Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC([C:5]1([C:10](OC)=O)[CH2:9][CH:8]=[CH:7][CH2:6]1)=O.[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OC(O[CH2:32][CH3:33])(OCC)OCC)C>C(O)C.O>[CH3:9][CH:5]=[CH:6][CH2:7][CH2:32][CH2:33][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:14][CH:20]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:5][CH3:10]
Reactant: COC(=O)C1(C(=O)OC)CC=CC1
Reactant: Cc1ccccc1
Reactant: CCOC(OCC)(OCC)OCC
Solvent: CCO
Solvent: O
Product: CC=CCCCCCCCCCC=CCCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a three-necked round-bottomed flask, equipped with a Dean-Stark trap (20 mL), a reflux condenser, a thermometer and a magnetic stir bar, was placed diol 1 (14.8 g, 115.5 mmol) and 370 mL of toluene under an atmosphere of N2. The mixture was brought to reflux and maintained at reflux temperature for 2 hours to azeotropically remove any moisture. About 100 mL (5×20 mL) of azeotropic mixture was collected in the Dean-Stark trap. The mixture was then allowed to slowly cool to room temperature and 0.2 g of anhydrous para-toluenesulfonic acid (PTSA) was added, followed by dropwise addition of tetraethylorthocarbonate (TEOC, 4563-91-2, 99.1%, 12.2 mL, 57.8 mmol). The resulting mixture was brought to reflux to azeotropically remove ethanol generated during this reaction. The azeotropic mixture was shaken with sale water to determine the amount (volume) of ethanol collected. After a total of 140 mL of azeotropic mixture (12.5 mL of ethanol) was collected, the reaction mixture was allowed to reflux for an additional 2 hours and then allowed to stir at 102° C. overnight. The reaction mixture was allowed to slowly cool to room temperature and then neutralized by the addition of 1 mL of triethylamine. The resulting mixture was allowed to stir at room temperature for an additional 30 min, and was stripped off solvents to give an off white solid. The crude material was then purified by flash chromatography (silica gel, CH2Cl2/hexanes 2/1 v/v) or by recrystallization from refluxing toluene. The desired product 7,9,17,18-tetroaxatrispiro[4.2.2.4.2.2]nonadeca-2,13-diene (DCP 3) was obtained as white crystals in 62% yield. Mp (DSC) 174.53° C.; 1H-NMR (CDCl3, 300 MHz) δ 5.61 (s, 2H), 3.82 (s, 4H), 2.29 (s, 4H); 13C-NMR (CDCl3, 300 MHz) δ 28.53, 114.14, 71.07, 39.79; FT-IR (CH2Cl2) (cm−1) 3052, 2947, 2928, 2880, 2842, 1614, 1481, 1267, 1210, 1171, 1014, 990, 738, 671; Anal. Calcd for C15H20O4: C, 68.16; H, 763; Found: C, 68.18; H, 7.81.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@H:6]([CH3:13])[N:5]([CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=3)[C:4]=2[N:3]=1.[C:25]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:25])[C:7](=[O:12])[C@H:6]([CH3:13])[N:5]([CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=3)[C:4]=2[N:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1c(C)cnc(CN2c3nc(N)ncc3NC(=O)[C@@H]2C)c1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C)cnc(CN2c3nc(N)ncc3N(C)C(=O)[C@@H]2C)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(7S)-2-amino-8-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7-methyl-7,8-dihydropteridin-6(5H)-one (Example 1)(164 mg, 0.5 mmol) was stirred in anhydrous THF (1 mL) and triphenylphosphine (400 mg, 1.53 mmol) and methanol (0.2 mL, 4.94 mmol) were added. DIAD (0.3 mL, 1.52 mmol) was added dropwise and the mixture was stirred at room temperature overnight. The reaction mixture was loaded onto a SCX cartridge and washed with THF and methanol, then eluting with methanolic ammonia (7M). The crude product was further purified by MPLC eluting with 0-15% methanol/DCM. The title compound was isolated as a colourless foam after trituration and re-concentration from ether (113 mg, 66%); 1H NMR spectrum (400 MHz, CDCl3) δ1.39 (3H, d), 2.17 (3H, s), 2.25 (3H, s), 3.26 (3H, s), 3.75 (3H, s), 4.03-4.15 (2H, m), 4.66 (2H, s), 5.71 (1H, d), 7.57 (1H, s), 8.18 (1H, s); Mass spectrum: (M+H)+ 343.
Reaction SMILES: [C:1]([N:8](C#N)[C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:16]([N:18](CC)CC)C.ClC(OCC(C)C)=O.[BH4-:31].[Na+:32]>C1COCC1.O>[BH4-:31].[Na+:32].[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([CH2:11][OH:13])[CH2:10][C:16]#[N:18])([CH3:5])([CH3:6])[CH3:7]
Reactant: C[C@@H](C(=O)O)N(C#N)C(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CO)CC#N
Temperature: -10 °C
Reaction time: 0.07 h
Yield: 64 %

