Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([CH:9]1[O:11][CH2:10]1)Cl.CC(C)([O-])C.[K+]>C(O)(C)(C)C.O1CCCC1>[O:11]1[CH2:10][CH:9]1[CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: ClCC1CO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: C1CCN(CC2CO2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Piperidine (3 ml) was dissolved in t-butyl alcohol (1.2 ml), and the solution was added dropwise with (±)-epichlorohydrin (2.45 ml) on an ice bath. The mixture was slowly warmed to room temperature as it was, and stirred for 18 hours. Then, the mixture was added dropwise with a solution of potassium t-butoxide (3.39 g) in tetrahydrofuran (18 ml) under ice cooling so that the internal temperature should not exceed 15° C. After the addition, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the resulting residue was added to distilled water, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=50:1) to obtain the title compound (1.55 g).
Reaction SMILES: [CH2:1]([N:8]=[CH:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(NCC1C=CC=CC=1O)C1C=CC=CC=1>>[CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[OH:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(O)c(C=NCc2ccccc2)c1
Agent: Oc1ccccc1CNCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(O)c(CNCc2ccccc2)c1

Procedure:
This compound was prepared from 1.0 g of 2-(benzylimino-methyl)-4-methoxy-phenol and 0.18 g of sodium borohydride using the procedure described 64b. Yield: 1.0 g (oil), EI-MS: 243 (M+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:16])([F:15])[C:5]1[N:6]=[C:7]([C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)[NH:8][CH:9]=1.[CH3:17][Si:18]([CH2:21][CH2:22][O:23][CH2:24]Cl)([CH3:20])[CH3:19]>CCCCCC>[F:16][C:4]([F:3])([F:15])[C:5]1[N:6]=[C:7]([C:10]2[N:14]([CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:13]=[CH:12][N:11]=2)[N:8]([CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:9]=1
Reactant: FC(F)(F)c1c[nH]c(-c2ncc[nH]2)n1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: C[Si](C)(C)CCOCn1ccnc1-c1nc(C(F)(F)F)cn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
To 14.4 g (0.3 mol) 50% NaH (washed 3 times with hexane to remove the mineral oil) and 300 ml DMF, was slowly added 26.3 g (0.13 mol) 4-(trifluoromethyl)-2,2'-bi-1H-imidazole as a solid. The reaction was stirred for 2 hours at room temperature and then heated at 40° C. for 2 hours. Next, 50 g (0.3 mol) SEM-Cl was added dropwise. After 1 hour, the reaction was quenched with water (1 liter) and the product extracted into EtOAc (3×150 ml). After drying (NaSO4) and concentration, 51.2 g crude product was obtained. Purification by preparative HPLC (37% EtOAc/63% hexane) gave 16.7 g (28%) desired product as a tan oil; 1H NMR (CDCl3) δ-0.14 (s, 18), 0.61-1.0 (m, 4), 3.25-3.70 (m, 4), 5.76 (s, 2), 5.81 (s, 2), 0.61-1.0 (m, 4), 3.25-3.70 (m, 4), 5.76 (s, 2), 5.81 (s, 2), 6.91-7.06 (m, 2), 7.36 (s br, 1); MS (CI/CH4) m/z 463 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:34]=[C:33]2[C:29]([C:30](=[O:43])[N:31]([CH3:42])[N:32]2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:25][C:26]3[CH:34]=[C:33]4[C:29]([C:30](=[O:43])[N:31]([CH3:42])[N:32]4[C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:28][CH:27]=3)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: Cn1c(=O)c2ccc(N)cc2n1C(=O)OC(C)(C)C
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CCC(C(=O)Nc1ccc2c(=O)n(C)n(C(=O)OC(C)(C)C)c2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
87 mg (0.25 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 74 mg (0.27 mmol, 1.1 eq.) of tert-butyl 6-amino-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate were reacted according to General Method 5A. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 112 mg (77% of theory)
Reaction SMILES: ClC(Cl)(Cl)COC(=O)[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:27][CH:26]([CH3:28])[O:25][CH:24]([CH3:29])[CH2:23]3)=[O:21])=[CH:16][C:15]=2[NH:30][C:31]2[C:32]3[CH:40]=[CH:39][C:38]([CH:41]([CH3:43])[CH3:42])=[N:37][C:33]=3[N:34]=[CH:35][N:36]=2)=[CH:9][CH:8]=1.[OH-].[Na+].Cl>O1CCOCC1.O.C(OCC)(=O)C>[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:27][CH:26]([CH3:28])[O:25][CH:24]([CH3:29])[CH2:23]3)=[O:21])=[CH:16][C:15]=2[NH:30][C:31]2[C:32]3[CH:40]=[CH:39][C:38]([CH:41]([CH3:43])[CH3:42])=[N:37][C:33]=3[N:34]=[CH:35][N:36]=2)=[CH:9][CH:8]=1
Reactant: CC1CN(C(=O)c2ccc(Sc3ccc(NC(=O)OCC(Cl)(Cl)Cl)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)CC(C)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1CN(C(=O)c2ccc(Sc3ccc(N)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)CC(C)O1
Temperature: 60 °C
Yield: 42.8 %

