Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:9]O)[C:2]([CH2:7][OH:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[OH:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH2:9][Br:12]
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccccc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: OCc1ccccc1CBr
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1,2 benzenedimethanol (1.41 g, 10 mmol), carbontetrabromide (3.648 g, 11 mmol), triphenylphosphine (2.885 g, 11 mmol) in dry methylene chloride (50 ml) was stirred at rt over 2 days under argon. The solvent was removed under reduced pressure and the residue chomatographed (flash silica gel, 1:1 t-butyl methyl ether:hexanes) to afford the title compound as a white solid. (0.99 g, 49%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([OH:19])[CH3:18])=[CH:12][CH:11]=2)[C:3]=1[N+:20]([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:20][C:3]1[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([OH:19])[CH3:18])=[CH:12][CH:11]=2)=[N:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(Nc2ccc(CC(C)O)cc2)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(N)c(Nc2ccc(CC(C)O)cc2)n1

Procedure:
A mixture of 1-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}-2-propanol (step 2, 500 mg, 1.66 mmol), iron powder (440 mg, 7.88 mmol), ammonium chloride (80 mg, 1.5 mmol) in ethanol/water (v/v, 31:8, 39 mL) was heated at reflux temperature for 2 h. The mixture was cooled and filtered through a pad of Celite. The filtrate was concentrated. The residue was diluted with dichloromethane (200 mL) and washed with water (2×100 mL). The organic layer was dried (MgSO4), and concentrated. Removal of solvent gave 450 mg (quant.) of the title compound as brown solids: TLC Rf 0.10 (hexane/ethyl acetate=1:1).
Reaction SMILES: [C:1](Cl)(=[O:9])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].[NH2:11][CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1.CCN(CC)CC.CCOC(C)=O>C1(C)C=CC=CC=1.O>[CH2:3]([CH:2]([CH2:6][CH2:7][CH3:8])[C:1]([NH:11][CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:9])[CH2:4][CH3:5]
Reactant: NC1CCc2ccccc21
Reactant: CCCC(CCC)C(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCC(CCC)C(=O)NC1CCc2ccccc21
Yield: 69.3 %

Procedure:
A solution of valproyl chloride (1.55 g, 9.6 mmole) in toluene (25 ml) was added dropwise to a stirred and ice-cooled solution of 1-aminoindan (1.47 g, 10.0 mmole) and Et3N (1.11 g, 11 mmole). The mixture was stirred at ambient temperature for 17 hours, EtOAc (60 ml) and water (50 ml) were added and the phases were separated. The organic phase was washed successively with 0.1N HCl (40 ml), 0.1N NaHCO3 (40 ml) and saturated NaCl (40 ml), dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue was treated with hexane (15 ml, 30 min stirring, RT) and filtered. The crude product was crystallized from hexane:EtOAc (70:30 mixture), to give 1.72 g (6.65 mmole, 69%) of a white crystalline solid, mpt: 133-4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([C:15]4([CH3:22])[NH:20][C:19](=O)[CH2:18][O:17][CH2:16]4)[CH:12]=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([C:15]4([CH3:22])[NH:20][C:19](=[S:34])[CH2:18][O:17][CH2:16]4)[CH:12]=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(c2cccc(-c3nc4ccc(Cl)cc4o3)c2)COCC(=O)N1
Product: CC1(c2cccc(-c3nc4ccc(Cl)cc4o3)c2)COCC(=S)N1
Yield: 79 %

Procedure:
In close analogy to the procedure described for the preparation of Intermediate XVIII-1, the reaction of (RS)-5-[3-(6-chloro-benzooxazol-2-yl)-phenyl]-5-methyl-morpholin-3-one with Lawesson's reagent yielded the title compound (79% of theory). MS (ISP): m/z=359.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[Cl:14]N1C(=O)CCC1=O>C(Cl)Cl.O>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([Cl:14])=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(Cl)c[nH]c2c1
Reaction time: 2 h
Yield: 630.5 %