Procedure:
A solution of N-Boc cyanoalanine (2 g, 9.3 mmol) in THF (30 mL) was cooled in an ice/NaCl bath to −10° C. and treated with triethylamine (0.94 g, 9.3 mmol) followed by dropwise addition of isobutyl chloroformate (1.35 g, 9.9 mmol). The reaction mixture was stirred for 4 minutes at −10° C. and filtered through a coarse scintered glass funnel. Meanwhile, in another flask, a solution of NaBH4 (0.71 g, 19 mmol) in water (10 mL) was prepared and cooled in an ice/water bath. The filtered solution of the mixed anhydride was added dropwise to the cold NaBH4 solution and the resulting mixture was stirred for 2 hours. The THF was removed on the rotary evaporator and the reaction was acidified with 5% NaHSO4 solution to pH 3 and diluted with ethyl acetate and water. The organics were extracted twice with aqueous NaHCO3 and dried over MgSO4. The solvent was removed to afford 1.2 g (64%) of (S)-(2-Cyano-1-hydroxymethyl-ethyl)-carbamic acid tert-butyl ester; 1H NMR (CDCl3, 400 MHz) δ 1.45 (s, 9H), 2.09-2.17 (m, 1H), 2.73 (d, 1H, J=6.0), 3.76 (dd, 1H, J1=4.7, J2=10.8), 3.80-3.86 (m, 1H), 3.91-3.99 (m, 1H), 4.98-5.07 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([OH:15])([C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1)[CH3:3].[H][H]>C(O)(C)C>[NH2:12][C:8]1[CH:7]=[C:6]([C:5]#[C:4][C:2]([CH3:3])([OH:15])[CH3:1])[CH:11]=[CH:10][CH:9]=1
Reactant: [H][H]
Reactant: CC(C)(O)C#Cc1cccc([N+](=O)[O-])c1
Solvent: CC(C)O
Product: CC(C)(O)C#Cc1cccc(N)c1
Reaction time: 0.25 h
Yield: 77 %

Procedure:
In an autoclave there are introduced—under nitrogen atmosphere—20.0 g of 2-methyl-4-(3-nitrophenyl)but-3-yn-2-ol and 300 mL of Isopropanol and 1.0 g of cobalt polysulfide paste (see U.S. Pat. No. 4,219,679A1). The mixture was hydrogenated for 1 hr and 15 minutes at 110° C. and 1000 psig of hydrogen pressure. After removing the catalyst by filtering, the solution was concentrated to dryness and the residue was crystallised from Toluene providing 13.1 g of the product of formula (IV) for a molar yield of 77%.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([CH3:7])=[CH:5][CH:6]=1.[Cl-].C([Al+]CC)C.[O:20]1[CH2:25][CH2:24][N:23]([S:26]([C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31](Cl)=[O:32])(=[O:28])=[O:27])[CH2:22][CH2:21]1>ClCCl>[CH3:7][C:4]1[N:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]([CH3:1])=[CH:6][C:5]=1[C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=1[S:26]([N:23]1[CH2:22][CH2:21][O:20][CH2:25][CH2:24]1)(=[O:28])=[O:27]
Reactant: O=C(Cl)c1ccccc1S(=O)(=O)N1CCOCC1
Reactant: CCOC(=O)Cn1c(C)ccc1C
Agent: CC[Al+]CC
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)cc(C(=O)c2ccccc2S(=O)(=O)N2CCOCC2)c1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 30.4 %