Procedure:
A solution of the product of Example 179A (56 mg, 0.0795 mmol) in 1,4-dioxane (2 mL) was treated with a solution of sodium hydroxide (8 mg, 0.1988 mmol) in water (1 mL), and heated at 60° C. for 30 minutes. The reaction was then cooled to room temperature and diluted with ethyl acetate (50 mL) and water (25 mL). The aqueous pH was adjusted to 5 with 1N aqueous hydrochloric acid, the layers were separated, and the organic phase washed with water (2×25 mL) and brine (25 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo. Purification of the residue by silica gel flash chromatography with 5% methanol/methylene chloride provided the title compound as an off-white solid (18 mg, 43%). 1H NMR (300 MHz, DMSO-d6/TFA) δ ppm: 0.91-1.25 (m, 6 H) 1.37 (d, J=6.99 Hz, 6 H) 2.70-2.97 (m, 1 H) 3.25-3.40 (m, 1 H) 3.45-3.64 (m, 4 H) 4.20-4.52 (m, 1 H) 5.72 (s, 2 H) 7.29 (d, J=8.09 Hz, 1 H) 7.35 (d, J=8.46 Hz, 2 H) 7.48 (dd, J=7.91, 2.02 Hz, 1 H) 7.50 (d, J=8.45 Hz, 2 H) 7.60 (d, J=1.84 Hz, 1 H) 7.96 (d, J=8.82 Hz, 1 H) 8.97 (s, 1 H) 9.07 (d, J=8.82 Hz, 1 H); MS (ESI+) m/z 529 (M+H)+, (ESI−) m/z 527 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:11][OH:12].C([O-])([O-])=O.[Na+].[Na+]>CCO.O>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([C:1](=[NH:2])[NH:11][OH:12])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1ccc(Br)cc1
Reaction time: 7 h
Yield: 86.2 %