Procedure:
To a solution of 1H-indole-6-carboxylic acid methyl ester (5.86 g, 33.5 mmol) in 30 mL of CH2Cl2 is added N-chlorosuccinimide (0.58, 4.33 mmol) portionwise over 1.5 hours. The mixture is stirred for 2 h, then diluted with water. The layers are separated and the organic phase is washed with water and saturated NaCl solution. The organic layer is dried over MgSO4, filtered and concentrated in vacuo to give the title compound (5.74 g, 27.3 mmol). The crude product is used in the next step without further purification. 1H NMR (CDCl3, 300 MHz) δ8.46 (bs, 1H), 8.19 (s, 1H), 7.90 (dd, 1H), 7.69 (d, 1H), 7.36 (d, 1H), 3.97 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1.F[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1>>[C:13]([C:12]1[CH:15]=[CH:16][CH:9]=[CH:10][C:11]=1[NH:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1)#[N:14]
Reactant: N#Cc1ccc(F)cc1
Reactant: Nc1cccnn1
Product: N#Cc1ccccc1Nc1cccnn1

Procedure:
Starting compounds: 3-aminopyridazine and 4-fluorobenzonitrile
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][OH:22])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.O>ClCCl.CS(C)=O>[CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C@H:11]([CH:21]=[O:22])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1CO
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C=O
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of tert-butyl (2S,4R)-4-(benzyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (20 g, 0.065 mol, Part A) and triethylamine (27 ml, 0.195 mol) in dichloromethane (200 mL) was added a solution of sulfur trioxide pyridine complex (31 g, 0.195 mol) in dimethyl sulfoxide (200 mL) at −15° C. The reaction mixture was stirred at that temperature for one hour and then another lot of sulfur trioxide pyridine complex (5.1 g, 0.033 mol) in dimethyl sulfoxide (35 mL) was added. The reaction mixture was allowed to stir at 20-25° C. for 18 hours, and then it was poured into cold water (400 mL) and extracted with ten-butyl methyl ether (200 mL×2). The combined organic layers were washed with 10% citric acid solution (200 mL), saturated sodium bicarbonate solution (200 mL), water (100 mL) and brine solution (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl (2S,4R)-4-(benzyloxy)-2-formylpyrrolidine-1-carboxylate (17 g, 85%) as pale yellow oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[NH3:15].O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:6]([NH2:15])[CH:7]=1
Reactant: N
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Solvent: CS(C)=O
Solvent: O
Product: Nc1cc(Cl)nc(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
An ice-cold suspension of pyrimidine 3 (44.34 g; 0.197 mol) in DMSO (366 mL) was saturated with ammonia, during which time a solution formed. After 24 h at rt, water (710 mL) was added dropwise. The suspension was cooled in an ice bath for 1 h then collected by filtration and washed with water (500 mL), yielding a light tan powder after drying in vacuo (37.84 g; 93%). LC (method B) tR=16.0 min; 1H NMR (200 MHz, CDCl3) δ 8.33 (m, 2H), 8.44 (m, 3H), 6.32 (s, 1H), 5.12 (brs, 2H); 13C NMR (50.3 MHz, CDCl3) δ 165.1, 164.0, 160.5, 136.7, 131.0, 128.4, 128.4, 101.4; ESIMS 205.9/207.8 (100/34) [MH+].
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10](=[O:11])[NH:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:7]=1)=[O:5])C>[OH-].[Na+]>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([N:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:10](=[O:11])[NH:9]2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: CCOC(=O)c1cn(-c2ccc([N+](=O)[O-])cc2)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cn(-c2ccc([N+](=O)[O-])cc2)[nH]c1=O

