, dd, J=1.8, 5.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>>[CH2:16]([O:15][C:13](=[O:14])[NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(Nc1ccc(F)cc1F)OCc1ccccc1
Reaction time: 2 h

Procedure:
The 2,4 difluoro aniline (5.06 ml, 49.6 mmole) put into a solution of 10% NaOH (76 ml). Cooled in an ice bath and added benzyl chloroformate (7.85 ml, 55 mmole). After stirring for for 2 hours the product was filtered, stirred with hexane, dried. Yield 9.4 g