Procedure:
A mixture of 4-cyano-bromobenzene (0.5 g, 2.75 mmol), HCl×NH2OH (0.476 g, 6.9 mmol) and Na2CO3 (0.731 g, 6.9 mmol) in a mixture of EtOH and H2O (25 ml: 5 ml) was stirred for 7 h at reflux. The solvent was evaporated to dryness and the residue was taken in EtOAc (100 ml) and washed with H2O. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give the product as colourless solid (0.51 g, 87%). 1H-NMR (DMSO-d6) 5.81 (broad s, 2H); 7.53 (d, 2H, J=6.66 Hz); 7.58 (d, 2H, J=6.54 Hz); 9.69 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([N:13]2[CH:17]=[CH:16][N:15]=[C:14]2S)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[OH-].[Na+]>[N+]([O-])(O)=O>[F:1][C:2]1[C:3]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2
Reactant: Cc1ccc2c(-n3ccnc3S)c(F)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Product: Cc1ccc2c(-n3ccnc3)c(F)ccc2n1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a flask containing 16.2 g (0.0625 mole) of 6-fluoro-5-(2-mercaptoimidazol-1-yl)-2-methylquinoline was added with stirring 300 ml of 20% nitric acid. After stirring for 30 minutes, the mixture was heated on a steam bath for an additional 30 minutes. The solution was allowed to cool to about 20° C., then made basic (pH 8 to 10) by adding 50% aqueous sodium hydroxide while cooling with an ice bath. The solid precipitate was separated by filtration, washed with water and dried. Recrystallization from aqueous ethanol provided 6-fluoro-5-(imidazol-1-yl)-2-methylquinoline, m.p. 159°-161° C. Analysis: Calculated for C13H10FN3 : %C, 68.7; %H, 4.4; %N, 18.5; Found: %C, 68.6; %H, 4.4; %N, 18.2.
Reaction SMILES: [C:1](OC)(=[O:7])[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH3:6].[CH:10]1([CH:13]([CH3:15])[OH:14])[CH2:12][CH2:11]1>>[C:1]([O:14][CH:13]([CH:10]1[CH2:12][CH2:11]1)[CH3:15])(=[O:7])[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH3:6]
Reactant: CC/C=C\CC(=O)OC
Reactant: CC(O)C1CC1
Product: CC/C=C\CC(=O)OC(C)C1CC1

Procedure:
Prepared from methyl (3Z)-3-hexenoate and cyclopropyl methyl carbinol according to the ester preparation method B described above.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]([NH:16][C:17]1[N:22]=[C:21]([C:23]2[C:31]3[C:26](=[N:27][C:28]([NH:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[N:29][CH:30]=3)[NH:25][N:24]=2)[CH:20]=[CH:19][N:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.Cl>CCO>[N:35]1([CH2:34][CH2:33][NH:32][C:28]2[N:27]=[C:26]3[NH:25][N:24]=[C:23]([C:21]4[CH:20]=[CH:19][N:18]=[C:17]([NH:16][CH:9]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=5)[CH2:8][NH2:7])[N:22]=4)[C:31]3=[CH:30][N:29]=2)[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)NCC(Nc1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: NCC(Nc1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(2-{4-[6-(2-Morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-pyrimidin-2-ylamino}-2-phenyl-ethyl)-carbamic acid tert-butyl ester (130 mg, 0.23 mmol) was dissolved in EtOH (4 mL), then HCl (4 mL) was added. The reaction mixture was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure to afford the crude product which was purified by prep-HPLC to afford N1-{4-[6-(2-morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-pyrimidin-2-yl}-1-phenyl-ethane-1,2-diamine; hydrochloride. (Yield 25 mg, 19.1%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C@@H:10]1[C@H:17]2[C@@H:13]([O:14]C(C)(C)[O:16]2)[C@H:12]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][CH:23]=[N:24][C:25]=3[NH:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[O:11]1>C(O)(=O)C.O>[CH:30]1([NH:29][C:25]2[N:24]=[CH:23][N:22]=[C:21]3[C:26]=2[N:27]=[CH:28][N:20]3[CH:12]2[C@H:13]([OH:14])[C@H:17]([OH:16])[C@@H:10]([CH2:9][S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[O:11]2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC1(C)O[C@@H]2[C@@H](O1)[C@@H](CSc1ccccc1F)O[C@H]2n1cnc2c(NC3CCCC3)ncnc21
Solvent: CC(=O)O
Solvent: O
Product: O[C@@H]1[C@@H](CSc2ccccc2F)OC(n2cnc3c(NC4CCCC4)ncnc32)[C@@H]1O