Procedure:
The ester prepared as in (a) above (300 mg, 1.08 mmol) in 0.5N sodium hydroxide (20 ml) was stirred under nitrogen at reflux for 1 hour. The reaction mixture was allowed to cool, washed with ethyl acetate and then acidified to pH 1.5. The aqueous solution was then extracted with ethyl acetate which on drying (MgSO4) and evaporation followed by ether trituration produced the title compound (267 mg). νmax (Nujol) 1680, 1615, 1499, 1580 cm-1, δ(CD3OD+D6DMSO) 8.30 (4H, ABq, J10 Hz, aryl protons), 8.86(1H, s, C3 pyrazole proton). Found: M+, 249.0386; C10H7N3O5 requires M, 249.0386.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1([NH:11][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][NH:5]1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)C.N>C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.CC(C)=O.C(O)(=O)C>[CH3:10][C:8]1[CH:7]=[CH:6][NH:5][C:4]([NH:11][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH:3]=[O:2])[CH:9]=1
Reactant: COC(=O)C1(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C=C(C)C=CN1
Agent: CC(C)C[Al+]CC(C)C
Agent: N
Agent: [H-]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC1=CC(C=O)(NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC=C1
Temperature: 25 °C

Procedure:
A solution of 1.0 g of 4-methyl-2-(trityl-amino)-picolinic acid methyl ester (compound B1) in 35 ml of dry toluene is treated dropwise at −70° C. with 2.9 ml of a 1.5 M solution of diisobutylaluminium hydride in toluene. After 0.5 h 5 ml of diethylether and 2.9 ml of diluted aqueous acetic acid (20% strength) are added. After further 0.5 h the reaction mixture is warmed to room temperature and 29 ml of an aqueous solution of ammonia (25% strength) are added. The colorless precipitate is filtered off with suction and washed with toluene. The filtrate is extracted with brine, the organic phase is dried using sodium sulfate and concentrated to dryness. After purification of the crude product on silica gel (eluent: toluene/ethyl acetate 20:1) and evaporation of the eluents, 0.438 g of the title compound are obtained as a colorless, amorphous solid. M.p. 213° C. MS: 379.1 (MH+). TLC: Rf=0.66 (toluene/acetone 10:1).
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[CH2:12][NH:11][CH2:10]1)C1C=CC=CC=1.C(O)C.[ClH:21]>[Pd]>[ClH:21].[OH:8][C@H:9]1[C@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[CH2:12][NH:11][CH2:10]1
Reactant: OC[C@H]1CNC[C@@H](OCc2ccccc2)[C@@H]1O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: OC[C@H]1CNC[C@@H](O)[C@@H]1O
Reaction time: 18 h

Procedure:
(3R,4R,5R)-3-Benzyloxy-4-hydroxy-5-hydroxymethylpiperidine (0.527 g, 2.2. mmol) was dissolved in 0.5M HCl (5.3 ml) and ethanol (50 ml) and 5% palladium charcoal (300 mg) was added. The mixture was hydrogenated at 101 kPa and 20° C. for 18 hours. The reaction mixture was filtrated and concentrated to give the product in 93% (0.375 g) yield. 13C-NMR (50 MHz, D2O): d 70.7 og 68.1 (C-3 og C-4); 58.6 (C-5'); 46.2 og 44.4 (C-2 og C-6); 40.6 (C-5). 1H-NMR (500 MHz, D2O, Ph<1, ref. 4.63 ppm): d 3.72 (dd, 1H, H-5b',J5a',5b' =11.5, J5,5b' =3.3 Hz); 3.67 (ddd, 1H, H-3, J3,2ax =11.2, J3,4 =8.9,J3,2eq =4.9 Hz); 3.64 (dd, 1H, H-5a', J5 a',5b'=11.5,J5a',5 =6.2 Hz); 3.43 (ddd, 1H, H-2eq, J2eq,2ax =12.7, J2eq,3 =4.9, J2eq,6eq =2.0); 3.42 (dd, 1H, H-4, J4,5 =10.5, J4,3 =8.9 (Hz); 3.41 (ddd, 1H, H-6eq, J6eq,6ax =13.4, J6eq,5 =3.8, J6eq,2eq =2.0 Hz); 2.87, 12.7, J2ax,3 =11.2 Hz); 1.86 ppm (ddddd, 1H, H-5). If necessary, the piperidine could be chromatographed using ethanol/NH4OH (25% aqueous) (10:1) to give the free piperidine. Analytical calculation for C6H13NO3 : C: 48.97; H: 8.90; N: 9.52. Found: C: 48.46; H: 9.33; N: 9.17.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16]CC=C)[CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].[CH:20]1[C:25](Cl)=CC=C(Cl)[CH:21]=1>>[C:1]([NH:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([CH2:25][CH:20]=[CH2:21])=[C:12]([OH:16])[CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: C=CCOc1cccc(C(NC(C)=O)C(=O)OC)c1
Reactant: Clc1ccc(Cl)cc1
Product: C=CCc1ccc(C(NC(C)=O)C(=O)OC)cc1O
Temperature: 350 °C