Procedure:
To a 0° C. solution of ethyl 2-(2,5-dimethyl-1H-pyrrol-1-yl)acetate (0.2 g, 1.10 mmol) in dichloromethane (8.0 mL) was added diethylaluminum chloride (1.66 mL, 1.66 mmol). The reaction was stirred at 0° C. for 15 minutes, after which a solution of 2-(morpholinosulfonyl)benzoyl chloride (0.384 g, 1.32 mmol) was added. The reaction was stirred for 30 minutes at 0° C., then allowed to warm to room temperature, and stirred for 3 hours at this temp. The reaction was quenched with sodium bicarbonate (15 mL), extracted with dichloromethane (3×50 mL), washed with brine, dried (sodium sulfate), filtered, and concentrated. Purification by column chromatography on silica gel using 30 to 100% ethyl acetate in hexanes afforded ethyl 2-(2,5-dimethyl-3-(2-(morpholinosulfonyl)benzoyl)-1H-pyrrol-1-yl)acetate (0.145 g, 0.334 mmol, 30% yield). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.84 (d, 1H), 7.61 (app. t, 1H), 7.55 (dd, 1H), 7.39 (d, 1H), 5.72 (s, 1H), 4.51 (s, 2H), 4.23 (q, 2H), 3.68-3.71 (m, 4H), 3.14-3.17 (m, 4H), 2.44 (s, 3H), 2.07 (s, 3H), 1.29 (t, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CO[C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O.[C:17]([Cl:20])(=O)C>>[Cl-:20].[CH3:11][C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[CH:17]=[N+:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CC(=O)Cl
Reactant: COc1ccccc1C=O
Product: Cc1ccccc1C=[N+]1CCOCC1
Product: [Cl-]

Procedure:
The reaction of 8.5 g (0.100 mol) morpholine and 7.0 g (0.050 mol) 2-methoxybenzaldehyde in accordance with general synthesis instructions 2 and subsequent reaction with 3.9 g (0.050 mol) acetyl chloride in accordance with general synthesis instructions 3 gave 7.1 g (corresponding to 58% of the yield calculated by theory) 4-(2-methyl-benzylidene)morpholin-4-ium chloride.
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[CH2:7][NH:6][C:5]1=[S:10])[CH:2]=[CH2:3].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.Cl>O>[CH2:1]([N:4]1[C:8](=[O:9])[C:7](=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:6][C:5]1=[S:10])[CH:2]=[CH2:3]
Reactant: O=Cc1ccccc1
Reactant: C=CCN1C(=O)CNC1=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CCN1C(=O)C(=Cc2ccccc2)NC1=S
Reaction time: 18 h

Procedure:
A flask equipped with a magnetic stirrer, condenser, and nitrogen pressure was charged with 3-allylthiohydantoin (15 g, 0.096 mol), water (90 mL), and benzaldehyde (10.2 g, 0.096 mol). As the mixture was stirred, triethylamine (19.4 g, 0.192 mol) was added slowly. After 18 hr, HPLC analysis indicated the absence of starting material, and the mixture was transferred to an Erlenmeyer flask. The mixture was stirred vigorously as 3 M hydrochloric acid was added dropwise until the pH reached 3 (65 mL). The mixture was stirred for an additional 90 min, and then the solid that had formed was collected by filtration. The still wet solid was resuspended in 100 mL of water, stirred for 30 min, and collected. After air drying, the orange solid weighed 18.4 g (79%). HPLC analysis indicated a purity of 95% at 215 nm. NMR (CDCl3) δ 9.3 (bs, 1H), 7.4 (s, 5H), 6.8 (s, 1H), 5.1-6.3 (m, 3H), 4.6 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:25]1(O)[CH2:30]CC[CH2:27][CH2:26]1.[C-]#N.[K+]>>[Br:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:27][CH2:26][CH2:25][CH2:30][CH2:20]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Reactant: OC1CCCCC1
Agent: [C-]#N
Agent: [K+]
Product: O=C(OC1CCCCC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Reaction time: 24 h