Procedure:
(9-{(4S,1R,2R,5R)-4-[(2-fluorophenylthio)methyl]-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl}purin-6-yl)cyclopentylamine, a compound of formula (4) (50 mg) was dissolved in a mixture of acetic acid (8 mL) and water (2 mL) and heated at 90 C for 16 hours. Solvents were removed under reduced pressure, and the residue was purified by preparative TLC [methanol-dichloromethane(1:9)] to afford (4S,5S,3R)-2-[6-(cyclopentylamino)purin-9-yl]-5-[(2-fluorophenylthio)methyl]oxolane-3,4-diol, a compound of Formula I. 1H NMR (CDCl3) δ 1.6-2.4 (m, 6H), 3.15-3.25 (m, 2H), 4.1 (bs, 1H), 4.4-4.65 (m, 4H), 6.0 (d, 1H), 6.8 (bs, 1H), 7.05 (m, 2H), 7.2 (m, 1H), 7.4 (m, 1H), 7.8 (s, 1H), 8.25 (s, 1H).
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6]([OH:9])[CH2:5][CH2:4]1)=O.[ClH:10]>>[ClH:10].[ClH:10].[OH:9][N:6]1[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1
Reactant: O=CN1CCN(O)CC1
Agent: Cl
Product: ON1CCNCC1
Reaction time: 0.33 h

Procedure:
3N Hydrochloric acid (50 ml) was added to 1-formyl-4-hydroxypiperazine (5.0 g) and the mixture was stirred at 77° to 87° C. for 20 minutes. After stirring, water was distilled off under reduced pressure to a pale yellow residue, which was washed with ethanol and recrystallized from a mixed solvent of water - ethanol to give 1-hydroxypiperazine dihydrochloride (5.0 g) as light brown prisms, m.p. 164°-175° C. (dec.).
Reaction SMILES: [CH2:1]([O:4][C@@H:5]([CH3:18])[C:6]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)=[O:7])[CH2:2][CH3:3].S(Cl)([Cl:21])=O>N1C=CC=CC=1>[CH2:1]([O:4][C@@H:5]([CH3:18])[C:6]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:21])=[O:14])=[CH:11][CH:10]=1)=[O:7])[CH2:2][CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CCCO[C@@H](C)C(=O)Oc1ccc(C(=O)O)cc1
Solvent: c1ccncc1
Product: CCCO[C@@H](C)C(=O)Oc1ccc(C(=O)Cl)cc1

Procedure:
The resulting carboxylic acid (2.45 g) was reacted with 10 ml of thionyl chloride and 0.2 ml of pyridine to obtain 2.61 g of 4-[(S)-2-propoxypropanoyloxy]benzoyl chloride.
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]3[C:17]([C:18]4[C:23]5[O:24][C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=6[C:22]=5[C:21]([N+:31]([O-])=O)=[CH:20][CH:19]=4)=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C(O)(=O)C.[OH-].N.[Zn]>[NH2:31][C:21]1[C:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][C:23]=2[C:18]([C:17]2[C:9]3[O:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:12][C:11](=[O:13])[C:10]=3[CH:14]=[CH:15][CH:16]=2)=[CH:19][CH:20]=1
Reactant: O=c1cc(N2CCOCC2)oc2c(-c3ccc([N+](=O)[O-])c4c3oc3ccccc34)cccc12
Agent: N
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc(-c2cccc3c(=O)cc(N4CCOCC4)oc23)c2oc3ccccc3c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of 2-morpholin-4-yl-8-(1-nitro-dibenzofuran-4-yl)-1-benzopyran-4-one (32, 2.5 mmol, 1.11 g) in acetic acid (50 ml) was added zinc dust (25 mmol, 1.64 g), portionwise over ten minutes. The mixture was then stirred at room temperature for 2 hrs, whereupon it was filtered through a Celite™ pad which was washed with methanol (20 ml) and CH2Cl2 (20 ml). Solvents were removed in vacuo to give a slurry which was then diluted with ammonia hydroxide (30 ml) and the resulting solid removed by filtration. The residue was purified by flash chromatography (SiO2) using MeOH; CH2Cl2-1:99 as eluent to give the desired product (75%) in analytically pure form. m/z 413.5 [M+H]+ (Rt=4.27 min).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C1C=CC=CC=1.Cl>O1CCCC1>[C:4]1([CH:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CC(O)c1ccccc1
Temperature: 30 °C
Reaction time: 24 h