Procedure:
A solution of methyl α-(acetylamino)-3-(2-propenoxy)benzeneacetate from Preparation 5 above (8.0 g, 32 mmol) in 15 g of p-dichlorobenzene is heated at 350° C. for 16 hours in a sealed tube. The reaction mixture is cooled and the contents of the tube are purified by silica gel chromatography, eluting with CHCl3 to remove the p-dichlorobenzene and then with 5% MeOH-CHCl2 to remove the rearrangement products (methyl α-(acetylamino)-3-hydroxy-2-(2-propenyl) benzeneacetate, methyl α-(acetylamino)-3-hydroxy-4-(2-propenyl)benzeneacetate). The rearrangement products (a 1:1 mixture of methyl α-(acetylamino)-3-hydroxy-2-(2-propenyl)-benzeneacetate, methyl α-(acetylamino)-3-hydroxy-4-(2propenyl)benzeneacetate) are separated by silica gel chromatography (Chromatotron/EtOAc). Recrystallization from diisopropylether/THF gives the compound of methyl α-(acetylamino)-3-hydroxy-4-(2-propenyl)benzeneacetate above (2.60 g, 33%) as a white solid, mp 143°-145° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.CC(O[CH2:12][C:13]1[CH2:22][S:21][C@@H:16]2[C@H:17]([NH2:20])[C:18](=[O:19])[N:15]2[C:14]=1[C:23]([OH:25])=[O:24])=O.Cl>C(N(CC)CC)C.O>[NH2:20][CH:17]1[C:18](=[O:19])[N:15]2[C:14]([C:23]([OH:25])=[O:24])=[C:13]([CH2:12][S:7][C:6]3[N:2]([CH3:1])[N:3]=[N:4][N:5]=3)[CH2:22][S:21][C@H:16]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cn1nnnc1S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 53 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
A solution of 72.5 g of 1-methyl-5-mercapto-1,2,3,4-tetrazole (MTA) in 87.5 ml of triethylamine in 3 liters of water was heated to 75° C. 68 g of 7-aminocephalosporanic acid (92%) were added, to give a suspension with pH 4.35. 28 ml of triethylamine were added at the same temperature and the solution thus formed, with pH 5.20, was held for 30 min at 75° C. and 60 min at 53° C. Throughout the whole operation the reaction isoelectric pH was held to 5.25 with the gradual addition of a solution of 20 g of thiol (MTA) in 175 ml of water. The formation rate of the precipitate increased on cooling to 53° C. The mixture was adjusted to pH 4.25 at 25° C. with concentrated hydrochloric acid. It was filtered, washed with water and then acetone to give 52.8 g of the compound of the title with a 70% yield. It was recrystallised out of an aqueous hydrochloric acid solution at pH 2.20 and isolated with a m.p. 224° C. (d).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[N:17]=[N:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24](O)([CH3:26])[CH3:25])=[CH:20][CH:19]=4)[C:13]=3[N:14]=2)[CH:5]=[N:4]1)[CH3:2].[N-:28]=[N+:29]=[N-:30].[Na+].FC(F)(F)C(O)=O>ClCCl>[N:28]([C:24]([C:21]1[CH:22]=[CH:23][C:18]([N:15]2[C:13]3[N:14]=[C:9]([NH:8][C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=4)[N:10]=[CH:11][C:12]=3[N:17]=[N:16]2)=[CH:19][CH:20]=1)([CH3:26])[CH3:25])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: CCn1cc(Nc2ncc3nnn(-c4ccc(C(C)(C)O)cc4)c3n2)cn1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1cc(Nc2ncc3nnn(-c4ccc(C(C)(C)N=[N+]=[N-])cc4)c3n2)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 2-{4-[5-(1-ethyl-1H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-phenyl}-propan-2-ol (237 mg, 0.65 mmol) and sodium azide (186 mg, 2.86 mmol) in dichloromethane (2.5 ml) is added dropwise under external cooling a solution of trifluoroacetic acid (822 μl, 10.7 mmol) in dichloromethane (2.5 ml). The reaction mixture is stirred for 18 hours at room temperature. The reaction mixture is partitioned between dichloromethane and diluted aqueous ammonia. The organic phase is dried over sodium sulfate and evaporated to afford {3-[4-(1-azido-1-methyl-ethyl)-phenyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl}-(1-ethyl-1H-pyrazol-4-yl)-amine as yellow-green powder; HPLC/MS 2.01 min (A), [M+H] 390.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:29][C:30]1[N:59]=[C:33]2[N:34]([C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([C:55]([F:58])([F:57])[F:56])[CH:50]=3)[C:35]([CH3:48])=[C:36]([C:46]#[N:47])[C@@H:37]([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=3)[N:32]2[N:31]=1>C1COCC1>[C:46]([C:36]1[C@@H:37]([C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)[N:32]2[N:31]=[C:30]([NH:29][C:3](=[O:5])[CH2:2][NH:1][C:6](=[O:7])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:59]=[C:33]2[N:34]([C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([C:55]([F:57])([F:56])[F:58])[CH:50]=2)[C:35]=1[CH3:48])#[N:47]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)CNC(=O)OC(C)(C)C)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an atmosphere of argon protective gas, N-Boc-Gly-OH (5 mg, 28 μmol) and NMM (5.3 mg, 52 μmol, 2.4 eq.) were dissolved in abs. THF (1 ml), and isobutyl chloroformate (4.2 mg, 31 μmol, 1.4 eq.) was added at −15° C. (solution A). At −78° C., (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (10 mg, 22 μmol) and NMM (2.2 mg, 22 μmol, 1 eq.) were added, and the mixture was stirred overnight, during which time it slowly warmed to RT. Since the conversion was still incomplete, more solution A consisting of in each case 285 μmol of N-Boc-Gly-OH, isobutyl chloroformate and NMM in abs. THF was added at −15° C., and the mixture was stirred for 3 d, warming to RT. The reaction mixture was then directly purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (6.3 mg, 50% of theory).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C:22]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C@@H:32]2[CH2:34][O:33]2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>C(O)C>[C:22]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C@@H:32]([OH:33])[CH2:34][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:28][CH:27]=1)([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Solvent: CCO
Product: CC(C)(C)c1ccc(OC[C@@H](O)CN2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)cc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 48.1 %