Procedure:
A mixture of 9.50 g (24.3 mmol) of ethyl (S)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 60 ml (560 mmol) of cyclohexanol and 300 mg of powdered potassium cyanide is stirred at 130° for 24 hours, a small amount of cyclohexanol being distilled off from time to time. The solution obtained is subsequently evaporated to dryness, the residue is taken up in chloroform, washed with water and dried over magnesium sulphate. After removal of the solvent, the residue is chromatographed on a silica gel column while eluting with ethyl acetate and subsequently recrystallized from ethyl acetate. There is obtained cyclohexyl (S)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 167°-168°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][N:7]=1.[CH3:14][S:15][C:16](S(C)=O)=[CH:17][N+:18]([O-:20])=[O:19]>CO>[OH2:12].[CH3:14][S:15][C:16]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][N:7]=1)=[CH:17][N+:18]([O-:20])=[O:19]
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: COc1ccnc(CSCCN)c1
Solvent: CO
Product: COc1ccnc(CSCCNC(=C[N+](=O)[O-])SC)c1
Product: O
Reaction time: 8 h
Yield: 110.2 %

Procedure:
A solution of 2-(2-aminoethylthiomethyl)-4-methoxypyridine (3.28 g) in methanol (40 cc) was added over 70 minutes to a stirred solution of 1-methylthio-1-methylsulphinyl-2-nitroethylene (3.01 g) in methanol (200 cc) at 30°. The mixture was allowed to stand overnight at room temperature and was evaporated to an oil which was crystallised from aqueous ethanol to give 1-methylthio-1-[2-(4-methoxy-2-pyridylmethylthio)ethylamino]-2-nitroethylene monohydrate (3.04 g) m.p. 52.5°-54.5°.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:12]4([C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]([CH2:21][C:22]5[CH:27]=[CH:26][C:25]([C:28](=O)[CH2:29][C:30]#[N:31])=[CH:24][CH:23]=5)[C:13]4=[O:33])[CH2:11][O:10][C:9]3=[CH:34][C:5]=2[O:4][N:3]=1.O.[NH2:36][NH2:37]>C(O)C>[NH2:31][C:30]1[CH:29]=[C:28]([C:25]2[CH:24]=[CH:23][C:22]([CH2:21][N:14]3[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:12]4([C:8]5[C:9](=[CH:34][C:5]6[O:4][N:3]=[C:2]([CH3:1])[C:6]=6[CH:7]=5)[O:10][CH2:11]4)[C:13]3=[O:33])=[CH:27][CH:26]=2)[NH:37][N:36]=1
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)N(Cc2ccc(C(=O)CC#N)cc2)c2ccccc21
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1noc2cc3c(cc12)C1(CO3)C(=O)N(Cc2ccc(-c3cc(N)n[nH]3)cc2)c2ccccc21
Temperature: 25 °C
Yield: 43 %

Procedure:
To a solution of 3-(4-((3-methyl-2′-oxo-6H-spiro[benzofuro[5,6-d]isoxazole-5,3′-indoline]-1′-yl)methyl)phenyl)-3-oxopropanenitrile in ethanol (20 mL) was added hydrazine hydrate (0.40 mL, 15 mmol). The solution was heated at reflux for 4 h, allowed to cool to ambient temperature and concentrated in vacuo. The resultant solid was dissolved in anhydrous methanol (10 mL) and a saturated solution of hydrogen chloride in anhydrous methanol (1.5 mL) was added, causing a precipitate to be deposited. The solid was collected by filtration to obtain 1′-[4-(3-amino-1H-pyrazol-5-yl)benzyl]-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one (0.14 g, 43%) as a pale yellow solid: mp 191-195° C. (methanol); 1H NMR (300 MHz, DMSO-d6) δ 7.82-7.71 (m, 3H), 7.52 (d, J=8.3 Hz, 2H), 7.31-7.18 (m, 2H), 7.10 (d, J=8.6 Hz, 1H), 7.04-6.97 (m, 2H), 6.40 (s, 1H), 5.16 (d, J=16.3 Hz, 1H), 5.05 (d, J=9.7 Hz, 1H), 4.98-4.89 (m, 2H), 2.42 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 176.3, 164.3, 157.8, 155.9, 145.7, 142.7, 138.0, 130.5, 129.7, 128.3, 127.5, 126.6, 124.7, 124.4, 123.8, 117.8, 109.2, 108.5, 108.4, 81.5, 56.1, 43.5, 9.8; MS (ES+) m/z 463.9 (M+1). Anal. Calcd. for C27H21N5O3.1.6HCl: C, 62.15; H, 4.37; N, 13.42. Found: C, 61.97; H, 4.52; N, 13.15.
Reaction SMILES: C(OCC)C.O[CH:7]([CH2:13][C:14]([CH2:17][Si](C)(C)C)=[C:15]=[CH2:16])[CH2:8][CH2:9][C:10](=[O:12])[CH3:11].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.O>C(OCC)(=O)C>[CH3:11][C:10]12[O:12][CH:7]([CH2:8][CH2:9]1)[CH2:13][C:14](=[CH2:17])[C:15]2=[CH2:16]
Reactant: C=C=C(CC(O)CCC(C)=O)C[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: C=C1CC2CCC(C)(O2)C1=C
Temperature: -78 °C
Yield: 94.3 %