Procedure:
Under an atmosphere of nitrogen, 1.80 ml of a 0.99 M solution of acetophenone in tetrahydrofuran was added to the solution of reagent (A), obtained in Example 1, and the mixture stirred at 30° C. for 24 hours. The reaction mixture was poured into a mixture of 15 ml of benzene and 10 ml of 2 M hydrochloric acid, extracted with benzene, and the extract was washed with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by distillation in vacuo (130°-135° C./25 mmHg) to give 185 mg of 1-phenylethanol, and an additional purification was carried out by a fractional gas chromatography to give 1-phenylethanol having the following optical rotation:
Reaction SMILES: [O-:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[Na+].[Na+].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([CH2:21][CH2:20][CH2:19][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:9]3)=[CH:4][CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=S(=O)([O-])c1ccc2ccc([O-])cc2c1
Reactant: ClCCCN1CCCCC1
Agent: [Na+]
Product: O=S(=O)(O)c1ccc2ccc(OCCCN3CCCCC3)cc2c1
Yield: 29.8 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 26B, sodium 7-oxidonaphthalene-2-sulfonate (Pfaltz and Bauer, 200 mg, 0.75 mmol) and 1-(3-chloropropyl)piperidine (121 mg, 0.75 mmol) were converted to the title compound (78 mg, 30%). MS(ESI+) m/z 336.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:10]=1)([CH3:5])[CH2:3][NH2:4].[F:21][C:22]([F:38])([F:37])[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[N:24]=1>>[CH3:5][C:2]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)[N:10]=1)([CH3:1])[CH2:3][NH:4][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[C:28]([C:25]2[N:24]=[C:23]([C:22]([F:38])([F:37])[F:21])[O:27][N:26]=2)[CH:29]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1nc(-c2ccc(C(F)(F)F)cc2)cs1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1nc(-c2ccc(C(F)(F)F)cc2)cs1
Yield: 24 %

Procedure:
This compound was synthesized from 2-methyl-2-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)propan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (10 mgs, 24% yield). 1H NMR (300 MHz, CDCl3) δ 8.51 (s, 1H), 8.25 (d, J=7.4 Hz, 1H), 8.09-7.96 (m, 4H), 7.64-7.53 (m, 3H), 3.82 (bs, 2H), 1.56 (s, 6H). MS (ESI) m/z: Calculated for C24H18F6N4O2S: 540.11. found: 541.1 (M+H)+.
Reaction SMILES: [Br-].[C:2]1([C:8]([PH3+])([C:15]2C=CC=CC=2)[C:9]2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:27]C1C=CC(C(=O)C)=CC=1>C1COCC1.CCCCCC>[Br:27][C:5]1[CH:6]=[CH:7][C:2]([C:8]([CH3:15])=[CH2:9])=[CH:3][CH:4]=1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(C)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
To a slurry of triphenylmethylphosphonium bromide (71.4 g, 200 mmole), in 500 ml dry THF at 0° C., were slowly added dropwise 135 ml (200 mmole) 1.44 M n-butyllithium in hexane. The mixture was stirred 30 minutes at 0° C., and a solution of 39.8 g (200 mmole) p-bromoacetophenone, in 100 ml dry THF, was slowly added dropwise. The mixture was allowed to warm slowly to ambient temperature, whereafter stirring was continued overnight. The stirred mixture was next filtered and the solvent removed by careful distillation at atmospheric pressure, the resulting residue was diluted with hexane, filtered, and the hexane removed by distillation. The remaining material was distilled, using a water aspirator vacuum, to produce 23.2 g (58.3% yield) of p-bromo-α-methylstyrene, bp 95°-98° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:16]=[C:15]([CH3:17])[NH:14][C:8]=3[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]2=[N:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:24]([N:14]1[C:8]2[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[C:7]=2[CH:16]=[C:15]1[CH3:17])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc2c(cc([N+](=O)[O-])c3nnc(C)n32)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc2c(cc([N+](=O)[O-])c3nnc(C)n32)n1Cc1ccccc1
Reaction time: 1 h