Procedure:
To a mixture of spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (10.0 g, 33.18 mmol) in absolute ethanol (100 mL) was added (2S)-2-[(4-tert-butylphenoxy)methyl]oxirane (8.9 g, 43.14 mmol). The reaction mixture was stirred at 90° C. for 15 h (sometimes the reaction is complete within 2-3 hours). The reaction mixture was cooled to room temperature the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (SiO2, 10% EtOAc in dichloromethane to 50% EtOAc in dichloromethane) to give the desired product as a purple solid (8.1 g, 49%). M.p.=155-157° C.; 400 MHz 1H NMR (CDCl3) δ: 8.1-8.03 (m, 1H), 7.8-7.74 (m, 1H), 7.7-7.6 (m, 1H), 7.55-7.45 (m, 1H), 7.35-7.28 (m, 2H), 6.9-6.8 (m, 2H), 4.10-4.17 (m, 1H), 4.0-3.93 (m, 2H), 2.99-2.95 (s, 3H), 2.86-2.74 (m, 2H), 2.7-2.64 (m, 2H), 2.6-2.51 (m, 1H), 2.22-2.13 (m, 2H), 1.98-1.84 (m, 2H), 1.3 (s, 9H); LCMS: 508 [M+H]; enantiomeric excess determined from chiral HPLC: 98%; Chiral HPLC Rt=50.98 min
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:27])=[N:5][O:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][CH2:24][CH2:25][N:26]=2)=[CH:18][CH:17]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C)C=O>[O:23]1[CH2:24][CH2:25][N:26]=[C:22]1[C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]2[O:6][N:5]=[C:4]([CH3:27])[C:3]=2[CH2:2][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:17][CH:18]=1
Reactant: Cc1noc(CCCCCCCOc2ccc(C3=NCCO3)cc2)c1CCl
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: Cc1noc(CCCCCCCOc2ccc(C3=NCCO3)cc2)c1CN1CCCC1
Reaction time: 8 h
Yield: 42.6 %