Procedure:
1.50 mL of diethyl ether was added to 5-hydroxy-7-trimethylsilanylmethyl-nona-7,8-diene-2-one (86 mg, 0.36 mmol) under nitrogen atmosphere. While stirring at −78° C., trimethylsilyl trifluoromethanesulfonate (TMSOTf; 64.7 μL, 0.36 mmol) was added. While stirring the reaction mixture, the reaction temperature was slowly increased to room temperature for 3 hours. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, H2O was added. After stirring for about 5 minutes, the reaction mixture was diluted with ethyl acetate (EtOAc) and washed with water and saturated brine. The organic layer was separated from the reaction mixture and dried with anhydrous magnesium sulfate (MgSO4). The solvent was removed under reduced pressure and the remaining material was purified with column chromatography (EtOAc/n-hexane=1/5) to obtain 51 mg of the product (94%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.C1C(=O)N([I:23])C(=O)C1.CN(C=O)C>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[I:23])[CH:13]=[CH:12][O:11]3)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc(-c2cn3ccoc3n2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc3occn3c2I)cc1
Reaction time: 3 h
Yield: 90.4 %

Procedure:
A solution of 6-(4-fluorophenyl)imidazo[2,1-b]oxazole (4.92 g, 24.3 mmol; prepared according to WO2004110990A2, Example 1, Steps 1-3), NIS (5.75 g, 25.6 mmol), and DMF (100 mL) was stirred at ambient temperature. After about 3 h, the reaction was poured into water (300 mL) and the resulting precipitate was filtered, washing with additional water, and dried in a vacuum oven at about 55-65° C. to give the title compound (7.21 g, 89%): LC/MS (Table 1, Method b) Rt, =2.09 min; MS m/z: 329.1 (M+H)+.
Reaction SMILES: C(O[C:9](=[O:26])[CH2:10][N:11]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1.[C:27](#[N:29])[CH3:28].[NH2-].[Na+].[CH2:32]([Mg]Cl)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CC(OC)(C)C>[NH2:29][C:27]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[CH:28][C:9](=[O:26])[CH2:10][N:11]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC#N
Reactant: Cl[Mg]Cc1ccccc1
Reactant: O=C(CN(Cc1ccccc1)Cc1ccccc1)OCc1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: NC(=CC(=O)CN(Cc1ccccc1)Cc1ccccc1)Cc1ccccc1

Procedure:
The title compound was prepared from N,N-dibenzyl-glycine benzyl ester, 54 mmole, and 3.3 mL, 64 mmole of acetonitrile. Following the procedure described in Example 2 the ester and nitrile mixture was added to 5.5 g, 127 mmole of sodium amide in MTBE. After solvent removal, benzyl magnesium chloride (PhCH2MgCl 145 mmole) was added following the procedure in Example 2. The resulting enamine was purified by chromatography, following the procedure described in Example 4. The yield of enamine was 22.3 g (50 mmole, 78%).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH:14]([CH3:16])[C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1.O>CN1CCCC1=O>[CH3:1][N:2]1[CH2:15][CH:14]([CH3:16])[C:5]2[N:6]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([C:20]([F:30])([F:19])[F:29])=[CH:26][CH:25]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3C
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)C(C)CN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2,3,4,5-tetrahydro-2,4,8-trimethyl-1H-pyrido[4,3-b]indole (200 mg, 0.934 mmol) in N-methyl-2-pyrolidone (2.5 mL) was added powdered KOH (463 mg, 8.27 mmol) and allow to stir for 10 min at RT. 2-Trifluoromethyl-5-vinyl pyridine (323 mg, 1.87 mmol) was added and stirred further for 12 h at RT. The reaction was monitored by TLC. After completion of reaction, water (10 mL) was added and the mixture filtered. Water was added to the filtrate and the product extracted with EtOAc (50 mL). The organic layer was dried over sodium sulfate, evaporated in vacuum and purified by HPLC to obtain the product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.[C:10]1([CH:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]2[CH2:20][C:19](=O)[CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CO>C(O)(=O)C>[C:10]1([CH:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]2[CH2:20][CH:19]([N:1]3[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]3)[CH2:18]2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: NC(=O)C1CCNCC1
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)C1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Temperature: 120 °C
Yield: 99.5 %