Procedure:
To a suspension of 1,7-dimethyl-4-nitro-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (0.30 g, 1.3 mmol, from Step 1) in N,N-dimethylformamide (5 mL) was added Cs2CO3 (0.51 g, 1.6 mmol). After stirring for 1 hour, benzyl bromide (0.18 mL, 1.6 mmol, Aldrich) was added, and the reaction mixture was stirred overnight, after which time water was added, and the reaction mixture was stirred for 5 minutes. Ethyl acetate was added, and the mixture was stirred overnight. The product, which had precipitated, was isolated by filtration. The product was washed sequentially with ethyl acetate, water, and again with ethyl acetate. Yield: (0.20 g, 48%). LCMS (M+H)+: 322.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7](=[O:18])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[O:16][CH3:17])=[O:4].[N-:19]=[N+:20]=[N-:21].[Na+].[I-].[K+]>CC(C)=O>[N:19]([CH2:2][C:3]([NH:5][CH2:6][C:7](=[O:18])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[O:16][CH3:17])=[O:4])=[N+:20]=[N-:21]
Reactant: COc1ccc(OC)c(C(=O)CNC(=O)CCl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(OC)c(C(=O)CNC(=O)CN=[N+]=[N-])c1
Temperature: 60 °C
Yield: 91 %

Procedure:
In a four neck round bottomed flask, 45 gm (0.165 mole) of 2-Chloro-N-(β-oxo-2,5-Dimethoxy phenethyl)-acetamide prepared according to step (b), 27 g (0.415 mole) sodium azide and 8.3 g (0.049 mole) potassium iodide and 900 ml of acetone is charged. The solution is refluxed at 60° C. for 5 hours. After completion of the reaction the reaction mass cooled and filtered to remove inorganics. Acetone is distilled off under atmospheric pressure. Water is added and the resulting yellow lumps are filtered. (Yield: 91%). The solid is recrystallized from methanol. The following physical properties are measured.
Reaction SMILES: [C:1]([NH:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[O:26][C@H:25]([CH2:27][O:28]C(=O)C(C)C)[C@@H:18]([O:19]C(=O)C(C)C)[CH2:17]2)=[C:9]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)[N:8]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[Cl-].[NH4+]>[OH-].[Na+]>[C:1]([NH:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:18]([OH:19])[CH2:17]2)=[C:9]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)[N:8]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Nc1nc(-c2cccs2)c2ncn([C@H]3C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O3)c2n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: CC(C)C(=O)Nc1nc(-c2cccs2)c2ncn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1
Reaction time: 0.25 h
Yield: 94.9 %

Procedure:
The compound (19) 212 mg (0.39 mmol) obtained by the above (B) was dissolved in 1 M sodium hydroxide solution (pyridine-methanol-water=13:6:1) 1.95 ml under ice-cooling and stirred for 15 minutes. The reaction mixture was neutralized by adding aqueous 5% ammonium chloride. Further added 1.2 g Celite to the mixture and the solvent was removed completely under reduced pressure. The residue was purified by short column (developer: 5-7% ethanol-dichloromethane) to obtain the product (20) 147 mg (0.37 mmol) (93.6%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][C:15]([I:17])=[CH:16][C:7]=3[C:6]=2[N:18]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOCC>N1C=CC=CC=1>[I:17][C:15]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[CH2:11][C:5]3[CH:4]=[N:3][C:2]([NH:1][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:18][C:6]=3[C:7]=2[CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ncc2c(n1)-c1cc(I)ccc1NC(=O)C2
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C1Cc2cnc(NC(=O)c3ccccc3)nc2-c2cc(I)ccc2N1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
2-Amino-10-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-51) (69.7 mg, 0.20 mmol) was dissolved in pyridine (800 μL) and benzoyl chloride (23 mL, 0.20 mmol). The mixture was stirred at 110° C. for 1 h, then cooled to 22° C. Et2O was added and the product was filtered from the solution to give I-83 (37%): MS (FA) Rt═1.49 min, m/z═457 (M+H).