Procedure:
A solution of 2.8 g of 4-chloromethyl-5-{7-[4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl}-3-methylisoxazole (Example 35) and 1.3 g of pyrrolidine in 50 ml of dimethylformamide was heated on a steam bath for six hours and then kept overnight at room temperature. The solvent was removed in vacuo, and the residue was dissolved in water and made basic with sodium bicarbonate solution. The solid product which separated was collected and dried to give 1.3 g of 5-{7-[4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl}-3-methyl-4-(1-pyrrolidylmethyl)isoxazole, m.p. 98°-99° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1.CO>CN(C=O)C>[N:33]1[CH:34]=[CH:35][CH:36]=[C:31]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[NH:11][C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=4)=[N:14][N:13]=3)=[CH:16][CH:17]=2)[CH:32]=1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)[nH]2)cc1
Reactant: Brc1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Product: FC(F)(F)c1cccc(Nc2nnc(-c3ccc(Oc4cccnc4)cc3)[nH]2)c1
Yield: 18.2 %

Procedure:
4-(5-{[3-(trifluoromethyl)phenyl]amino}-4H-1,2,4-triazol-3-yl)phenol (100 mg, 0.31 mmol) was dissolved in 2 mL of anhydrous DMF in 2-5 mL microwave vial (Personal Chemistry). Solid Cs2CO3 (203.4 mg, 0.62 mmol) was added, followed by 3-bromopyridine (74.0 mg, 0.468 mmol). The vial was capped and microwaved at 250° C. for 30 min. Then ca. 1 mL of MeOH was added to dissolve the formed suspension. The resulting reddish-brown solution was filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetontrile/water system with 0.01% of TFA. The fractions, containing the product, were collected and partitioned between EtOAc and saturated aqueous NaHCO3. Ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title compound as a yellow solid (22.4 mg).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[SH:12][C:13]1[S:14][C:15]([SH:18])=[N:16][N:17]=1>C(O)(C)C>[C:6]1([O:5][CH2:1][CH:2]([OH:4])[CH2:3][S:12][C:13]2[S:14][C:15]([S:18][CH2:3][CH:2]([OH:4])[CH2:1][O:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[N:16][N:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: Sc1nnc(S)s1
Solvent: CC(C)O
Product: OC(COc1ccccc1)CSc1nnc(SCC(O)COc2ccccc2)s1

Procedure:
Phenyl glycidyl ether (179.4 grams, 1.20 moles) and isopropanol (200 ml) were charged into the reaction vessel. 2,5-Dimercapto-1,3,4-thiadiazole (85 grams, 0.568 moles) was added in increments and with stirring. The reaction mixture was refluxed for 5 minutes. The solvent was stripped off by using a rotary evaporator at about 20 mm Hg and 115° C. The product solidified on cooling and was characterized by the infrared absorption bands at 3400, 3060, 2920, 1600, 1500, 1380, 1240, 1040, 750, and 690 cm-1.