Procedure:
To a mixture of piperidine-4-carboxamide (1.05 g, 8.2 mmol), 1-(diphenylmethyl)azetidin-3-one (see Bioorg. Med. Chem. Lett.; 13; 2003; 2191-2194, 1.94 g, 8.2 mmol), methanol (30 mL) and acetic acid (3 mL) was added (polystyrylmethyl)trimethylammonium cyanoborohydride (4.1 mmol/g, 1.9 g). The reaction mixture was heated for 5 min at 120° C. using microwave single node heating. The resin was filtered off and the solvent was removed by evaporation. There was obtained 2.85 g (99%) of 1-[1-(diphenylmethyl)azetidin-3-yl]piperidine-4-carboxamide. 1H NMR (500 MHz, CDCl3): 1.6-1.9 (m, 6H), 2.1-2.2 (m, 1H), 2.7-2.8 (d, 2H), 2.9-3.0 (m, 3H), 3.4 (t, 2H), 4.4 (s, 1H), 5.7-5.8 (b, 1H), 6.2 (b, 1H), 7.2 (t, 2H), 7.2-7.3 (t, 4H), 7.4 (d, 4H); LCMS: m/z 350 (M+1)+.
Reaction SMILES: CCCCC.C([Li])(C)(C)C.O1CCCC1.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=3)[N:26]=[C:25]([C:39]3[CH:44]=[CH:43][C:42]([C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:41][CH:40]=3)[N:24]=2)=[CH:19][CH:18]=1.Br[C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:52][N:51]=1>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:35]([C:32]1[CH:31]=[CH:30][C:29]([C:27]2[N:26]=[C:25]([C:39]3[CH:44]=[CH:43][C:42]([C:45]([CH3:47])([CH3:48])[CH3:46])=[CH:41][CH:40]=3)[N:24]=[C:23]([C:20]3[CH:19]=[CH:18][C:17]([C:50]4[CH:55]=[CH:54][C:53]([C:56]5[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=5)=[CH:52][N:51]=4)=[CH:22][CH:21]=3)[N:28]=2)=[CH:34][CH:33]=1)([CH3:36])([CH3:37])[CH3:38]
Reactant: Brc1ccc(-c2ccccc2)cn1
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(Br)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(-c4ccc(-c5ccccc5)cn4)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
Under a stream of argon, 3.5 ml of a pentane solution containing 5.2 mmol of tert-butyl lithium was slowly added to 15 ml of tetrahydrofuran cooled to −78° C., and 10 ml of tetrahydrofuran in which 0.61 g of 2-bromo-5-phenylpyridine had been dissolved was further added dropwise to this solution. After stirring at −78° C. for 30 minutes, 1.64 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 35 ml portion of tetrahydrofuran prepared by dissolving 1.00 g of 2-(4-bromophenyl)-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine synthesized by the method of Reference Example 1 and 0.12 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 10 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was recrystallized from dichloromethane-methanol. The thus obtained crude product was purified by a silica gel column chromatography (eluting solution hexane:dichloromethane=3:2 to 4:3) and then again recrystallized from dichloromethane-methanol to obtain a white solid of the intended 2,4-bis(4-tert-butylphenyl)-6-[4-(5-phenylpyridin-2-yl)phenyl]-1,3,5-triazine (1.05 g, yield 91%). Its melting point is shown in Table 4. In this case, a distinct point of glass transition was not observed.